Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition
Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition
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DOI：
10.2337/db16-0381
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发表时间：
2017-02-01
期刊：
影响因子：
7.7
通讯作者：
Moriggl, Richard
中科院分区：
文献类型：
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作者：
Mueller, Kristina M.;Hartmann, Kerstin;Moriggl, Richard
糖皮质激素（GC）是全身能量代谢的重要调节剂，异常GC作用与代谢功能障碍有关。然而，脂肪细胞中正常和病理生理能量代谢在多大程度上依赖于GC受体（GR）仍不清楚。在这里，我们证明了小鼠脂肪细胞GR缺乏显著影响不同能量状态下的全身代谢。血浆代谢组学和生化分析显示，GR缺乏对全身代谢物丰度有显著的全球影响，因此，在进食和禁食状态下底物分配。这与吸收后和禁食条件下GR缺陷脂肪细胞的脂解能力降低相关，这是由于β-肾上腺素能受体到腺苷酸环化酶的信号转导受损所致。在长时间禁食后，受损的脂解反应导致异常底物利用和瘦体重消耗。相反，GR缺乏减弱了衰老/饮食相关的肥胖、脂肪细胞肥大和肝脏脂肪变性。肥胖GR缺陷小鼠的全身葡萄糖耐量得到改善，这与肌肉和脂肪组织中胰岛素信号的增加有关。我们的结论是，GR在脂肪细胞发挥中央，但不同的作用，在调节代谢稳态取决于能量状态。脂肪细胞GR对于进食-禁食过渡是不可或缺的，但也会促进脂肪喂养和老年小鼠的肥胖和相关代谢紊乱。
Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from beta-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.