INSERM, Saint-Antoine Research Center, Sorbonne University, Paris, France.
Hospital-Universitary Institute, Institute of Cardiometabolism and Nutrition, Paris, France.
Diabetes. 2019 Feb;68(2):305-317. doi: 10.2337/db17-1577. Epub 2018 Nov 19.
Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications has not been elucidated. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR knockout [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators.
糖皮质激素因其抗炎和免疫抑制特性而被广泛应用，但它们也会导致糖尿病和脂肪营养不良的发生。尽管越来越多的研究集中在脂肪细胞糖皮质激素受体（GR）上，但它在这些并发症的分子机制中的确切作用尚未阐明。为了实现这一目标，我们构建了一种条件性脂肪细胞特异性 GR 缺失（AdipoGR 敲除 [KO] 小鼠）的小鼠模型。有趣的是，当给予皮质酮处理以模拟高皮质醇状态时，AdipoGR-KO 小鼠表现出改善的葡萄糖耐量和胰岛素敏感性。这与脂肪组织中胰岛素信号通路的脂肪特异性激活有关，该激活导致脂肪量增加，并导致脂肪组织中抗炎型巨噬细胞极化的转变。此外，这些小鼠还能防止肝脏内异位脂质积累，并改善脂质谱，从而改善其整体健康表型。总之，我们的研究结果表明，脂肪细胞 GR 是脂肪组织扩张和葡萄糖及脂质代谢控制的关键因素，在进一步设计脂肪细胞 GR 选择性调节剂时应考虑这一点。
