Fan WuQiang, Yanase Toshihiko, Nishi Yoshihiro, Chiba Seiichi, Okabe Taijiro, Nomura Masatoshi, Yoshimatsu Hironobu, Kato Shigeaki, Takayanagi Ryoichi, Nawata Hajime
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.
Endocrinology. 2008 Dec;149(12):6028-36. doi: 10.1210/en.2008-0431. Epub 2008 Aug 14.
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.
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。