Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding.
Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding.
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DOI：
10.1016/j.molmet.2017.06.013
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发表时间：
2017-10
影响因子：
8.1
通讯作者：
Rosen ED
中科院分区：
文献类型：
--
作者：
Shen Y;Roh HC;Kumari M;Rosen ED
脂肪组织在能量和营养平衡中的关键作用受到许多外部因素的影响，包括营养过剩，炎症和外源性激素。先前的研究表明，糖皮质激素（GC）特别是脂肪细胞的生理和病理生理变化的主要驱动因素。为了确定这些作用是否直接需要脂肪细胞内的糖皮质激素受体（GR），我们产生了脂肪细胞特异性GR敲除（AGRKO）小鼠。AGRKO和对照小鼠喂食普通饲料或高脂肪饮食（HFD）14周。或者，AGRKO和对照小鼠注射地塞米松两个月。评估葡萄糖耐量、胰岛素敏感性、肥胖、脂解、产热和胰岛素信号传导。我们发现与高脂肪喂养相关的肥胖、胰岛素抵抗和血糖异常并不需要脂肪细胞中完整的GR。然而，外源性地塞米松（Dex）促进小鼠的代谢功能障碍，并且这种作用在脂肪细胞中缺乏GR的小鼠中降低。在这些动物中，Dex促进棕色脂肪“变白”的能力也降低。我们还表明，GR是β-肾上腺素能和冷刺激介导的脂解所需的关键脂解酶ATGL的表达。我们的数据表明，GR通过对脂解的影响在正常脂肪生理学中起作用，并介导外源性类固醇对代谢功能的至少一些不良影响。这些数据还表明，脂肪细胞内GR在与营养过剩相关的局部和全身病理学中的作用比以前认为的要小。脂肪细胞糖皮质激素受体在肥胖诱导的胰岛素抵抗中起着令人惊讶的次要作用。脂肪细胞糖皮质激素受体部分介导地塞米松诱导的胰岛素抵抗。糖皮质激素受体介导地塞米松诱导的棕色脂肪脂质蓄积。脂肪细胞糖皮质激素受体在脂解中起关键作用。
The critical role of adipose tissue in energy and nutrient homeostasis is influenced by many external factors, including overnutrition, inflammation, and exogenous hormones. Prior studies have suggested that glucocorticoids (GCs) in particular are major drivers of physiological and pathophysiological changes in adipocytes. In order to determine whether these effects directly require the glucocorticoid receptor (GR) within adipocytes, we generated adipocyte-specific GR knockout (AGRKO) mice. AGRKO and control mice were fed chow or high fat diet (HFD) for 14 weeks. Alternatively, AGRKO and control mice were injected with dexamethasone for two months. Glucose tolerance, insulin sensitivity, adiposity, lipolysis, thermogenesis, and insulin signaling were assessed. We find that obesity, insulin resistance, and dysglycemia associated with high fat feeding do not require an intact GR in the adipocyte. However, exogenous dexamethasone (Dex) promotes metabolic dysfunction in mice, and this effect is reduced in mice lacking GR in adipocytes. The ability of Dex to promote “whitening” of brown fat is also reduced in these animals. We also show that GR is required for β-adrenergic and cold stimulation-mediated lipolysis via expression of the key lipolytic enzyme ATGL. Our data suggest that the GR plays a role in normal adipose physiology via effects on lipolysis and mediates at least some of the adverse effects of exogenous steroids on metabolic function. The data also indicate that intra-adipocyte GR plays less of a role than previously believed in the local and systemic pathology associated with overnutrition. Adipocyte glucocorticoid receptor plays a surprisingly minor role in obesity-induced insulin resistance. Adipocyte glucocorticoid receptor partially mediates dexamethasone-induced insulin resistance. Glucocorticoid receptor mediates dexamethasone-induced brown fat lipid accumulation. Adipocyte glucocorticoid receptor is critical for lipolysis.
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影响因子：
29
作者：
Eguchi, Jun;Yan, Qing-Wu;Rosen, Evan D.
通讯作者：
Rosen, Evan D.
影响因子：
29
作者：
Ramage LE;Akyol M;Fletcher AM;Forsythe J;Nixon M;Carter RN;van Beek EJ;Morton NM;Walker BR;Stimson RH
通讯作者：
Stimson RH
影响因子：
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作者：
Cat, Aurelie Nguyen Dinh;Antunes, Tayze T.;Touyz, Rhian M.
通讯作者：
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影响因子：
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作者：
van den Beukel, Johanna C.;Grefhorst, Aldo;Themmen, Axel P. N.
通讯作者：
Themmen, Axel P. N.
影响因子：
64.8
作者：
Houstis, N;Rosen, ED;Lander, ES
通讯作者：
Lander, ES