Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14458, Nuthetal, Germany.
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14458, Nuthetal, Germany.
Sci Rep. 2024 Nov 6;14(1):26989. doi: 10.1038/s41598-024-77448-w.
Recent research has identified growth differentiation factor 15 (GDF15) as a crucial factor in various physiological and pathological processes, particularly in energy balance regulation. While the role of GDF15 in modulating energy metabolism through hindbrain GDNF family receptor alpha-like (GFRAL) signaling has been extensively studied, emerging evidence suggests direct peripheral metabolic actions of GDF15. Using knockout mouse models, we investigated GDF15 and GFRAL's roles in adipose tissue metabolism. Our findings indicate that C57BL/6/129/SvJ Gdf15-KO mice exhibit impaired expression of de novo lipogenesis enzymes in subcutaneous adipose tissue (sWAT). In contrast, C57BL/6J Gfral-KO mice showed no impairments compared to wild-type (WT) littermates. RNA-Seq analysis of sWAT in Gdf15-KO mice revealed a broad downregulation of genes involved in lipid metabolism. Importantly, our study uncovered sex-specific effects, with females being more affected by GDF15 loss than males. Additionally, we observed a fasting-induced upregulation of GDF15 gene expression in sWAT of both mice and humans, reinforcing this factor's role in adipose tissue lipid metabolism. In conclusion, our research highlights an essential role for GDF15 in sWAT lipid metabolic homeostasis. These insights enhance our understanding of GDF15's functions in adipose tissue physiology and underscore its potential as a therapeutic target for metabolic disorders.
最近的研究表明，生长分化因子 15（GDF15）是各种生理和病理过程中的关键因素，特别是在能量平衡调节中。虽然 GDF15 通过调节下丘脑 GDNF 家族受体α样（GFRAL）信号来调节能量代谢的作用已经得到了广泛的研究，但新的证据表明 GDF15 具有直接的外周代谢作用。使用基因敲除小鼠模型，我们研究了 GDF15 和 GFRAL 在脂肪组织代谢中的作用。我们的研究结果表明，C57BL/6/129/SvJ Gdf15-KO 小鼠的皮下脂肪组织（sWAT）中从头合成脂肪生成酶的表达受损。相比之下，C57BL/6J Gfral-KO 小鼠与野生型（WT）同窝仔相比没有任何损伤。Gdf15-KO 小鼠 sWAT 的 RNA-Seq 分析显示，参与脂质代谢的基因广泛下调。重要的是，我们的研究揭示了性别特异性效应，即 GDF15 缺失对雌性的影响比雄性更大。此外，我们观察到在两种小鼠和人类的 sWAT 中，禁食诱导 GDF15 基因表达上调，进一步证实了该因子在脂肪组织脂质代谢中的作用。总之，我们的研究强调了 GDF15 在 sWAT 脂质代谢平衡中的重要作用。这些发现加深了我们对 GDF15 在脂肪组织生理学中的作用的理解，并强调了它作为代谢紊乱治疗靶点的潜力。
