Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), F-75013, Paris, France.
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, F-75012, Paris, France.
J Steroid Biochem Mol Biol. 2019 Jan;185:150-162. doi: 10.1016/j.jsbmb.2018.08.010. Epub 2018 Aug 23.
Insulin resistance is frequently present in patients with glucocorticoid (GC) excess (Cushing's syndrome) or treated with high doses of GCs. Furthermore, others similarities between metabolic syndrome (visceral obesity, elevated blood glucose levels, dyslipidemia) and Cushing's syndrome suggest that GCs could play a role in obesity-linked complications. Here we reported that long-term corticosterone (CORT) exposure in mice induced weight gain, dyslipidemia as well as hyperglycaemia and systemic insulin resistance. CORT-treated mice exhibited an increased 11β-Hsd1 expression and corticosterone levels in fat depots but a specific upregulation of glucocorticoid receptor (Gr) and hexose-6-phosphate dehydrogenase only in gonadal adipose tissue, suggesting that GC could act differentially on various fat depots. Despite fat accumulation in all depots, an increased expression of adipogenic (Pparγ, C/ebpα) and lipogenic (Acc, Fas) key genes was restricted to gonadal adipose tissue. Hypertrophied adipocytes observed in both visceral and subcutaneous depots also resulted from reduced lipolytic activity due to CORT treatment. Surprisingly, GC treatment promoted macrophage infiltration (F4/80, Cd68) within all adipose tissues along with predominant M2-like macrophage phenotype, and can directly act on macrophages to induce this phenotype. Moreover, macrophage infiltration preceded mass gain and adipocyte hypertrophy. Of note, specific macrophage depletion in gonadal fat preferentially reduced the M2-like macrophage content, and partially restored insulin sensitivity in mice with GC-induced obesity and insulin resistance. These data provide evidence that GCs act on adipose tissue in a depot-dependent manner and that gonadal adipose macrophages are key effectors of GC-associated insulin resistance.
胰岛素抵抗在糖皮质激素（GC）过多（库欣综合征）或接受高剂量 GC 治疗的患者中经常出现。此外，代谢综合征（内脏肥胖、血糖升高、血脂异常）和库欣综合征之间的其他相似之处表明，GC 可能在肥胖相关并发症中发挥作用。在这里，我们报告说，长期给予小鼠皮质酮（CORT）会导致体重增加、血脂异常以及高血糖和全身胰岛素抵抗。CORT 处理的小鼠在脂肪组织中表现出 11β-Hsd1 表达和皮质酮水平升高，但在性腺脂肪组织中特异性地上调糖皮质激素受体（Gr）和己糖激酶 6 磷酸脱氢酶，表明 GC 可能对不同的脂肪组织发挥不同的作用。尽管所有脂肪组织都有脂肪堆积，但脂肪生成（Pparγ、C/ebpα）和脂生成（Acc、Fas）关键基因的表达增加仅限于性腺脂肪组织。在内脏和皮下脂肪组织中观察到的肥大脂肪细胞也由于 CORT 处理而导致脂肪分解活性降低。令人惊讶的是，GC 处理会促进所有脂肪组织中的巨噬细胞浸润（F4/80、Cd68），并伴有主要的 M2 样巨噬细胞表型，并且可以直接作用于巨噬细胞诱导这种表型。此外，巨噬细胞浸润先于体重增加和脂肪细胞肥大。值得注意的是，性腺脂肪中特定的巨噬细胞耗竭会优先降低 M2 样巨噬细胞含量，并部分恢复 GC 诱导肥胖和胰岛素抵抗小鼠的胰岛素敏感性。这些数据提供了证据表明，GC 以脂肪组织依赖的方式作用于脂肪组织，并且性腺脂肪巨噬细胞是 GC 相关胰岛素抵抗的关键效应物。
