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雄激素受体对瘦素信号转导子和转录激活子3信号的功能增强作用。

Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor.

作者信息

Fan WuQiang, Yanase Toshihiko, Nishi Yoshihiro, Chiba Seiichi, Okabe Taijiro, Nomura Masatoshi, Yoshimatsu Hironobu, Kato Shigeaki, Takayanagi Ryoichi, Nawata Hajime

机构信息

Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.

出版信息

Endocrinology. 2008 Dec;149(12):6028-36. doi: 10.1210/en.2008-0431. Epub 2008 Aug 14.

Abstract

Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.

摘要

性腺功能减退与男性体脂增加及代谢稳态失调有关。我们之前的研究表明,雄激素受体(AR)缺失的雄性小鼠(ARL - /Y)会出现迟发性肥胖且对瘦素抵抗。本研究评估了下丘脑AR如何影响中枢瘦素信号转导及转录激活因子3(STAT3)信号通路。我们评估了野生型和ARL - /Y小鼠中的瘦素作用、下丘脑AR与瘦素信号通路之间的解剖学共关系,以及AR对瘦素介导的STAT3转录激活和核转位的影响。雄性小鼠AR缺失导致在明显肥胖发生之前,瘦素诱导的食物摄入抑制和体重下降作用减弱。在野生型雄性而非雌性小鼠中,AR在下丘脑的多个核团中高表达,这些核团也表达长型瘦素受体(OBRB),并且直接与OBRB共同存在于弓状核神经元中。在体外,AR显著增强了STAT3介导的包括POMC和SOCS3在内的瘦素靶基因的转录。这种作用依赖于AR的N端激活功能-1(AF - 1)结构域,并且对AR具有特异性,因为所测试的其他性类固醇激素受体均未显示出类似作用。AR在体外增强了低浓度瘦素诱导的STAT3核转位,接受瘦素的ARL - /Y小鼠弓状核神经元中的STAT3核定位受损。这些发现表明,下丘脑AR作为中枢瘦素 - OBRB - STAT3信号通路的调节因子,在雄性小鼠的能量稳态和代谢调节中具有生理作用。

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