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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Pediatric Obesity and the Immune System</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Obesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related di..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Pediatric Obesity and the Immune System"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Obesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related di..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="Obesity,Immune System,Inflammation,Adipokines,Atopy,Autoimmun disease"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2019.00487/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="7"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Pediatrics"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Pediatr."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="2296-2360"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fped.2019.00487"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="474967"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Pediatric Obesity and the Immune System"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="Obesity; Immune System; Inflammation; Adipokines; Atopy; Autoimmun disease"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Obesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related diseases, recent evidence suggested that obesity might affect immune system function. Adipose tissue is considered an endocrine organ that actively secretes cytokines also referred to as “adipokines.” Adipokines play an important role in the control of human metabolism. The dysfunctional adipose tissue in obese individuals is characterized by an altered cytokine secretion pattern that promotes chronic low-grade inflammation. Epidemiological evidence highlights the association between obesity and allergic and immune-mediated diseases, such as asthma, allergic rhinitis, rheumatic arthritis, and psoriasis. Less is known about underlying pathogenic mechanisms. However, several recent <italic>in vivo</italic> and <italic>in vitro</italic> studies have reported that adipokines are involved in inflammatory and autoimmune disorders by influencing both innate and acquired immune responses. In addition, obesity has been associated with reduced immune surveillance and increased risk of cancer. This paper reviews the evidence regarding the role of adipokines in immune system regulation, with particular emphasis on autoimmune, allergic, and inflammatory disorders. Understanding how obesity affects immune system functions may enable researchers to find new potential therapeutic targets in the management of allergic and autoimmune diseases.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2019.00487/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2019/11/06"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2019/11/22"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Umano, Giuseppina Rosaria"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Department of the Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Italy"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Pistone, Carmelo"><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="School of Pediatrics, University of Pavia, Italy"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Tondina, Enrico"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="School of Pediatrics, University of Pavia, Italy"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Moiraghi, Alice"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="School of Pediatrics, University of Pavia, Italy"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Lauretta, Daria"><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Department of the Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Italy"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Miraglia del Giudice, Emanuele"><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="Department of the Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Italy"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Brambilla, Ilaria"><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fped.2019.00487"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2019.00487/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":2.2544,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"dcc485ef04d6e9fa"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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<div class="Ibar__spacer"></div> <a href="https://www.frontiersin.org/submission/submit?domainid=2&fieldid=61&specialtyid=0&entitytype=2&entityid=606" data-event="iBarJournal-a-submit" class="Ibar__button Ibar__submit"><span>Submit</span> <span> your research</span></a> <a href="/search" aria-label="Search" data-event="iBar-a-search" class="Ibar__icon Ibar__icon--search"><span>Search</span></a>    <div class="Ibar__userArea"></div></div></div></nav> <div class="ArticlePage"><div><div class="Layout Layout--withAside Layout--withIbarMix ArticleDetails"> <main class="Layout__main"> <div class="ArticleDetails__main"><div class="ArticleLayoutHeader"><div class="ArticleLayoutHeader__info"><p class="ArticleLayoutHeader__info__title"> REVIEW article </p> <p class="ArticleLayoutHeader__info__journalDate"><span>Front. Pediatr.</span> <span>, 22 November 2019</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Pediatric Immunology </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 7 - 2019 | </span> <a href="https://doi.org/10.3389/fped.2019.00487" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fped.2019.00487 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Translational Insights into Pediatric Immune-Related Diseases</span> <span class="Link__wrapper"><a aria-label="View all 13 articles" href="https://www.frontiersin.org/research-topics/9192/translational-insights-into-pediatric-immune-related-diseases/articles" target="_self" data-event="customLink-link-a_viewAll13Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 13 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Pediatric Obesity and the Immune System</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper notranslate"> <a href="https://loop.frontiersin.org/people/748093" class="user-id-748093"><img class="pr5" src="https://loop.frontiersin.org/images/profile/748093/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="\nGiuseppina Rosaria Umano
">Giuseppina Rosaria Umano</a><sup>1</sup><sup>*</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Carmelo Pistone" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Carmelo Pistone<sup>2</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/850798" class="user-id-850798"><img class="pr5" src="https://loop.frontiersin.org/images/profile/850798/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Enrico Tondina">Enrico Tondina</a><sup>2</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/851025" class="user-id-851025"><img class="pr5" src="https://loop.frontiersin.org/images/profile/851025/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Alice Moiraghi">Alice Moiraghi</a><sup>2</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/850834" class="user-id-850834"><img class="pr5" src="https://loop.frontiersin.org/images/profile/850834/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Daria Lauretta">Daria Lauretta</a><sup>1</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/666582" class="user-id-666582"><img class="pr5" src="https://loop.frontiersin.org/images/profile/666582/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Emanuele Miraglia del Giudice">Emanuele Miraglia del Giudice</a><sup>1</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/850848" class="user-id-850848"><img class="pr5" src="https://loop.frontiersin.org/images/profile/850848/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Ilaria Brambilla">Ilaria Brambilla</a><sup>3</sup></span></div> <ul class="notes"> <li><span><sup>1</sup></span>Department of the Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy</li> <li><span><sup>2</sup></span>School of Pediatrics, University of Pavia, Pavia, Italy</li> <li><span><sup>3</sup></span>Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy</li> </ul> <p>Obesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related diseases, recent evidence suggested that obesity might affect immune system function. Adipose tissue is considered an endocrine organ that actively secretes cytokines also referred to as “adipokines.” Adipokines play an important role in the control of human metabolism. The dysfunctional adipose tissue in obese individuals is characterized by an altered cytokine secretion pattern that promotes chronic low-grade inflammation. Epidemiological evidence highlights the association between obesity and allergic and immune-mediated diseases, such as asthma, allergic rhinitis, rheumatic arthritis, and psoriasis. Less is known about underlying pathogenic mechanisms. However, several recent <i>in vivo</i> and <i>in vitro</i> studies have reported that adipokines are involved in inflammatory and autoimmune disorders by influencing both innate and acquired immune responses. In addition, obesity has been associated with reduced immune surveillance and increased risk of cancer. This paper reviews the evidence regarding the role of adipokines in immune system regulation, with particular emphasis on autoimmune, allergic, and inflammatory disorders. Understanding how obesity affects immune system functions may enable researchers to find new potential therapeutic targets in the management of allergic and autoimmune diseases.</p> <div class="clear"></div> </div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb15">The obesity epidemic represents a major health issue of the twenty-first century. The prevalence of the disease has significantly increased in the last decades worldwide, including low-income countries (<a href="#B1">1</a>). In addition, it has been reported that pediatric obesity significantly increases the risk of obesity and its cardiovascular complications during childhood and adulthood (<a href="#B2">2</a>, <a href="#B3">3</a>).</p> <p class="mb15">The constant increase in obesity prevalence might be ascribed to changes in lifestyle habits, namely, assumption of junk food and sedentary behavior. Moreover, genetic background plays a role by affecting energy expenditure and food intake (<a href="#B4">4</a>). The excess of fat present in obese individuals results in a hypertrophic white adipose tissue with a consequent derangement in adipocytes metabolic activity. Adipose tissue in some obese subjects displays a pro-inflammatory activity and has been associated with obesity-related comorbidities in both adults and children (<a href="#B5">5</a>–<a href="#B8">8</a>). Adipocytes actively secrete several hormones and cytokines, also referred to as adipokines that exert metabolic and immunological functions, as they could modulate the innate and acquired immune cell activity. Moreover, they are capable of promoting pro-inflammatory signals leading to a chronic systemic low-grade inflammation. In addition, growing evidence reports the association between obesity and immune disorders, such as cancer, autoimmunity, and atopy (<a href="#B9">9</a>). Therefore, the altered secretion pattern of adipokines in obesity is considered the link between obesity and its metabolic and immunological comorbidities (<a href="#B10">10</a>).</p> <p class="mb0">In this review, we summarize the current knowledge on the basis of endocrine and immunological functions of white adipose tissue. In particular, we describe the interplay between adipokines and both innate and acquired immunity. Moreover, we report the evidences and possible mechanisms of the association between pediatric obesity and immunological disorders.</p> <a id="h3" name="h3"></a><h2>Obesity and Inflammation</h2> <p class="mb15">Clinical studies have observed a significant association between serum markers of chronic low-grade inflammation and obesity-related comorbidities in children and adolescents (<a href="#B11">11</a>–<a href="#B13">13</a>). Serum levels of C-reactive protein (CRP) directly correlate with insulin resistance and carotid intima-media thickness (cIMT) in children and adolescents with overweight and obesity (<a href="#B11">11</a>). Moreover, it has been reported that white blood cell count is predictive of increased cIMT and ventricular hypertrophy in obese children and adolescents (<a href="#B12">12</a>). In addition, weight loss after lifestyle intervention trial was effective in reducing both serum inflammatory markers and insulin resistance in obese children and adolescents (<a href="#B14">14</a>).</p> <p class="mb15">Inflammation is a mechanism that involves a series of non-cellular and cellular mediators involved in the response to infections, tissue damage, cellular death, and cancer. Obesity is accompanied by a sterile chronic low-grade inflammation in the adipose tissue that is not related to infection or tissue damage (<a href="#B15">15</a>). This process is also referred to as metabolic inflammation or metainflammation. Metainflammation is an active player in the development of obesity-related comorbidities, as obesity-related inflammation might impair the function of other organs (<a href="#B16">16</a>). Adipose tissue immune response is mediated by adipose tissue-resident immune cells, namely, macrophages, mast cells, neutrophils, and T and B lymphocytes, which are the second more represented cellular type, after adipocytes (<a href="#B17">17</a>). Mechanisms triggering adipose tissue inflammation are not completely clear. However, adipose tissue hyperplasia and hypertrophy occurring in obese individuals may exert an important role (<a href="#B18">18</a>). In fact, an increase of adipocyte size leads to hypoxia, intracellular oxidative stress, and release of pro-inflammatory molecules (<a href="#B18">18</a>). However, some studies have shown that metabolically unhealthy obese adolescents tend to have smaller adipose cells (<a href="#B19">19</a>), which allows for a smaller storage capacity and favor a more pronounced flux of free fatty acids. Inflammasome activation in subcutaneous adipose tissue (SAT) has been associated with an altered abdominal fat distribution (<a href="#B19">19</a>). The inflammasome chronic activation impairs the SAT storage capability leading to a lipid spill over into visceral adipose tissue (VAT) (<a href="#B19">19</a>).</p> <p class="mb0">The excess of free fatty acids contributes to an unfavorable metabolic phenotype probably through the macrophage activation in adipose tissue. In fact, free fatty acids directly activate immune cells and induce secretion of pro-inflammatory mediators through interacting with toll-like receptors (TLRs) (<a href="#B20">20</a>). In VAT, adipocytes develop a dysfunctional phenotype characterized by smaller adipose cells and expression of adhesion molecules for monocytes/macrophages (<a href="#B21">21</a>).</p> <h3>Macrophages</h3> <p class="mb0">Macrophages are the most common immune cell type in adipose tissue. The number of macrophages has been associated with size of adipocytes and severity of obesity (<a href="#B21">21</a>). A small amount of adipose tissue macrophages (ATMs) derives from pre-adipocyte maturation, while the majority comes from systemic circulation (<a href="#B22">22</a>). Hypertrophic adipose tissue promotes macrophage migration and infiltration via secretion of chemokines. Several chemokines are involved in this pathway. Among them, monocyte-chemoattracting protein 1/chemokine C–C motif receptor 2 (MCP1/CCR2) binds macrophage receptor CCR2, leading to infiltration (<a href="#B23">23</a>). Moreover, obesity alters the phenotype and distribution of macrophages. Macrophages could be distinguished in two subsets according to membrane antigen and cytokine secretion: classically activated M1 type and alternative activated M2 type. M1 type exerts a pro-inflammatory and antibacterial role; it expresses receptor for inflammatory mediators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, and lipopolysaccharides (LPS). Conversely, M2 phenotype is induced by anti-inflammatory molecules, namely, IL-13, IL-10, IL-4, and macrophage colony-stimulating factor (M-CSF), and displays anti-inflammatory and anti-parasitic functions (<a href="#B24">24</a>, <a href="#B25">25</a>). The different polarization of macrophages in human adipose tissue is influenced by nutritional status. In normal weight subjects, the prevalence of eosinophils, T-lymphocytes, and natural killer (NK) cells promote a polarization toward M2 type. These macrophages, in a favorable environment, exert homeostatic actions, regulating cellular proliferation, extracellular matrix deposition, and removing cellular debris in stromal matrix. In obese subjects, oxidative stress, necrotic cellular debris, and overload of free fatty acids lead to a polarization toward an M1 phenotype. In contrast to M2, M1 macrophages do not migrate in stromal matrix; they tend to create aggregates surrounding necrotic adipocytes, in a typical crown-like structure (<a href="#B26">26</a>). In humans, the number of M1 macrophages directly correlates with systemic inflammation, insulin resistance, type 2 diabetes, and fatty liver disease (<a href="#B15">15</a>).</p> <h3>Lymphocytes</h3> <p class="mb0">The second largest immune cell subset in adipose tissue is represented by T-lymphocytes. T-cells could be divided in CD4+ and CD8+ according to surface antigens. The cytokine secretion pattern of CD4+ allows a further categorization in Th1 (INF-γ), Th2 (IL-4, IL-5, and IL-13), Treg (IL-10 and transforming growth factor B), and Th17 (IL-17, IL-21, and IL-22). CD8+ are cytotoxic cells that secrete perforins, granzymes, and a variety of cytokines that mediate activation of other immune cells. In dysfunctional adipose tissue, the T-lymphocyte subpopulation pattern is polarized toward a pro-inflammatory activity. Therefore, Th1, Th17, and CD8+ are more represented compared to anti-inflammatory Th2 and Treg (<a href="#B15">15</a>).</p> <h3>Other Adipose Tissue-Resident Immune Cells</h3> <p class="mb0">Neutrophils, mast cells, and dendritic cells constitute a small fraction of immune cells in adipose tissue. Nevertheless, they play an important role in amplifying inflammation process via secretion of pro-inflammatory mediators. The amount of eosinophils, instead, is reduced. They promote M2 macrophage and Th2 differentiation and suppress inflammatory stimuli (<a href="#B15">15</a>).</p> <a id="h4" name="h4"></a><h2>Adipokines as Immune Modulators</h2> <p class="mb0">In the last years, a number of adipose tissue-derived cytokines have been characterized, the so-called adipokines (<a href="#F1">Figure 1</a>). Besides adipocytes, the vascular-stromal component of adipose tissue concurs with cytokine secretion in an adiposity-dependent manner. Adipokines play a crucial role not only in energy homeostasis but also in inflammatory and immune reaction, most of them promoting inflammation (<a href="#B27">27</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1</strong>. Adipokines secreted from white adipose tissue and their immunological functions. RBP-4, retinol binding protein 4; TNF-α, tumor necrosis factor alpha; Th-1, T-helper 1.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Leptin</h3> <p class="mb0">Leptin was first described by Zhang et al. (<a href="#B28">28</a>) in a murine model. It is encoded by murine <i>ob</i> gene and human homologous <i>LEP</i> gene. Animals and human models showed that inhibition of leptin action results in food assumption and insulin resistance (<a href="#B27">27</a>, <a href="#B28">28</a>). Leptin secretion is positively correlated with adipose tissue mass; therefore, obese subjects show high leptin plasmatic levels. Nevertheless, obese subjects develop leptin resistance with a decreased sensitivity to anorexinergic hormone stimulus. Leptin has pleiotropic activities. The main role is suppression of food assumption via inhibiting hypothalamic nuclei that stimulate hunger and stimulation of those which promote satiety (<a href="#B29">29</a>). Leptin loss of function is associated with hyperphagia, rapid weight gain, and insulin resistance (<a href="#B30">30</a>). Moreover, leptin influences pubertal development and shows immunomodulatory activity (<a href="#B31">31</a>). In fact, several immune cell types express leptin receptor (LEPR) (<a href="#F2">Figure 2</a>). In neutrophils, leptin activates anti-apoptotic signals, resulting in cell survival. In addition, it induces neutrophil activation in terms of chemotaxis, tissue infiltration, and oxygen radicals' release. Similarly, eosinophils and basophils express LEPR on the cellular surface. As for neutrophils, leptin acts as a survival cytokine for these cells and stimulates tissue infiltration and pro-inflammatory molecule release (<a href="#B32">32</a>). Moreover, leptin is crucial for monocyte/macrophage function. In experimental models of <i>LepR</i>, knock-out mice impaired macrophages killing activity and phagocytosis has been reported (<a href="#B33">33</a>). Additionally, leptin has been shown to enhance monocyte and macrophage survival, migration, release of pro-inflammatory cytokines (namely, IL-6 and TNF-α), and expression of surface markers (CD39, CD69, CD25, CD71, and IL-1Rα). Leptin also stimulates proliferation and cytotoxicity of NK cell and constitutes a survival cytokine for dendritic cells. With regard to adaptive immune response, hormone inhibits T-lymphocyte apoptosis, promotes Th1 response, suppresses Th2 activity, and enhances IL-2 and INF-γ production. Moreover, it sustains Th17 pro-inflammatory function and B-lymphocyte activity (<a href="#B34">34</a>). In general, leptin displays a pro-inflammatory activity, interacting with both innate and adaptive immune system. These data highlight the crucial role of leptin in pathogenesis of obesity-related comorbidities, in terms of metabolic derangement and chronic inflammation.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" name="figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a> <p><strong>Figure 2</strong>. Leptin action on immune cells. Leptin promotes cell survival, stimulates the secretion of pro-inflammatory cytokines, and suppresses cell apoptosis. It induces M1 polarization of macrophages and stimulates Th1 pathway in T-lymphocytes.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Resistin</h3> <p class="mb0">Resistin is mainly secreted by monocytes and macrophages and a small fraction derives from adipocytes. It is associated with insulin resistance as it inhibits insulin receptor signaling via suppression of cytokine signaling-3 (SOCS-3). Consequently, it can influence plasmatic glucose levels and insulin sensitivity (<a href="#B35">35</a>). Moreover, it stimulates the release of IL-6 and TNF-α from neutrophils and counteracts adiponectin anti-inflammatory activity on endothelial cells (<a href="#B36">36</a>).</p> <h3>Interleukin-6 (IL-6)</h3> <p class="mb0">One of the most important pro-inflammatory cytokines is IL-6. About one-third of total circulating levels of IL-6 derives from adipocytes (<a href="#B37">37</a>). IL-6 directly stimulates secretion of active phase proteins, such as CRP and fibrinogen. Waist circumference mainly correlates with IL-6 and CRP plasma levels, highlighting the crucial role of visceral adiposity in inflammation (<a href="#B38">38</a>). In addition, it promotes expression of adhesion molecules on endothelial cells for leucocytes, enhancing vascular damage and inflammation (<a href="#B38">38</a>, <a href="#B39">39</a>).</p> <h3>Tumor Necrosis Factor-Alpha (TNF-α)</h3> <p class="mb0">TNF-α has a central role in pathogenesis of several inflammatory and autoimmune diseases. Monocyte/macrophage cells are responsible for the major fraction of serum TNF-α. In addition, cytokine levels positively correlate with adiposity measures and insulin resistance. TNF-α inhibits the expression of PPAR-γ (peroxisome proliferator-activated receptor-gamma). PPAR-γ exerts anti-inflammatory activity throughout, reducing pro-inflammatory cytokine secretion in human macrophages (<a href="#B40">40</a>). Furthermore, it interferes with insulin receptor IRS-1 phosphorylation, leading to insulin resistance (<a href="#B41">41</a>). Moreover, TNF-α antagonist treatment in subjects affected by autoimmune diseases improves insulin sensitivity (<a href="#B42">42</a>). However, these findings have not been confirmed in models of obesity-related insulin resistance (<a href="#B43">43</a>).</p> <h3>Retinol Binding Protein-4 (RBP-4)</h3> <p class="mb15">Retinol-binding protein 4 (RBP-4) is an adipokine involved in the pathogenesis of insulin resistance. In particular, it reduces insulin sensitivity, decreasing IRS-1 insulin-induced phosphorylation. Hepatocytes are the main source of RBP-4, while visceral adipocytes and macrophages secrete a minor fraction. However, RBP-4 is secreted in a dependent manner to VAT mass, as it has been suggested as a marker of visceral adiposity and chronic low-grade inflammation (<a href="#B43">43</a>).</p> <p class="mb0">A variety of pro-inflammatory adipokines have been described, namely, visfatin, lipocalin, angiopoietin-like protein 2 (ANGPTL2), CC-chemokine ligand 2 (CCL2), and CXC-motif chemokine ligand 5 (CXCL5) (<a href="#F3">Figure 3</a>). However, their role in metainflammation has not been completely understood (<a href="#B43">43</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 3</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" name="figure3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g003.jpg" alt="www.frontiersin.org" id="F3" loading="lazy"> </picture> </a> <p><strong>Figure 3</strong>. Altered adipokine secretion pattern in dysfunctional adipose tissue. ANGPTL2, angiopoietin-like protein 2; CCL2, CC-chemokine ligand 2; CXCL5, CXC-chemokine ligand 5; CTRP, C1q/TNF-related protein-3; CTRP, C1q/TNF-related protein-6; CTRP, C1q/TNF-related protein-9; PEDF, pigment epithelium-derived factor; RBP-4, retinol binding protein 4; SFRP5, secreted frizzled related protein 5.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Adiponectin</h3> <p class="mb15">Adipose tissue releases a small amount of adipokines with an anti-inflammatory activity, among them adiponectin is the best characterized (<a href="#F3">Figure 3</a>). Adiponectin stimulates fatty acid oxidation and glucose uptake in skeletal muscle and liver, thus improving insulin sensitivity (<a href="#B44">44</a>). In macrophages, adiponectin signal promotes an M2 phenotype polarization, reduction of TNF-α secretion, and enhancement of scavenger activity. Moreover, it stimulates release of anti-inflammatory IL-10. Pro-inflammatory cytokines (IL-6 and TNF-α), oxidative stress, and adipocyte hypoxia decrease adiponectin secretion. In fact, clinical studies have reported that hormone levels are inversely correlated with CRP plasma levels (<a href="#B45">45</a>). Moreover, obesity is associated with lower adiponectin levels and increased risk of cardiovascular diseases (<a href="#B46">46</a>, <a href="#B47">47</a>). Similarly to adiponectin, the C1q/TNF-related proteins (CTRPs) promote anti-inflammatory pathway. Some CTRPs are expressed in adipose tissue, such as CTRP3, CTRP6, CTRP9, and CTRP12, and inhibit macrophage pro-inflammatory activity (<a href="#B48">48</a>). In addition, omentin-1 is secreted from VAT and reduces vascular inflammation <i>via</i> inhibition of endothelial adhesion molecules expression (<a href="#B48">48</a>).</p> <p class="mb0">In conclusion, adipokine secretion pattern from adipose tissue exerts a central role in the link between obesity and altered immune response, leading to systemic inflammation and reduced immune tolerance.</p> <a id="h5" name="h5"></a><h2>Obesity, Atopy, and Asthma</h2> <p class="mb0">Paralleling with the obesity epidemic, a rise in the prevalence of allergic diseases has been registered. The higher exposure to indoor and outdoor air pollutants has a crucial role in this phenomenon. However, evidence suggests that obesity and obesity-related inflammation might be at least in part responsible of this process. Data from the National Health and Nutrition Examination Study III (NHANES III) have reported a positive association between BMI and atopy rates (<a href="#B49">49</a>). Nevertheless, obese subjects do not show a significant increase of serum atopy markers, such as IgE plasma levels and eosinophils count (<a href="#B50">50</a>, <a href="#B51">51</a>). In addition, evidence about a possible link between obesity and other allergic disorders, namely, allergic rhinitis and atopic dermatitis, is sparse. Therefore, this field needs to be more deeply investigated. Conversely, several data are available about the relation between asthma and obesity in both adults and children (<a href="#B9">9</a>). Cross-sectional epidemiological studies have reported that obese children are frequently affected by asthma (<a href="#B49">49</a>, <a href="#B52">52</a>, <a href="#B53">53</a>). Moreover, a metanalysis including six perspective studies found that obese children show a twofold higher risk for asthma compared to normal weight children (<a href="#B54">54</a>). In addition, obese children commonly show a more severe asthma phenotype, which tend to be resistant to pharmacologic therapies with frequent exacerbations. Nevertheless, obese children do not show elevation of expiratory levels of inflammatory markers, such as exhaled nitric oxygen (eNO). Several underlying mechanisms have been proposed for obesity-related asthma (<a href="#F4">Figure 4</a>). In particular, excess of truncal adiposity leads to a mechanical overload to respiratory muscles. This results in reduced functional residual capacity, decreased residual volume, and expiratory reserve volume. This volume reduction exposes obese children to an impairment of forced expiratory volume in 1 s and forced vital capacity ratio (FEV1/FVC). In addition to mechanical overload, metabolic derangement might also play a role in obesity-related asthma. Dyslipidemia and insulin resistance have been associated with an impaired FEV1/FVC ratio. Insulin is a trophic stimulus for low airway smooth muscle cells. It stimulates laminin production through phospho-inositide-3 kinase/Akt (PI3K/AKT) pathway, leading to muscle hypertrophy. Additionally, it enhances airway hyper-responsiveness via stimulating parasympathetic innervation. These mechanisms promote airway obstruction during physical exercise and a perception of respiratory effort during inspiration (<a href="#B55">55</a>). Moreover, chronic low-grade inflammation occurring in obesity plays an important role. In obese children, imbalance between Th1/Th2 phenotype toward a Th1 reaction has been related to decrease FEV1/FVC ratio. Similarly, macrophage pro-inflammatory M1 type induces airway obstruction (<a href="#B56">56</a>). Finally, derangement of adipokines' milieu has a role in adult asthma. In particular, leptin serum levels are inversely correlated with pulmonary volumes and FEV1/FVC ratio, while it increases bronchial hyper-responsiveness (<a href="#B57">57</a>). However, most of the available evidence is based on cross-sectional studies, and this makes it difficult to completely understand underlying mechanisms of obesity-related asthma.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 4</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" name="figure4" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/474967/fped-07-00487-HTML/image_m/fped-07-00487-g004.jpg" alt="www.frontiersin.org" id="F4" loading="lazy"> </picture> </a> <p><strong>Figure 4</strong>. Potential mechanisms involved in obesity-related asthma.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <a id="h6" name="h6"></a><h2>Obesity and Autoimmunity</h2> <p class="mb15">The characterization of immunological function of adipose tissue has suggested a possible link between obesity and autoimmune disorders. Autoimmunity is strongly influenced by genetic background; however, environmental factors are central in the beginning of immune response. Several observational studies have reported the association between obesity and a number of autoimmune diseases, namely, autoimmune thyroiditis, type 1 diabetes, multiple sclerosis, rheumatic arthritis, systemic lupus erythematosus, inflammatory bowel diseases, and psoriasis. However, data for pediatric age are sparse. Longitudinal studies have reported that obese children and adolescents display a twofold higher risk of developing multiple sclerosis in adulthood; this risk is higher in girls compared to boys and increases in subjects with a predisposing genetic background (HLA DRB1<sup>*</sup>15) (<a href="#B58">58</a>–<a href="#B60">60</a>). Several potential underlying mechanisms have been proposed: vitamin D deficiency, imbalance of macrophages M1/M2 phenotypes, increased levels of leptin, and reduced adiponectin levels (<a href="#B60">60</a>). With regard to rheumatoid arthritis (RA), obese subjects present a 20% higher risk of RA in longitudinal studies (<a href="#B61">61</a>). In addition, RA severity and treatment responsiveness is negatively influenced by adiposity, as obese subjects are more prone to develop a severe disease with reduced remission and high rate of comorbidities (<a href="#B62">62</a>). Adipokines are involved in joint damage; they stimulate secretion of pro-inflammatory cytokines and metalloproteinases from synovial chondrocytes and fibroblasts (<a href="#B63">63</a>). Conversely, no solid evidence is available to confirm the hypothesized relationship between obesity and systemic lupus erythematosus pathogenesis, while it has been reported that obesity increases disease activity (<a href="#B64">64</a>, <a href="#B65">65</a>). More solid evidence confirms that obesity and psoriasis are correlated (<a href="#B66">66</a>), but the pathogenic underpinnings of this association are still debated. Subjects with psoriasis and psoriatic arthritis tend to gain weight because of a sedentary lifestyle; obesity worsens disease severity and the risk of comorbidities (<a href="#B67">67</a>). Additionally, weight loss improves disease control and response to treatment (<a href="#B68">68</a>). Several mechanisms underlie this observation. First of all, altered adipokines' milieu characterized by a prevalence of IL-6, TNF-α, and leptin promotes immune cell activation, proliferation, and migration (<a href="#B30">30</a>). Moreover, reduction of Treg cells with a concurrent increase of Th17 has been associated with autoimmunity (<a href="#B11">11</a>). Nutrients also play a role, as a western diet with high-fat and high-sugar content leads to intestinal dysbiosis and Th17/Treg imbalance (<a href="#B69">69</a>).</p> <p class="mb15">Furthermore, adipose tissue is involved in peripheral aromatization of androgens to estrogens, and this may represent a means through which excess adiposity might predispose to autoimmunity. In fact, females are more affected by autoimmune diseases compared to males. This observation might be related to the influence of sexual hormones on immune tolerance. Interestingly, women show higher leptin plasma levels compared to men. It is well-known that estrogens and dehydroepiandrosterone (DHEA) are the major mediators of females' susceptibility to autoimmune disorders. These hormones promote immunoglobulin release, stimulate adaptive immune responses, and induce secretion of pro-inflammatory cytokines (<a href="#B70">70</a>).</p> <p class="mb0">As for RA, adipokines are central players in this scenario. Leptin and resistin plasma levels are elevated in subjects with psoriasis. Moreover, <i>in vitro</i> experiment showed that leptin stimulates cytokine release in human keratinocytes. Contrasting results have been produced about the role of adiponectin in psoriasis pathogenesis and severity (<a href="#B63">63</a>). In conclusion, more studies are needed to confirm and investigate the pathophysiological mechanisms underlying the potential relationship between autoimmunity and obesity.</p> <a id="h7" name="h7"></a><h2>Obesity and Cancer</h2> <p class="mb15">Previous studies have shown that nutritional status affects immunocompetence, as both undernutrition and overweight influence immune system functions. Epidemiological studies reported that subjects with obesity are at higher risk of infectious disease, infectious disease-related complications, and cancer (<a href="#B71">71</a>, <a href="#B72">72</a>). In regard to cancer, it has been estimated that up to 50% of a variety of cancer types, namely, endometrial, breast, colon, liver, and prostate, might be attributed to obesity in adults (<a href="#B73">73</a>). Additionally, a growing body of evidence suggests that pediatric obesity might increase the risk for cancer occurrence in adulthood. As for atopy and autoimmunity, more complex mechanisms interplay in obesity-related carcinogenesis. The chronic low-grade systemic inflammation has been recognized as the trigger of carcinogenesis and cytokines exert a crucial role in this process. IL-6 and IL-1β promote cell proliferation and survival. Moreover, TNF-α can increase DNA damage and cell proliferation through the NF-KB pathway with upregulation of anti-apoptotic proteins (<a href="#B74">74</a>). In addition, IL-6 induces transcription of genes involved in angiogenesis, invasiveness, and metastasis via STAT3 activation. Similarly, leptin activates STAT3 pathway, enhancing cell proliferation and angiogenesis. Conversely, adiponectin has an anti-inflammatory and anti-tumorigenic activity through activation of AMPK (adenosine monophosphate-activated protein kinase) and inhibition of mTORC1 and other tumorigenic mediators. Therefore, dysfunctional hypertrophic adipose tissue secretes a relatively higher amount of carcinogenic mediators over anti-tumorigenic molecules. On the other hand, obesity is associated with impaired immune surveillance as suggested by increased risk of infection and lower response to immunization. Obese subjects have a reduced number of NK, dendritic, and CD8+ cells that mediate cytotoxic functions (<a href="#B75">75</a>). In addition, Michelet et al. observed that NK cells from obese humans secrete lower amounts of INF-γ. The authors hypothesized that free fatty acid overload induces a shift in NK cell metabolism from glycolysis to lipid beta-oxidation, thus deranging cellular homeostasis and function. The direct consequence of reduced immune surveillance is tumor growth and invasiveness (<a href="#B76">76</a>).</p> <p class="mb0">To date, data in pediatric age are sparse, epidemiological evidence comes from adult population, and potential mechanisms have been investigated only in mice. However, it might be hypothesized that these processes might initiate already during childhood.</p> <a id="h8" name="h8"></a><h2>Conclusions</h2> <p class="mb0">Obesity is a major risk factor for allergic, autoimmune, and neoplastic diseases, and it is at least in part responsible for the recent burden of these disorders. Dysfunctional adipose tissue is the key pathogenic factor leading to this association. However, to date, a small number of studies have addressed this issue in obese children and adolescents; therefore, more studies are needed to confirm these observations and to understand the complex interplay between adipose tissue and immune system. The gain in knowledge in metainflammation patterns and mediators might allow the development of novel treatments for pediatric obesity. To date, there are no studies evaluating inflammatory targets in the treatment of pediatric obesity. However, PPAR-γ and PPAR-α agonists have shown to modulate monocyte function in activated human adipose tissue <i>in vitro</i>. Moreover, they reduced the release of pro-inflammatory mediators and expression of adhesion molecules in monocytes (<a href="#B77">77</a>). Therefore, they could represent a promising tool in the treatment of obesity-related inflammation and insulin resistance.</p> <a id="h9" name="h9"></a><h2>Author Contributions</h2> <p class="mb0">GU and IB wrote the manuscript. CP and ET selected the articles. AM and DL realized the figures. 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Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist aleglitazar in attenuating TNF-alpha-mediated inflammation and insulin resistance in human adipocytes. <i>Pharmacol Res.</i> (2016) 107:125–36. doi: 10.1016/j.phrs.2016.02.027</p> <p style="margin-left:1em;" class="ReferencesCopy2"><a href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=26976796" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.phrs.2016.02.027" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M+Massaro&author=E+Scoditti&author=M+Pellegrino&author=MA+Carluccio&author=N+Calabriso&author=M+Wabitsch+&publication_year=2016&title=Therapeutic+potential+of+the+dual+peroxisome+proliferator+activated+receptor+(PPAR)alpha%2Fgamma+agonist+aleglitazar+in+attenuating+TNF-alpha-mediated+inflammation+and+insulin+resistance+in+human+adipocytes&journal=Pharmacol+Res.&volume=107&pages=125-36" target="_blank">Google Scholar</a></p> </div> </div> <div class="thinLineM20"></div> <div class="AbstractSummary"> <p><span>Keywords:</span> obesity, immune system, inflammation, adipokines, atopy, autoimmune diseases</p> <p><span>Citation:</span> Umano GR, Pistone C, Tondina E, Moiraghi A, Lauretta D, Miraglia del Giudice E and Brambilla I (2019) Pediatric Obesity and the Immune System. <i>Front. Pediatr.</i> 7:487. doi: 10.3389/fped.2019.00487</p> <p id="timestamps"><span>Received:</span> 28 May 2019; <span>Accepted:</span> 06 November 2019;<br> <span>Published:</span> 22 November 2019.</p> <div><p>Edited by:</p> <a href="http://loop.frontiersin.org/people/23588/overview">Luigi Daniele Notarangelo</a>, National Institute of Allergy and Infectious Diseases (NIAID), United States</div> <div><p>Reviewed by:</p> <a href="http://loop.frontiersin.org/people/470792/overview">Sigrun Ruth Hofmann</a>, Universitätsklinikum Carl Gustav Carus, Germany<br> <a href="http://loop.frontiersin.org/people/629496/overview">Eugênia Terra Granado</a>, Brazilian National Cancer Institute (INCA), Brazil</div> <p><span>Copyright</span> © 2019 Umano, Pistone, Tondina, Moiraghi, Lauretta, Miraglia del Giudice and Brambilla. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p> <p><span>*Correspondence:</span> Giuseppina Rosaria Umano, <a id="encmail">Z2l1c2VwcGluYXJvc2FyaWEudW1hbm9AdW5pY2FtcGFuaWEuaXQ=</a></p> <div class="clear"></div> </div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/23588/32" alt="Luigi Daniele Notarangelo" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Luigi Daniele Notarangelo </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIH), United States </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/470792/overview" data-event="editorInfo-a-sigrunRuthHofmann" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/470792/32" alt="Sigrun Ruth Hofmann" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Sigrun Ruth Hofmann </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Department of Pediatrics, Vivantes Clinic in Friedrichshain, Germany </div></div></a><a href="https://loop.frontiersin.org/people/629516/overview" data-event="editorInfo-a-eugeniaGranado" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/629516/32" alt="Eugenia Granado" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Eugenia Granado </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> National Cancer Institute (INCA), Brazil </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"> <li><a href="#h1">Abstract</a></li> <li><a href="#h2">Introduction</a></li> <li><a href="#h3">Obesity and Inflammation</a></li> <li><a href="#h4">Adipokines as Immune Modulators</a></li> <li><a href="#h5">Obesity, Atopy, and Asthma</a></li> <li><a href="#h6">Obesity and Autoimmunity</a></li> <li><a href="#h7">Obesity and Cancer</a></li> <li><a href="#h8">Conclusions</a></li> <li><a href="#h9">Author Contributions</a></li> <li><a href="#h10">Conflict of Interest</a></li> <li><a href="#h11">References</a></li> </ul></div></div>  <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeOutline 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Loving mother hand holding cute sleeping newborn baby child; Shutterstock ID 218070889; purchase_order: Main Visual; job: ; client: ; other:",orientation:I,userCreated:"Caroline Sutter",watermarked:m,dateModified:ab,datePublished:"2022-06-27T09:27:09Z",ecsArchiveFiles:[],propertyOptions:["414FB2D4-2283-43FD-BE14E534ECA67928","6C18119B-14BD-4951-B437696F4357BD33","7C692885-DB25-4858-B1FB4FF47B241E9B","D88C0047-EC30-4506-A7DF28A4D765E1CF"],property_Channel:["frontiersin_org"],"property_Sub-Type":["Main_Visual"],property_Asset_Type:["Photography"],activeOriginalFocusPoint:{x:2880,y:y},property_Office_Department:["Publishing"]}],description:"Explores research that meets ongoing challenges in pediatric patient care and child health, from neonatal screening to adolescent development.",mission:"\u003Cp\u003EFrontiers in Pediatrics is a multidisciplinary journal publishing research that addresses challenges in pediatric patient care and child health.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Dr Andrew S. Day (University of Otago, New Zealand), Frontiers in Pediatrics is indexed in PubMed Central (PMC), Web of Science (SCIE), and the DOAJ, among others, and publishes both basic and clinical research related to all aspects of pediatrics.\u003C\u002Fp\u003E\n\n\u003Cp\u003ETopics include, but are not limited to:\u003C\u002Fp\u003E\n\u003Cul\u003E\n \u003Cli\u003Echildren and health\u003C\u002Fli\u003E\n \u003Cli\u003Egeneral pediatrics and pediatric emergency care\u003C\u002Fli\u003E\n \u003Cli\u003Egenetics of common and rare diseases\u003C\u002Fli\u003E\n \u003Cli\u003Eneonatology\u003C\u002Fli\u003E\n \u003Cli\u003Eobstetric and pediatric pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric cardiology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric critical care\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric endocrinology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric gastroenterology, hepatology and nutrition\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric hematology and hematological malignancies\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric immunology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric infectious diseases\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric neurology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric obesity\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric oncology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric orthopedics\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric otolaryngology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric occupational therapy\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric pulmonology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric rheumatology\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric surgery\u003C\u002Fli\u003E\n \u003Cli\u003Epediatric urology.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EIn particular, the journal welcomes submissions which support and advance the UN’s Sustainable Development Goals (SDGs), notably SDG 3: ensure healthy lives and promote well-being for all at all ages.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus on adult medicine, public health, or non-pediatric surgical procedures are not suitable for publication in this journal. Studies that do not directly relate to the health and well-being of children and adolescents, including those focusing on parental education or socio-economic factors without a fundamental basis in pediatric health outcomes, will not be considered.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Pediatrics is committed to advancing developments in the field of pediatrics by allowing unrestricted access to articles, and communicating scientific knowledge to researchers and the public alike, to enable the scientific breakthroughs of the future.\u003C\u002Fp\u003E",palette:"red",impactFactor:"2.6",citeScore:"3.3",citations:"70000",showTagline:e,twitter:"@FrontPediatrics",__typename:"Journal"},currentFrontiersJournal:{id:u,name:r,slug:v,printISSN:e,shortName:J,electronicISSN:K,abbreviation:ac,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:ad,domainId:n,__typename:ae},__typename:a},articleHubSlug:g,articleHubPage:L,currentArticle:{id:474967,doi:af,title:M,acceptanceDate:new Date(1573032394000),receptionDate:new Date(1559055186000),publicationDate:new Date(1574380800000),isPublished:h,abstract:ag,researchTopic:{id:9192,title:"Translational Insights into Pediatric Immune-Related Diseases",articlesCount:N,isMagazinePage:l,slug:"translational-insights-into-pediatric-immune-related-diseases",isOpenForSubmission:l},articleType:{id:27,name:"Review"},stage:{id:O,name:g},keywords:["Obesity","Immune System","Inflammation","Adipokines","Atopy","Autoimmun disease"],authors:[{id:ah,firstName:ai,lastName:"Umano",givenNames:ai,isCorresponding:l,isProfilePublic:h,userId:ah,affiliations:[{organizationName:P,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:m,firstName:aj,lastName:"Pistone",givenNames:aj,isCorresponding:l,isProfilePublic:l,userId:m,affiliations:[{organizationName:Q,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:ak,firstName:al,lastName:"Tondina",givenNames:al,isCorresponding:l,isProfilePublic:h,userId:ak,affiliations:[{organizationName:Q,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:am,firstName:an,lastName:"Moiraghi",givenNames:an,isCorresponding:l,isProfilePublic:h,userId:am,affiliations:[{organizationName:Q,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:ao,firstName:ap,lastName:"Lauretta",givenNames:ap,isCorresponding:l,isProfilePublic:h,userId:ao,affiliations:[{organizationName:P,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:aq,firstName:ar,lastName:"Miraglia del Giudice",givenNames:ar,isCorresponding:l,isProfilePublic:h,userId:aq,affiliations:[{organizationName:P,countryName:o,cityName:g,stateName:g,zipCode:g}]},{id:as,firstName:at,lastName:"Brambilla",givenNames:at,isCorresponding:l,isProfilePublic:h,userId:as,affiliations:[{organizationName:"Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia",countryName:o,cityName:g,stateName:g,zipCode:g}]}],editors:[{id:au,firstName:"Luigi",lastName:"Notarangelo",givenNames:"Luigi Daniele",isCorresponding:l,isProfilePublic:h,userId:au,affiliations:[{organizationName:"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIH)",countryName:"United States",cityName:g,stateName:g,zipCode:g}]}],reviewers:[{id:av,firstName:"Sigrun",lastName:"Hofmann",givenNames:"Sigrun Ruth",isCorresponding:l,isProfilePublic:h,userId:av,affiliations:[{organizationName:"Department of Pediatrics, Vivantes Clinic in Friedrichshain",countryName:"Germany",cityName:g,stateName:g,zipCode:g}]},{id:aw,firstName:ax,lastName:"Granado",givenNames:ax,isCorresponding:l,isProfilePublic:h,userId:aw,affiliations:[{organizationName:"National Cancer Institute (INCA)",countryName:"Brazil",cityName:g,stateName:g,zipCode:g}]}],journal:{id:u,slug:v,name:r,shortName:J,electronicISSN:K,field:{id:ad,domainId:n,__typename:ae},specialtyId:e,journalSectionPaths:[{section:ay,__typename:"journal_journalSectionPath"}],__typename:a},section:ay,impactMetrics:{views:10297,downloads:3033,citations:35},volume:z,articleVolume:"Volume 7 - 2019",relatedArticles:[],isPublishedV2:l,contents:{titleHtml:M,fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\n\n\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F748093\" class=\"user-id-748093\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F748093\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"\\nGiuseppina Rosaria Umano
\"\u003EGiuseppina Rosaria Umano\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003Csup\u003E*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Carmelo Pistone\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ECarmelo Pistone\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F850798\" class=\"user-id-850798\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F850798\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Enrico Tondina\"\u003EEnrico Tondina\u003C\u002Fa\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F851025\" class=\"user-id-851025\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F851025\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Alice Moiraghi\"\u003EAlice Moiraghi\u003C\u002Fa\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F850834\" class=\"user-id-850834\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F850834\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Daria Lauretta\"\u003EDaria Lauretta\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F666582\" class=\"user-id-666582\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F666582\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Emanuele Miraglia del Giudice\"\u003EEmanuele Miraglia del Giudice\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F850848\" class=\"user-id-850848\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F850848\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Ilaria Brambilla\"\u003EIlaria Brambilla\u003C\u002Fa\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\n\u003Cul class=\"notes\"\u003E\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDepartment of the Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy\u003C\u002Fli\u003E\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ESchool of Pediatrics, University of Pavia, Pavia, Italy\u003C\u002Fli\u003E\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDepartment of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\u003Cp\u003EObesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related diseases, recent evidence suggested that obesity might affect immune system function. Adipose tissue is considered an endocrine organ that actively secretes cytokines also referred to as “adipokines.” Adipokines play an important role in the control of human metabolism. The dysfunctional adipose tissue in obese individuals is characterized by an altered cytokine secretion pattern that promotes chronic low-grade inflammation. Epidemiological evidence highlights the association between obesity and allergic and immune-mediated diseases, such as asthma, allergic rhinitis, rheumatic arthritis, and psoriasis. Less is known about underlying pathogenic mechanisms. However, several recent \u003Ci\u003Ein vivo\u003C\u002Fi\u003E and \u003Ci\u003Ein vitro\u003C\u002Fi\u003E studies have reported that adipokines are involved in inflammatory and autoimmune disorders by influencing both innate and acquired immune responses. In addition, obesity has been associated with reduced immune surveillance and increased risk of cancer. This paper reviews the evidence regarding the role of adipokines in immune system regulation, with particular emphasis on autoimmune, allergic, and inflammatory disorders. Understanding how obesity affects immune system functions may enable researchers to find new potential therapeutic targets in the management of allergic and autoimmune diseases.\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"JournalFullText\"\u003E\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe obesity epidemic represents a major health issue of the twenty-first century. The prevalence of the disease has significantly increased in the last decades worldwide, including low-income countries (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E). In addition, it has been reported that pediatric obesity significantly increases the risk of obesity and its cardiovascular complications during childhood and adulthood (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E, \u003Ca href=\"#B3\"\u003E3\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EThe constant increase in obesity prevalence might be ascribed to changes in lifestyle habits, namely, assumption of junk food and sedentary behavior. Moreover, genetic background plays a role by affecting energy expenditure and food intake (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). The excess of fat present in obese individuals results in a hypertrophic white adipose tissue with a consequent derangement in adipocytes metabolic activity. Adipose tissue in some obese subjects displays a pro-inflammatory activity and has been associated with obesity-related comorbidities in both adults and children (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E–\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E). Adipocytes actively secrete several hormones and cytokines, also referred to as adipokines that exert metabolic and immunological functions, as they could modulate the innate and acquired immune cell activity. Moreover, they are capable of promoting pro-inflammatory signals leading to a chronic systemic low-grade inflammation. In addition, growing evidence reports the association between obesity and immune disorders, such as cancer, autoimmunity, and atopy (\u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E). Therefore, the altered secretion pattern of adipokines in obesity is considered the link between obesity and its metabolic and immunological comorbidities (\u003Ca href=\"#B10\"\u003E10\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EIn this review, we summarize the current knowledge on the basis of endocrine and immunological functions of white adipose tissue. In particular, we describe the interplay between adipokines and both innate and acquired immunity. Moreover, we report the evidences and possible mechanisms of the association between pediatric obesity and immunological disorders.\u003C\u002Fp\u003E\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EObesity and Inflammation\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EClinical studies have observed a significant association between serum markers of chronic low-grade inflammation and obesity-related comorbidities in children and adolescents (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E–\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E). Serum levels of C-reactive protein (CRP) directly correlate with insulin resistance and carotid intima-media thickness (cIMT) in children and adolescents with overweight and obesity (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). Moreover, it has been reported that white blood cell count is predictive of increased cIMT and ventricular hypertrophy in obese children and adolescents (\u003Ca href=\"#B12\"\u003E12\u003C\u002Fa\u003E). In addition, weight loss after lifestyle intervention trial was effective in reducing both serum inflammatory markers and insulin resistance in obese children and adolescents (\u003Ca href=\"#B14\"\u003E14\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EInflammation is a mechanism that involves a series of non-cellular and cellular mediators involved in the response to infections, tissue damage, cellular death, and cancer. Obesity is accompanied by a sterile chronic low-grade inflammation in the adipose tissue that is not related to infection or tissue damage (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E). This process is also referred to as metabolic inflammation or metainflammation. Metainflammation is an active player in the development of obesity-related comorbidities, as obesity-related inflammation might impair the function of other organs (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E). Adipose tissue immune response is mediated by adipose tissue-resident immune cells, namely, macrophages, mast cells, neutrophils, and T and B lymphocytes, which are the second more represented cellular type, after adipocytes (\u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E). Mechanisms triggering adipose tissue inflammation are not completely clear. However, adipose tissue hyperplasia and hypertrophy occurring in obese individuals may exert an important role (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E). In fact, an increase of adipocyte size leads to hypoxia, intracellular oxidative stress, and release of pro-inflammatory molecules (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E). However, some studies have shown that metabolically unhealthy obese adolescents tend to have smaller adipose cells (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E), which allows for a smaller storage capacity and favor a more pronounced flux of free fatty acids. Inflammasome activation in subcutaneous adipose tissue (SAT) has been associated with an altered abdominal fat distribution (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E). The inflammasome chronic activation impairs the SAT storage capability leading to a lipid spill over into visceral adipose tissue (VAT) (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe excess of free fatty acids contributes to an unfavorable metabolic phenotype probably through the macrophage activation in adipose tissue. In fact, free fatty acids directly activate immune cells and induce secretion of pro-inflammatory mediators through interacting with toll-like receptors (TLRs) (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E). In VAT, adipocytes develop a dysfunctional phenotype characterized by smaller adipose cells and expression of adhesion molecules for monocytes\u002Fmacrophages (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003EMacrophages\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EMacrophages are the most common immune cell type in adipose tissue. The number of macrophages has been associated with size of adipocytes and severity of obesity (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E). A small amount of adipose tissue macrophages (ATMs) derives from pre-adipocyte maturation, while the majority comes from systemic circulation (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E). Hypertrophic adipose tissue promotes macrophage migration and infiltration via secretion of chemokines. Several chemokines are involved in this pathway. Among them, monocyte-chemoattracting protein 1\u002Fchemokine C–C motif receptor 2 (MCP1\u002FCCR2) binds macrophage receptor CCR2, leading to infiltration (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). Moreover, obesity alters the phenotype and distribution of macrophages. Macrophages could be distinguished in two subsets according to membrane antigen and cytokine secretion: classically activated M1 type and alternative activated M2 type. M1 type exerts a pro-inflammatory and antibacterial role; it expresses receptor for inflammatory mediators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, and lipopolysaccharides (LPS). Conversely, M2 phenotype is induced by anti-inflammatory molecules, namely, IL-13, IL-10, IL-4, and macrophage colony-stimulating factor (M-CSF), and displays anti-inflammatory and anti-parasitic functions (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E, \u003Ca href=\"#B25\"\u003E25\u003C\u002Fa\u003E). The different polarization of macrophages in human adipose tissue is influenced by nutritional status. In normal weight subjects, the prevalence of eosinophils, T-lymphocytes, and natural killer (NK) cells promote a polarization toward M2 type. These macrophages, in a favorable environment, exert homeostatic actions, regulating cellular proliferation, extracellular matrix deposition, and removing cellular debris in stromal matrix. In obese subjects, oxidative stress, necrotic cellular debris, and overload of free fatty acids lead to a polarization toward an M1 phenotype. In contrast to M2, M1 macrophages do not migrate in stromal matrix; they tend to create aggregates surrounding necrotic adipocytes, in a typical crown-like structure (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E). In humans, the number of M1 macrophages directly correlates with systemic inflammation, insulin resistance, type 2 diabetes, and fatty liver disease (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003ELymphocytes\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EThe second largest immune cell subset in adipose tissue is represented by T-lymphocytes. T-cells could be divided in CD4+ and CD8+ according to surface antigens. The cytokine secretion pattern of CD4+ allows a further categorization in Th1 (INF-γ), Th2 (IL-4, IL-5, and IL-13), Treg (IL-10 and transforming growth factor B), and Th17 (IL-17, IL-21, and IL-22). CD8+ are cytotoxic cells that secrete perforins, granzymes, and a variety of cytokines that mediate activation of other immune cells. In dysfunctional adipose tissue, the T-lymphocyte subpopulation pattern is polarized toward a pro-inflammatory activity. Therefore, Th1, Th17, and CD8+ are more represented compared to anti-inflammatory Th2 and Treg (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003EOther Adipose Tissue-Resident Immune Cells\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003ENeutrophils, mast cells, and dendritic cells constitute a small fraction of immune cells in adipose tissue. Nevertheless, they play an important role in amplifying inflammation process via secretion of pro-inflammatory mediators. The amount of eosinophils, instead, is reduced. They promote M2 macrophage and Th2 differentiation and suppress inflammatory stimuli (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAdipokines as Immune Modulators\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EIn the last years, a number of adipose tissue-derived cytokines have been characterized, the so-called adipokines (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E). Besides adipocytes, the vascular-stromal component of adipose tissue concurs with cytokine secretion in an adiposity-dependent manner. Adipokines play a crucial role not only in energy homeostasis but also in inflammatory and immune reaction, most of them promoting inflammation (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g001.jpg\" alt=\"www.frontiersin.org\" id=\"F1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 1\u003C\u002Fstrong\u003E. Adipokines secreted from white adipose tissue and their immunological functions. RBP-4, retinol binding protein 4; TNF-α, tumor necrosis factor alpha; Th-1, T-helper 1.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ch3\u003ELeptin\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003ELeptin was first described by Zhang et al. (\u003Ca href=\"#B28\"\u003E28\u003C\u002Fa\u003E) in a murine model. It is encoded by murine \u003Ci\u003Eob\u003C\u002Fi\u003E gene and human homologous \u003Ci\u003ELEP\u003C\u002Fi\u003E gene. Animals and human models showed that inhibition of leptin action results in food assumption and insulin resistance (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E, \u003Ca href=\"#B28\"\u003E28\u003C\u002Fa\u003E). Leptin secretion is positively correlated with adipose tissue mass; therefore, obese subjects show high leptin plasmatic levels. Nevertheless, obese subjects develop leptin resistance with a decreased sensitivity to anorexinergic hormone stimulus. Leptin has pleiotropic activities. The main role is suppression of food assumption via inhibiting hypothalamic nuclei that stimulate hunger and stimulation of those which promote satiety (\u003Ca href=\"#B29\"\u003E29\u003C\u002Fa\u003E). Leptin loss of function is associated with hyperphagia, rapid weight gain, and insulin resistance (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). Moreover, leptin influences pubertal development and shows immunomodulatory activity (\u003Ca href=\"#B31\"\u003E31\u003C\u002Fa\u003E). In fact, several immune cell types express leptin receptor (LEPR) (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E). In neutrophils, leptin activates anti-apoptotic signals, resulting in cell survival. In addition, it induces neutrophil activation in terms of chemotaxis, tissue infiltration, and oxygen radicals' release. Similarly, eosinophils and basophils express LEPR on the cellular surface. As for neutrophils, leptin acts as a survival cytokine for these cells and stimulates tissue infiltration and pro-inflammatory molecule release (\u003Ca href=\"#B32\"\u003E32\u003C\u002Fa\u003E). Moreover, leptin is crucial for monocyte\u002Fmacrophage function. In experimental models of \u003Ci\u003ELepR\u003C\u002Fi\u003E, knock-out mice impaired macrophages killing activity and phagocytosis has been reported (\u003Ca href=\"#B33\"\u003E33\u003C\u002Fa\u003E). Additionally, leptin has been shown to enhance monocyte and macrophage survival, migration, release of pro-inflammatory cytokines (namely, IL-6 and TNF-α), and expression of surface markers (CD39, CD69, CD25, CD71, and IL-1Rα). Leptin also stimulates proliferation and cytotoxicity of NK cell and constitutes a survival cytokine for dendritic cells. With regard to adaptive immune response, hormone inhibits T-lymphocyte apoptosis, promotes Th1 response, suppresses Th2 activity, and enhances IL-2 and INF-γ production. Moreover, it sustains Th17 pro-inflammatory function and B-lymphocyte activity (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). In general, leptin displays a pro-inflammatory activity, interacting with both innate and adaptive immune system. These data highlight the crucial role of leptin in pathogenesis of obesity-related comorbidities, in terms of metabolic derangement and chronic inflammation.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" name=\"figure2\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g002.jpg\" alt=\"www.frontiersin.org\" id=\"F2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 2\u003C\u002Fstrong\u003E. Leptin action on immune cells. Leptin promotes cell survival, stimulates the secretion of pro-inflammatory cytokines, and suppresses cell apoptosis. It induces M1 polarization of macrophages and stimulates Th1 pathway in T-lymphocytes.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ch3\u003EResistin\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EResistin is mainly secreted by monocytes and macrophages and a small fraction derives from adipocytes. It is associated with insulin resistance as it inhibits insulin receptor signaling via suppression of cytokine signaling-3 (SOCS-3). Consequently, it can influence plasmatic glucose levels and insulin sensitivity (\u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E). Moreover, it stimulates the release of IL-6 and TNF-α from neutrophils and counteracts adiponectin anti-inflammatory activity on endothelial cells (\u003Ca href=\"#B36\"\u003E36\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003EInterleukin-6 (IL-6)\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EOne of the most important pro-inflammatory cytokines is IL-6. About one-third of total circulating levels of IL-6 derives from adipocytes (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E). IL-6 directly stimulates secretion of active phase proteins, such as CRP and fibrinogen. Waist circumference mainly correlates with IL-6 and CRP plasma levels, highlighting the crucial role of visceral adiposity in inflammation (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E). In addition, it promotes expression of adhesion molecules on endothelial cells for leucocytes, enhancing vascular damage and inflammation (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E, \u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003ETumor Necrosis Factor-Alpha (TNF-α)\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003ETNF-α has a central role in pathogenesis of several inflammatory and autoimmune diseases. Monocyte\u002Fmacrophage cells are responsible for the major fraction of serum TNF-α. In addition, cytokine levels positively correlate with adiposity measures and insulin resistance. TNF-α inhibits the expression of PPAR-γ (peroxisome proliferator-activated receptor-gamma). PPAR-γ exerts anti-inflammatory activity throughout, reducing pro-inflammatory cytokine secretion in human macrophages (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E). Furthermore, it interferes with insulin receptor IRS-1 phosphorylation, leading to insulin resistance (\u003Ca href=\"#B41\"\u003E41\u003C\u002Fa\u003E). Moreover, TNF-α antagonist treatment in subjects affected by autoimmune diseases improves insulin sensitivity (\u003Ca href=\"#B42\"\u003E42\u003C\u002Fa\u003E). However, these findings have not been confirmed in models of obesity-related insulin resistance (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ch3\u003ERetinol Binding Protein-4 (RBP-4)\u003C\u002Fh3\u003E\n\u003Cp class=\"mb15\"\u003ERetinol-binding protein 4 (RBP-4) is an adipokine involved in the pathogenesis of insulin resistance. In particular, it reduces insulin sensitivity, decreasing IRS-1 insulin-induced phosphorylation. Hepatocytes are the main source of RBP-4, while visceral adipocytes and macrophages secrete a minor fraction. However, RBP-4 is secreted in a dependent manner to VAT mass, as it has been suggested as a marker of visceral adiposity and chronic low-grade inflammation (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EA variety of pro-inflammatory adipokines have been described, namely, visfatin, lipocalin, angiopoietin-like protein 2 (ANGPTL2), CC-chemokine ligand 2 (CCL2), and CXC-motif chemokine ligand 5 (CXCL5) (\u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E). However, their role in metainflammation has not been completely understood (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" name=\"figure3\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g003.jpg\" alt=\"www.frontiersin.org\" id=\"F3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 3\u003C\u002Fstrong\u003E. Altered adipokine secretion pattern in dysfunctional adipose tissue. ANGPTL2, angiopoietin-like protein 2; CCL2, CC-chemokine ligand 2; CXCL5, CXC-chemokine ligand 5; CTRP, C1q\u002FTNF-related protein-3; CTRP, C1q\u002FTNF-related protein-6; CTRP, C1q\u002FTNF-related protein-9; PEDF, pigment epithelium-derived factor; RBP-4, retinol binding protein 4; SFRP5, secreted frizzled related protein 5.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ch3\u003EAdiponectin\u003C\u002Fh3\u003E\n\u003Cp class=\"mb15\"\u003EAdipose tissue releases a small amount of adipokines with an anti-inflammatory activity, among them adiponectin is the best characterized (\u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E). Adiponectin stimulates fatty acid oxidation and glucose uptake in skeletal muscle and liver, thus improving insulin sensitivity (\u003Ca href=\"#B44\"\u003E44\u003C\u002Fa\u003E). In macrophages, adiponectin signal promotes an M2 phenotype polarization, reduction of TNF-α secretion, and enhancement of scavenger activity. Moreover, it stimulates release of anti-inflammatory IL-10. Pro-inflammatory cytokines (IL-6 and TNF-α), oxidative stress, and adipocyte hypoxia decrease adiponectin secretion. In fact, clinical studies have reported that hormone levels are inversely correlated with CRP plasma levels (\u003Ca href=\"#B45\"\u003E45\u003C\u002Fa\u003E). Moreover, obesity is associated with lower adiponectin levels and increased risk of cardiovascular diseases (\u003Ca href=\"#B46\"\u003E46\u003C\u002Fa\u003E, \u003Ca href=\"#B47\"\u003E47\u003C\u002Fa\u003E). Similarly to adiponectin, the C1q\u002FTNF-related proteins (CTRPs) promote anti-inflammatory pathway. Some CTRPs are expressed in adipose tissue, such as CTRP3, CTRP6, CTRP9, and CTRP12, and inhibit macrophage pro-inflammatory activity (\u003Ca href=\"#B48\"\u003E48\u003C\u002Fa\u003E). In addition, omentin-1 is secreted from VAT and reduces vascular inflammation \u003Ci\u003Evia\u003C\u002Fi\u003E inhibition of endothelial adhesion molecules expression (\u003Ca href=\"#B48\"\u003E48\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EIn conclusion, adipokine secretion pattern from adipose tissue exerts a central role in the link between obesity and altered immune response, leading to systemic inflammation and reduced immune tolerance.\u003C\u002Fp\u003E\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EObesity, Atopy, and Asthma\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EParalleling with the obesity epidemic, a rise in the prevalence of allergic diseases has been registered. The higher exposure to indoor and outdoor air pollutants has a crucial role in this phenomenon. However, evidence suggests that obesity and obesity-related inflammation might be at least in part responsible of this process. Data from the National Health and Nutrition Examination Study III (NHANES III) have reported a positive association between BMI and atopy rates (\u003Ca href=\"#B49\"\u003E49\u003C\u002Fa\u003E). Nevertheless, obese subjects do not show a significant increase of serum atopy markers, such as IgE plasma levels and eosinophils count (\u003Ca href=\"#B50\"\u003E50\u003C\u002Fa\u003E, \u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E). In addition, evidence about a possible link between obesity and other allergic disorders, namely, allergic rhinitis and atopic dermatitis, is sparse. Therefore, this field needs to be more deeply investigated. Conversely, several data are available about the relation between asthma and obesity in both adults and children (\u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E). Cross-sectional epidemiological studies have reported that obese children are frequently affected by asthma (\u003Ca href=\"#B49\"\u003E49\u003C\u002Fa\u003E, \u003Ca href=\"#B52\"\u003E52\u003C\u002Fa\u003E, \u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E). Moreover, a metanalysis including six perspective studies found that obese children show a twofold higher risk for asthma compared to normal weight children (\u003Ca href=\"#B54\"\u003E54\u003C\u002Fa\u003E). In addition, obese children commonly show a more severe asthma phenotype, which tend to be resistant to pharmacologic therapies with frequent exacerbations. Nevertheless, obese children do not show elevation of expiratory levels of inflammatory markers, such as exhaled nitric oxygen (eNO). Several underlying mechanisms have been proposed for obesity-related asthma (\u003Ca href=\"#F4\"\u003EFigure 4\u003C\u002Fa\u003E). In particular, excess of truncal adiposity leads to a mechanical overload to respiratory muscles. This results in reduced functional residual capacity, decreased residual volume, and expiratory reserve volume. This volume reduction exposes obese children to an impairment of forced expiratory volume in 1 s and forced vital capacity ratio (FEV1\u002FFVC). In addition to mechanical overload, metabolic derangement might also play a role in obesity-related asthma. Dyslipidemia and insulin resistance have been associated with an impaired FEV1\u002FFVC ratio. Insulin is a trophic stimulus for low airway smooth muscle cells. It stimulates laminin production through phospho-inositide-3 kinase\u002FAkt (PI3K\u002FAKT) pathway, leading to muscle hypertrophy. Additionally, it enhances airway hyper-responsiveness via stimulating parasympathetic innervation. These mechanisms promote airway obstruction during physical exercise and a perception of respiratory effort during inspiration (\u003Ca href=\"#B55\"\u003E55\u003C\u002Fa\u003E). Moreover, chronic low-grade inflammation occurring in obesity plays an important role. In obese children, imbalance between Th1\u002FTh2 phenotype toward a Th1 reaction has been related to decrease FEV1\u002FFVC ratio. Similarly, macrophage pro-inflammatory M1 type induces airway obstruction (\u003Ca href=\"#B56\"\u003E56\u003C\u002Fa\u003E). Finally, derangement of adipokines' milieu has a role in adult asthma. In particular, leptin serum levels are inversely correlated with pulmonary volumes and FEV1\u002FFVC ratio, while it increases bronchial hyper-responsiveness (\u003Ca href=\"#B57\"\u003E57\u003C\u002Fa\u003E). However, most of the available evidence is based on cross-sectional studies, and this makes it difficult to completely understand underlying mechanisms of obesity-related asthma.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 4\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" name=\"figure4\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F474967\u002Ffped-07-00487-HTML\u002Fimage_m\u002Ffped-07-00487-g004.jpg\" alt=\"www.frontiersin.org\" id=\"F4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 4\u003C\u002Fstrong\u003E. Potential mechanisms involved in obesity-related asthma.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EObesity and Autoimmunity\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe characterization of immunological function of adipose tissue has suggested a possible link between obesity and autoimmune disorders. Autoimmunity is strongly influenced by genetic background; however, environmental factors are central in the beginning of immune response. Several observational studies have reported the association between obesity and a number of autoimmune diseases, namely, autoimmune thyroiditis, type 1 diabetes, multiple sclerosis, rheumatic arthritis, systemic lupus erythematosus, inflammatory bowel diseases, and psoriasis. However, data for pediatric age are sparse. Longitudinal studies have reported that obese children and adolescents display a twofold higher risk of developing multiple sclerosis in adulthood; this risk is higher in girls compared to boys and increases in subjects with a predisposing genetic background (HLA DRB1\u003Csup\u003E*\u003C\u002Fsup\u003E15) (\u003Ca href=\"#B58\"\u003E58\u003C\u002Fa\u003E–\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E). Several potential underlying mechanisms have been proposed: vitamin D deficiency, imbalance of macrophages M1\u002FM2 phenotypes, increased levels of leptin, and reduced adiponectin levels (\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E). With regard to rheumatoid arthritis (RA), obese subjects present a 20% higher risk of RA in longitudinal studies (\u003Ca href=\"#B61\"\u003E61\u003C\u002Fa\u003E). In addition, RA severity and treatment responsiveness is negatively influenced by adiposity, as obese subjects are more prone to develop a severe disease with reduced remission and high rate of comorbidities (\u003Ca href=\"#B62\"\u003E62\u003C\u002Fa\u003E). Adipokines are involved in joint damage; they stimulate secretion of pro-inflammatory cytokines and metalloproteinases from synovial chondrocytes and fibroblasts (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E). Conversely, no solid evidence is available to confirm the hypothesized relationship between obesity and systemic lupus erythematosus pathogenesis, while it has been reported that obesity increases disease activity (\u003Ca href=\"#B64\"\u003E64\u003C\u002Fa\u003E, \u003Ca href=\"#B65\"\u003E65\u003C\u002Fa\u003E). More solid evidence confirms that obesity and psoriasis are correlated (\u003Ca href=\"#B66\"\u003E66\u003C\u002Fa\u003E), but the pathogenic underpinnings of this association are still debated. Subjects with psoriasis and psoriatic arthritis tend to gain weight because of a sedentary lifestyle; obesity worsens disease severity and the risk of comorbidities (\u003Ca href=\"#B67\"\u003E67\u003C\u002Fa\u003E). Additionally, weight loss improves disease control and response to treatment (\u003Ca href=\"#B68\"\u003E68\u003C\u002Fa\u003E). Several mechanisms underlie this observation. First of all, altered adipokines' milieu characterized by a prevalence of IL-6, TNF-α, and leptin promotes immune cell activation, proliferation, and migration (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). Moreover, reduction of Treg cells with a concurrent increase of Th17 has been associated with autoimmunity (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). Nutrients also play a role, as a western diet with high-fat and high-sugar content leads to intestinal dysbiosis and Th17\u002FTreg imbalance (\u003Ca href=\"#B69\"\u003E69\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EFurthermore, adipose tissue is involved in peripheral aromatization of androgens to estrogens, and this may represent a means through which excess adiposity might predispose to autoimmunity. In fact, females are more affected by autoimmune diseases compared to males. This observation might be related to the influence of sexual hormones on immune tolerance. Interestingly, women show higher leptin plasma levels compared to men. It is well-known that estrogens and dehydroepiandrosterone (DHEA) are the major mediators of females' susceptibility to autoimmune disorders. These hormones promote immunoglobulin release, stimulate adaptive immune responses, and induce secretion of pro-inflammatory cytokines (\u003Ca href=\"#B70\"\u003E70\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EAs for RA, adipokines are central players in this scenario. Leptin and resistin plasma levels are elevated in subjects with psoriasis. Moreover, \u003Ci\u003Ein vitro\u003C\u002Fi\u003E experiment showed that leptin stimulates cytokine release in human keratinocytes. Contrasting results have been produced about the role of adiponectin in psoriasis pathogenesis and severity (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E). In conclusion, more studies are needed to confirm and investigate the pathophysiological mechanisms underlying the potential relationship between autoimmunity and obesity.\u003C\u002Fp\u003E\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EObesity and Cancer\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EPrevious studies have shown that nutritional status affects immunocompetence, as both undernutrition and overweight influence immune system functions. Epidemiological studies reported that subjects with obesity are at higher risk of infectious disease, infectious disease-related complications, and cancer (\u003Ca href=\"#B71\"\u003E71\u003C\u002Fa\u003E, \u003Ca href=\"#B72\"\u003E72\u003C\u002Fa\u003E). In regard to cancer, it has been estimated that up to 50% of a variety of cancer types, namely, endometrial, breast, colon, liver, and prostate, might be attributed to obesity in adults (\u003Ca href=\"#B73\"\u003E73\u003C\u002Fa\u003E). Additionally, a growing body of evidence suggests that pediatric obesity might increase the risk for cancer occurrence in adulthood. As for atopy and autoimmunity, more complex mechanisms interplay in obesity-related carcinogenesis. The chronic low-grade systemic inflammation has been recognized as the trigger of carcinogenesis and cytokines exert a crucial role in this process. IL-6 and IL-1β promote cell proliferation and survival. Moreover, TNF-α can increase DNA damage and cell proliferation through the NF-KB pathway with upregulation of anti-apoptotic proteins (\u003Ca href=\"#B74\"\u003E74\u003C\u002Fa\u003E). In addition, IL-6 induces transcription of genes involved in angiogenesis, invasiveness, and metastasis via STAT3 activation. Similarly, leptin activates STAT3 pathway, enhancing cell proliferation and angiogenesis. Conversely, adiponectin has an anti-inflammatory and anti-tumorigenic activity through activation of AMPK (adenosine monophosphate-activated protein kinase) and inhibition of mTORC1 and other tumorigenic mediators. Therefore, dysfunctional hypertrophic adipose tissue secretes a relatively higher amount of carcinogenic mediators over anti-tumorigenic molecules. On the other hand, obesity is associated with impaired immune surveillance as suggested by increased risk of infection and lower response to immunization. Obese subjects have a reduced number of NK, dendritic, and CD8+ cells that mediate cytotoxic functions (\u003Ca href=\"#B75\"\u003E75\u003C\u002Fa\u003E). In addition, Michelet et al. observed that NK cells from obese humans secrete lower amounts of INF-γ. The authors hypothesized that free fatty acid overload induces a shift in NK cell metabolism from glycolysis to lipid beta-oxidation, thus deranging cellular homeostasis and function. The direct consequence of reduced immune surveillance is tumor growth and invasiveness (\u003Ca href=\"#B76\"\u003E76\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003ETo date, data in pediatric age are sparse, epidemiological evidence comes from adult population, and potential mechanisms have been investigated only in mice. However, it might be hypothesized that these processes might initiate already during childhood.\u003C\u002Fp\u003E\n\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConclusions\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EObesity is a major risk factor for allergic, autoimmune, and neoplastic diseases, and it is at least in part responsible for the recent burden of these disorders. Dysfunctional adipose tissue is the key pathogenic factor leading to this association. However, to date, a small number of studies have addressed this issue in obese children and adolescents; therefore, more studies are needed to confirm these observations and to understand the complex interplay between adipose tissue and immune system. The gain in knowledge in metainflammation patterns and mediators might allow the development of novel treatments for pediatric obesity. To date, there are no studies evaluating inflammatory targets in the treatment of pediatric obesity. However, PPAR-γ and PPAR-α agonists have shown to modulate monocyte function in activated human adipose tissue \u003Ci\u003Ein vitro\u003C\u002Fi\u003E. Moreover, they reduced the release of pro-inflammatory mediators and expression of adhesion molecules in monocytes (\u003Ca href=\"#B77\"\u003E77\u003C\u002Fa\u003E). Therefore, they could represent a promising tool in the treatment of obesity-related inflammation and insulin resistance.\u003C\u002Fp\u003E\n\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EGU and IB wrote the manuscript. CP and ET selected the articles. AM and DL realized the figures. EM revised the manuscript.\u003C\u002Fp\u003E\n\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\n\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\n\u003Cdiv class=\"References\" style=\"margin-bottom:0.5em; margin-left:2em;\"\u003E\n\u003Cp class=\"ReferencesCopy1\" style=\"margin-left:0.7em; text-indent:-1.1em;\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E 1. NCD Risk Factor Collaboration. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. \u003Ci\u003ELancet\u003C\u002Fi\u003E. 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Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)alpha\u002Fgamma agonist aleglitazar in attenuating TNF-alpha-mediated inflammation and insulin resistance in human adipocytes. \u003Ci\u003EPharmacol Res.\u003C\u002Fi\u003E (2016) 107:125–36. doi: 10.1016\u002Fj.phrs.2016.02.027\u003C\u002Fp\u003E\n\u003Cp style=\"margin-left:1em;\" class=\"ReferencesCopy2\"\u003E\u003Ca href=\"http:\u002F\u002Fwww.ncbi.nlm.nih.gov\u002Fsites\u002Fentrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=26976796\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.phrs.2016.02.027\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M+Massaro&author=E+Scoditti&author=M+Pellegrino&author=MA+Carluccio&author=N+Calabriso&author=M+Wabitsch+&publication_year=2016&title=Therapeutic+potential+of+the+dual+peroxisome+proliferator+activated+receptor+(PPAR)alpha%2Fgamma+agonist+aleglitazar+in+attenuating+TNF-alpha-mediated+inflammation+and+insulin+resistance+in+human+adipocytes&journal=Pharmacol+Res.&volume=107&pages=125-36\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"AbstractSummary\"\u003E\n\u003Cp\u003E\u003Cspan\u003EKeywords:\u003C\u002Fspan\u003E obesity, immune system, inflammation, adipokines, atopy, autoimmune diseases\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Umano GR, Pistone C, Tondina E, Moiraghi A, Lauretta D, Miraglia del Giudice E and Brambilla I (2019) Pediatric Obesity and the Immune System. \u003Ci\u003EFront. Pediatr.\u003C\u002Fi\u003E 7:487. doi: 10.3389\u002Ffped.2019.00487\u003C\u002Fp\u003E\n\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 28 May 2019; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 06 November 2019;\u003Cbr\u003E \u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 22 November 2019.\u003C\u002Fp\u003E\n\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F23588\u002Foverview\"\u003ELuigi Daniele Notarangelo\u003C\u002Fa\u003E, National Institute of Allergy and Infectious Diseases (NIAID), United States\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F470792\u002Foverview\"\u003ESigrun Ruth Hofmann\u003C\u002Fa\u003E, Universitätsklinikum Carl Gustav Carus, Germany\u003Cbr\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F629496\u002Foverview\"\u003EEugênia Terra Granado\u003C\u002Fa\u003E, Brazilian National Cancer Institute (INCA), Brazil\u003C\u002Fdiv\u003E\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2019 Umano, Pistone, Tondina, Moiraghi, Lauretta, Miraglia del Giudice and Brambilla. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Giuseppina Rosaria Umano, \u003Ca id=\"encmail\"\u003EZ2l1c2VwcGluYXJvc2FyaWEudW1hbm9AdW5pY2FtcGFuaWEuaXQ=\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EObesity and Inflammation\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003EAdipokines as Immune Modulators\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EObesity, Atopy, and Asthma\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EObesity and Autoimmunity\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EObesity and Cancer\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h8\"\u003EConclusions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h9\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h10\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h11\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E"},files:[{name:"EPUB.epub",fileServerPackageEntryId:g,type:{code:aC,name:aC}},{name:aD,fileServerPackageEntryId:"fped-07-00487\u002Ffped-07-00487.pdf",type:{code:s,name:s}},{name:aD,fileServerPackageEntryId:g,type:{code:s,name:s}},{name:"fped-07-00487.xml",fileServerPackageEntryId:"fped-07-00487\u002Ffped-07-00487.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional 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Emanuele"},{hid:"citation_author_institution_5",name:q,content:R},{hid:"citation_author_6",name:p,content:"Brambilla, Ilaria"},{hid:"citation_author_institution_6",name:q,content:"Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 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In addition to metabolic and cardiovascular obesity-related diseases, recent evidence suggested that obesity might affect immune system function. Adipose tissue is considered an endocrine organ that actively secretes cytokines also referred to as “adipokines.” Adipokines play an important role in the control of human metabolism. The dysfunctional adipose tissue in obese individuals is characterized by an altered cytokine secretion pattern that promotes chronic low-grade inflammation. Epidemiological evidence highlights the association between obesity and allergic and immune-mediated diseases, such as asthma, allergic rhinitis, rheumatic arthritis, and psoriasis. Less is known about underlying pathogenic mechanisms. However, several recent \u003Citalic\u003Ein vivo\u003C\u002Fitalic\u003E and \u003Citalic\u003Ein vitro\u003C\u002Fitalic\u003E studies have reported that adipokines are involved in inflammatory and autoimmune disorders by influencing both innate and acquired immune responses. In addition, obesity has been associated with reduced immune surveillance and increased risk of cancer. This paper reviews the evidence regarding the role of adipokines in immune system regulation, with particular emphasis on autoimmune, allergic, and inflammatory disorders. Understanding how obesity affects immune system functions may enable researchers to find new potential therapeutic targets in the management of allergic and autoimmune diseases.\u003C\u002Fp\u003E",748093,"Giuseppina Rosaria","Carmelo",850798,"Enrico",851025,"Alice",850834,"Daria",666582,"Emanuele",850848,"Ilaria",23588,470792,629516,"Eugenia",{},791,"Pediatric Immunology","pediatric-immunology","EPUB","fped-07-00487.pdf","Frontiers | Pediatric Obesity and the Immune System","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpediatrics\u002Farticles\u002F10.3389\u002Ffped.2019.00487\u002Ffull","Obesity has reached pandemic proportion and represents a major risk for several comorbidities. 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