Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor
Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor
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DOI：
10.1210/en.2008-0431
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Nawata, Hajime
中科院分区：
文献类型：
--
作者：
Fan, WuQiang;Yanase, Toshihiko;Nawata, Hajime
性腺功能减退症与男性脂肪质量增加和代谢平衡失调有关。我们先前的研究表明，雄激素受体(AR)缺失的雄性小鼠(AR(L-/Y))会出现迟发性肥胖，并且对瘦素具有抵抗力。本研究评估了下丘脑AR在中枢瘦素信号转导和转录激活子3(STAT3)信号通路中的作用。我们评估了瘦素在野生型和AR(L-/Y)小鼠中的作用，AR和下丘脑瘦素信号之间的解剖相互关系，以及AR对瘦素介导的STAT3反式激活和核转位的影响。雄性小鼠的AR缺失导致瘦素诱导的较弱的食物摄入抑制和体重下降，甚至在显性肥胖开始之前就是如此。在野生型雄性而不是雌性小鼠中，AR在下丘脑的各种核中高度表达，这些核也表达长型瘦素受体(OBRB)，并直接与OBRB共存于弓状神经元。在体外，AR显著增强STAT3介导的瘦素靶基因转录，包括POMC和SOCS3。这种作用依赖于AR N末端激活功能-1(AF-1)结构域，并且是AR所特有的，因为测试的其他性类固醇激素受体都没有表现出类似的作用。AR(L-/Y)可增强低浓度瘦素诱导的STAT3在体外的核转位，AR(Leptin-/Y)小鼠可损害STAT3在弓状神经元中的定位。这些发现表明，下丘脑中的AR作为中枢Leptin-OBRB-STAT3信号的调节器，在雄性小鼠的能量平衡和代谢调节中具有生理作用。(内分泌学149：6028-6036,2008)
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 (AR(L-/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 AR(L-/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 wildtype 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 AR(L-/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. (Endocrinology 149: 6028-6036, 2008)