A negative feedback loop between TET2 and leptin in adipocyte regulates body weight
Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46783-x |
| _version_ | 1797219705091522560 |
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| author | Qin Zeng Jianfeng Song Xiaoxiao Sun Dandan Wang Xiyan Liao Yujin Ding Wanyu Hu Yayi Jiao Wuqian Mai Wufuer Aini Fanqi Wang Hui Zhou Limin Xie Ying Mei Yuan Tang Zhiguo Xie Haijing Wu Wei Liu Tuo Deng |
| author_facet | Qin Zeng Jianfeng Song Xiaoxiao Sun Dandan Wang Xiyan Liao Yujin Ding Wanyu Hu Yayi Jiao Wuqian Mai Wufuer Aini Fanqi Wang Hui Zhou Limin Xie Ying Mei Yuan Tang Zhiguo Xie Haijing Wu Wei Liu Tuo Deng |
| author_sort | Qin Zeng |
| collection | DOAJ |
| description | Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity. |
| first_indexed | 2024-04-24T12:37:53Z |
| format | Article |
| id | doaj.art-fcb87b2f32094238a0283b1fb7d3cb6e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:37:53Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fcb87b2f32094238a0283b1fb7d3cb6e2024-04-07T11:24:41ZengNature PortfolioNature Communications2041-17232024-04-0115111710.1038/s41467-024-46783-xA negative feedback loop between TET2 and leptin in adipocyte regulates body weightQin Zeng0Jianfeng Song1Xiaoxiao Sun2Dandan Wang3Xiyan Liao4Yujin Ding5Wanyu Hu6Yayi Jiao7Wuqian Mai8Wufuer Aini9Fanqi Wang10Hui Zhou11Limin Xie12Ying Mei13Yuan Tang14Zhiguo Xie15Haijing Wu16Wei Liu17Tuo Deng18National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityDepartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South UniversityDepartment of Biliopancreatic Surgery and Bariatric Surgery, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South UniversityAbstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.https://doi.org/10.1038/s41467-024-46783-x |
| spellingShingle | Qin Zeng Jianfeng Song Xiaoxiao Sun Dandan Wang Xiyan Liao Yujin Ding Wanyu Hu Yayi Jiao Wuqian Mai Wufuer Aini Fanqi Wang Hui Zhou Limin Xie Ying Mei Yuan Tang Zhiguo Xie Haijing Wu Wei Liu Tuo Deng A negative feedback loop between TET2 and leptin in adipocyte regulates body weight Nature Communications |
| title | A negative feedback loop between TET2 and leptin in adipocyte regulates body weight |
| title_full | A negative feedback loop between TET2 and leptin in adipocyte regulates body weight |
| title_fullStr | A negative feedback loop between TET2 and leptin in adipocyte regulates body weight |
| title_full_unstemmed | A negative feedback loop between TET2 and leptin in adipocyte regulates body weight |
| title_short | A negative feedback loop between TET2 and leptin in adipocyte regulates body weight |
| title_sort | negative feedback loop between tet2 and leptin in adipocyte regulates body weight |
| url | https://doi.org/10.1038/s41467-024-46783-x |
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