Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice.
Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice.
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DOI：
10.1016/j.isci.2022.105569
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发表时间：
2022-12-22
期刊：
影响因子：
5.8
通讯作者：
Jurczak, Michael J.
中科院分区：
文献类型：
--
作者：
Xie, Bingxian;Murali, Anjana;Vandevender, Amber M.;Chen, Jeffrey;Silva, Agustin Gil;Bello, Fiona M.;Chuan, Byron;Bahudhanapati, Harinath;Sipula, Ian;Dedousis, Nikolaos;Shah, Faraaz A.;O'Donnell, Christopher P.;Alder, Jonathan K.;Jurczak, Michael J.
生长分化因子15 （GDF15）是一种应激诱导的分泌蛋白，其循环水平在肥胖的情况下增加。重组GDF15在肥胖模型中降低体重和改善血糖，这在很大程度上归因于GDF15抑制摄食和降低体重的中枢作用。尽管在知识方面取得了这些进展，但肥胖期间GDF15产生的组织特异性位点尚不清楚，调节循环GDF15水平对胰岛素敏感性的影响尚未得到直接评估。在这里，我们证明肝细胞Gdf15表达足以改变肥胖期间Gdf15的循环水平，并且在Gdf15基因敲除小鼠的肝细胞中特异性地恢复Gdf15表达可显著改善高胰岛素血症、肝脏胰岛素敏感性，并在较小程度上改善外周胰岛素敏感性。这些数据支持肝细胞是肥胖患者循环GDF15的主要来源。肝细胞是肥胖期间循环GDF15的主要来源肝细胞GDF15足以逆转高脂肪饮食引起的体重增加恢复GDF15敲除小鼠的肝细胞GDF15表达改善肝脏胰岛素敏感性细胞生理；分子遗传学;糖尿病学
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. Hepatocytes are the primary source of circulating GDF15 during obesity Hepatocyte Gdf15 is sufficient to reverse high-fat diet-induced weight gain Restoring hepatocyte Gdf15 expression in Gdf15 knockout mice improves liver insulin sensitivity Cellular physiology; Molecular genetics; Diabetology
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