Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice
Summary: Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels are increased in the context of obesity. Recombinant GDF15 reduces body weight and improves glycemia in obese models, which is largely attributed to the central action of GDF15 to suppress...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222018417 |
| _version_ | 1797987161115459584 |
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| author | Bingxian Xie Anjana Murali Amber M. Vandevender Jeffrey Chen Agustin Gil Silva Fiona M. Bello Byron Chuan Harinath Bahudhanapati Ian Sipula Nikolaos Dedousis Faraaz A. Shah Christopher P. O’Donnell Jonathan K. Alder Michael J. Jurczak |
| author_facet | Bingxian Xie Anjana Murali Amber M. Vandevender Jeffrey Chen Agustin Gil Silva Fiona M. Bello Byron Chuan Harinath Bahudhanapati Ian Sipula Nikolaos Dedousis Faraaz A. Shah Christopher P. O’Donnell Jonathan K. Alder Michael J. Jurczak |
| author_sort | Bingxian Xie |
| collection | DOAJ |
| description | Summary: Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels are increased in the context of obesity. Recombinant GDF15 reduces body weight and improves glycemia in obese models, which is largely attributed to the central action of GDF15 to suppress feeding and reduce body weight. Despite these advances in knowledge, the tissue-specific sites of GDF15 production during obesity are unknown, and the effects of modulating circulating GDF15 levels on insulin sensitivity have not been evaluated directly. Here, we demonstrate that hepatocyte Gdf15 expression is sufficient for changes in circulating levels of GDF15 during obesity and that restoring Gdf15 expression specifically in hepatocytes of Gdf15 knockout mice results in marked improvements in hyperinsulinemia, hepatic insulin sensitivity, and to a lesser extent peripheral insulin sensitivity. These data support that liver hepatocytes are the primary source of circulating GDF15 in obesity. |
| first_indexed | 2024-04-11T07:44:16Z |
| format | Article |
| id | doaj.art-be2159910df74c8da53dc69784e093fc |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-11T07:44:16Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-be2159910df74c8da53dc69784e093fc2022-12-22T04:36:23ZengElsevieriScience2589-00422022-12-012512105569Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese miceBingxian Xie0Anjana Murali1Amber M. Vandevender2Jeffrey Chen3Agustin Gil Silva4Fiona M. Bello5Byron Chuan6Harinath Bahudhanapati7Ian Sipula8Nikolaos Dedousis9Faraaz A. Shah10Christopher P. O’Donnell11Jonathan K. Alder12Michael J. Jurczak13Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding authorDivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding authorSummary: Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels are increased in the context of obesity. Recombinant GDF15 reduces body weight and improves glycemia in obese models, which is largely attributed to the central action of GDF15 to suppress feeding and reduce body weight. Despite these advances in knowledge, the tissue-specific sites of GDF15 production during obesity are unknown, and the effects of modulating circulating GDF15 levels on insulin sensitivity have not been evaluated directly. Here, we demonstrate that hepatocyte Gdf15 expression is sufficient for changes in circulating levels of GDF15 during obesity and that restoring Gdf15 expression specifically in hepatocytes of Gdf15 knockout mice results in marked improvements in hyperinsulinemia, hepatic insulin sensitivity, and to a lesser extent peripheral insulin sensitivity. These data support that liver hepatocytes are the primary source of circulating GDF15 in obesity.http://www.sciencedirect.com/science/article/pii/S2589004222018417Cellular physiologyMolecular geneticsDiabetology |
| spellingShingle | Bingxian Xie Anjana Murali Amber M. Vandevender Jeffrey Chen Agustin Gil Silva Fiona M. Bello Byron Chuan Harinath Bahudhanapati Ian Sipula Nikolaos Dedousis Faraaz A. Shah Christopher P. O’Donnell Jonathan K. Alder Michael J. Jurczak Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice iScience Cellular physiology Molecular genetics Diabetology |
| title | Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice |
| title_full | Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice |
| title_fullStr | Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice |
| title_full_unstemmed | Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice |
| title_short | Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice |
| title_sort | hepatocyte derived gdf15 suppresses feeding and improves insulin sensitivity in obese mice |
| topic | Cellular physiology Molecular genetics Diabetology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222018417 |
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