Sex Difference in Corticosterone-Induced Insulin Resistance in Mice
Sex Difference in Corticosterone-Induced Insulin Resistance in Mice
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DOI：
10.1210/en.2019-00194
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发表时间：
2019-10-01
期刊：
影响因子：
4.8
通讯作者：
Visser, Jenny A.
中科院分区：
文献类型：
--
作者：
Kaikaew, Kasiphak;Steenbergen, Jacobie;Visser, Jenny A.
长期暴露于糖皮质激素（GCs）会导致各种代谢紊乱。其中包括肥胖和胰岛素抵抗，因为抑制脂肪组织中的葡萄糖利用是GCs的主要功能。尽管脂肪组织分布和葡萄糖稳态是性别依赖调节的，但尚未评估gc是否以性别依赖的方式影响糖代谢和脂肪组织功能。在本研究中，C57BU6J小鼠的高剂量皮质酮（啮齿动物GC）治疗仅在雄性小鼠中导致非空腹高血糖，而两性均表现出空腹血糖水平正常的高胰岛素血症，表明胰岛素抵抗。使用稳定同位素标记葡萄糖技术的代谢测试揭示了性别特异性皮质酮驱动的葡萄糖不耐受。皮质酮治疗增加了两性的脂肪组织质量，这反映在血清瘦素水平升高上。然而，雌性小鼠比雄性小鼠表现出更多的脂肪组织代谢保护适应性，表现为更高的血清总脂联素和高分子量脂联素水平，更多的增生性形态学改变，以及更强的脂肪生成分化标记物mRNA表达增加。随后，对3T3-L1（白色）和T37i（棕色）脂肪细胞的体外研究表明，瘦素和脂联素水平的升高主要是由胰岛素水平升高引起的。总之，本研究表明，gc诱导的胰岛素抵抗在雄性小鼠中比雌性小鼠更严重，这可以部分解释为脂肪组织的性别依赖性适应。
Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sexdependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BU6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.