Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
Endocrinology. 2019 Mar 1;160(3):504-521. doi: 10.1210/en.2018-01029.
In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome. Under chronic treatment with corticosterone, AGRKO mice underwent healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity. These changes were associated with Atgl-mediated lipolysis through a novel intronic glucocorticoid-responsive element. Additionally, integrated analysis with RNA sequencing of AGRKO mice and clinical samples revealed that healthy adipose expansion was associated with dysregulation of tissue remodeling, preadipocyte proliferation, and expression of the circadian gene. Thus, our study revealed the roles of adipocyte GR on healthy adipose expansion and its multiple mechanisms in Cushing syndrome.
在库欣综合征中，过量的糖皮质激素导致代谢紊乱，如胰岛素抵抗、脂肪细胞肥大和肝脂肪变性。体外实验强调了脂肪细胞糖皮质激素受体 (GR) 的重要性，但在库欣综合征中，其在体内的代谢作用尚未完全阐明。在这项研究中，我们使用来自库欣综合征患者的临床样本和脂肪细胞特异性 GR 敲除 (AGRKO) 小鼠，研究了脂肪细胞 GR 在库欣综合征中的作用及其临床相关性。在长期接受皮质酮治疗下，AGRKO 小鼠进行了健康的脂肪扩张，异位脂质沉积减少，胰岛素敏感性提高。这些变化与 Atgl 介导的脂肪分解有关，通过一个新的内含子糖皮质激素反应元件。此外，与 AGRKO 小鼠和临床样本的 RNA 测序的综合分析表明，健康的脂肪扩张与组织重塑、前脂肪细胞增殖和昼夜节律基因表达的失调有关。因此，我们的研究揭示了脂肪细胞 GR 在健康脂肪扩张中的作用及其在库欣综合征中的多种机制。
