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HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes | bioRxiv
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This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="DC.Contributor" content="Hongchen Li" /> <meta name="DC.Contributor" content="Xinchao Zhang" /> <meta name="DC.Contributor" content="Xiaoben Liang" /> <meta name="DC.Contributor" content="Shuyan Li" /> <meta name="DC.Contributor" content="Ziyi Cui" /> <meta name="DC.Contributor" content="Xinyu Zhao" /> <meta name="DC.Contributor" content="Kai Wang" /> <meta name="DC.Contributor" content="Bingbing Zha" /> <meta name="DC.Contributor" content="Haijie Ma" /> <meta name="DC.Contributor" content="Ming Xu" /> <meta name="DC.Contributor" content="Lei Lv" /> <meta name="DC.Contributor" content="Yanping Xu" /> <meta name="article:published_time" content="2025-02-12" /> <meta name="article:section" content="Confirmatory Results" /> <meta name="citation_title" content="HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes" /> <meta name="citation_abstract" lang="en" content="<p>The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.</p>" /> <meta name="citation_journal_title" content="bioRxiv" /> <meta name="citation_publisher" content="Cold Spring Harbor Laboratory" /> <meta name="citation_publication_date" content="2025/01/01" /> <meta name="citation_mjid" content="biorxiv;2024.09.29.615677v2" /> <meta name="citation_id" content="2024.09.29.615677v2" /> <meta name="citation_public_url" content="https://www.biorxiv.org/content/10.1101/2024.09.29.615677v2" /> <meta name="citation_abstract_html_url" content="https://www.biorxiv.org/content/10.1101/2024.09.29.615677v2.abstract" /> <meta name="citation_full_html_url" content="https://www.biorxiv.org/content/10.1101/2024.09.29.615677v2.full" /> <meta name="citation_pdf_url" content="https://www.biorxiv.org/content/biorxiv/early/2025/02/12/2024.09.29.615677.full.pdf" /> <meta name="citation_doi" content="10.1101/2024.09.29.615677" /> <meta name="citation_num_pages" content="35" /> <meta name="citation_article_type" content="Article" /> <meta name="citation_section" content="Confirmatory Results" /> <meta name="citation_firstpage" content="2024.09.29.615677" /> <meta name="citation_author" content="Hongchen Li" /> <meta name="citation_author_institution" content="Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University" /> <meta name="citation_author" content="Xinchao Zhang" /> <meta name="citation_author_institution" content="Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University" /> <meta 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content="lvlei@fudan.edu.cn" /> <meta name="citation_author_email" content="mixu@uchc.edu" /> <meta name="citation_author_email" content="haijie215@163.com" /> <meta name="citation_author" content="Ming Xu" /> <meta name="citation_author_institution" content="Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota" /> <meta name="citation_author_institution" content="Institute on the Biology of Aging and Metabolism, University of Minnesota" /> <meta name="citation_author_email" content="yanpingxu@tongji.edu.cn" /> <meta name="citation_author_email" content="lvlei@fudan.edu.cn" /> <meta name="citation_author_email" content="mixu@uchc.edu" /> <meta name="citation_author_email" content="haijie215@163.com" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-4477-939X" /> <meta name="citation_author" content="Lei Lv" /> <meta name="citation_author_institution" content="MOE Key Laboratory of Metabolism and Molecular Medicine, Department of 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Nucleic Acids Res. 2017;45(W1):W98–W102." /> <meta name="twitter:title" content="HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes" /> <meta name="twitter:site" content="@biorxivpreprint" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="twitter:description" content="The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="og-title" property="og:title" content="HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes" /> <meta name="og-url" property="og:url" content="https://www.biorxiv.org/content/10.1101/2024.09.29.615677v2" /> <meta name="og-site-name" property="og:site_name" content="bioRxiv" /> <meta name="og-description" property="og:description" content="The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="citation_date" content="2025-02-12" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/10.1101/2024.09.29.615677v2.ppt" /> <meta name="description" content="bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution" /> <meta name="generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://www.biorxiv.org/content/10.1101/2024.09.29.615677v2" 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data-apath="/biorxiv/early/2025/02/12/2024.09.29.615677.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-biorxiv-article-top clearfix has-author-tooltip" > <span class="biorxiv-article-type"> Confirmatory Results </span> <h1 class="highwire-cite-title" id="page-title">HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes</h1> <div class="highwire-cite-authors" ><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">Hongchen</span> <span class="nlm-surname">Li</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">Xinchao</span> <span class="nlm-surname">Zhang</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">Xiaoben</span> <span class="nlm-surname">Liang</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">Shuyan</span> <span class="nlm-surname">Li</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">Ziyi</span> <span class="nlm-surname">Cui</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">Xinyu</span> <span class="nlm-surname">Zhao</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">Kai</span> <span class="nlm-surname">Wang</span></span>, <span class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">Bingbing</span> <span class="nlm-surname">Zha</span></span>, <span class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">Haijie</span> <span class="nlm-surname">Ma</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="9"><a href="http://orcid.org/0000-0002-4477-939X" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Ming</span> <span class="nlm-surname">Xu</span></span>, <span class="highwire-citation-author" data-delta="10"><span class="nlm-given-names">Lei</span> <span class="nlm-surname">Lv</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="11"><a href="http://orcid.org/0000-0003-2750-5466" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Yanping</span> <span class="nlm-surname">Xu</span></span></span></div> <div class="highwire-cite-metadata" ><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">doi:</span> https://doi.org/10.1101/2024.09.29.615677 </span></div> </div> <div id="hw-article-author-popups-node-4405476--2849034516" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Hongchen Li </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University</span>, Shanghai 200092, <span class='nlm-country'>China</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Hongchen%2BLi%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Li%20H&link_type=AUTHORSEARCH" 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Molecular Biology, School of Basic Medical Sciences, Fudan University</span>, Shanghai 200032, <span class='nlm-country'>China</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Xinchao%2BZhang%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Zhang%20X&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AXinchao%2BZhang%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">Xiaoben Liang </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University</span>, Shanghai 200092, <span class='nlm-country'>China</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Xiaoben%2BLiang%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Liang%20X&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AXiaoben%2BLiang%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">Shuyan Li </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine</span>, Shanghai 200000, <span class='nlm-country'>China</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Shuyan%2BLi%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Li%20S&link_type=AUTHORSEARCH" 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class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>4</span><span class='nlm-institution'>Department of Endocrinology, Fifth People’s Hospital of Shanghai, Fudan University</span>, Shanghai, 200240, <span class='nlm-country'>China</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Kai%2BWang%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Wang%20K&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AKai%2BWang%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this 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Aging and Metabolism, University of Minnesota</span>, Minneapolis, MN, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ming%2BXu%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Xu%20M&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AMing%2BXu%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link"><a href="http://orcid.org/0000-0002-4477-939X" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Ming 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class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2 class="">Abstract</h2><p id="p-3">The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.</p></div><h3>Competing Interest Statement</h3><p id="p-4">The authors have declared no competing interest.</p><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn-update fn-group-summary-of-updates" id="fn-2"><p id="p-5">The studies are very mechanistic,indicating that this interaction occurs via demethylation of HNF4a. Phosphorylation of HNF4a at ser 313 induced by metformin also controls the interaction between Tet2 and FBP1.Following reviewer suggestion, we added the details in method section, including the generation of whole-body Tet2 KO mice and liver-specific Tet2 knockdown mice (AAV8-shTet2), the missing information of reagent, antibody, primer sequences and mutant generation, and the methods of chromatin immunoprecipitation (ChIP) and immunofluorescence. The interpretation of the results was also further developed according to reviewer comments.All the comments from reviewers have been addressed to satisfy their concerns.</p></li></ul></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-biorxiv-copyright" > <div class="pane-content"> <div class="field field-name-field-highwire-copyright field-type-text field-label-inline clearfix"><div class="field-label">Copyright </div><div class="field-items"><div class="field-item even">The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.<span class="license-type"> It is made available under a <a href="http://creativecommons.org/licenses/by/4.0/" class="" data-icon-position="" data-hide-link-title="0">CC-BY 4.0 International license</a>.</span></div></div></div> </div> </div> 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