Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-κB-mediated PTP1B expression.
Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-κB-mediated PTP1B expression.
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作者：
Yu IC;Lin HY;Liu NC;Sparks JD;Yeh S;Fang LY;Chen L;Chang C
临床研究强调了接受雄激素剥夺治疗（ADT）的前列腺癌（PCa）患者中代谢综合征的发生率增加。使用全雄激素受体（AR）敲除小鼠的研究表明，AR缺乏导致男性胰岛素抵抗的发展。然而，单个器官中AR协调调节胰岛素敏感性的机制仍有待探讨。在这里，我们测试的假设，功能AR在大脑中有助于全身胰岛素敏感性调节和AR缺陷的雄性小鼠的代谢异常。建立了中枢神经系统中选择性缺乏AR的小鼠模型和表达AR的GT 1 -7神经元细胞，并用于描述AR调节胰岛素信号传导的分子机制。神经元AR缺乏导致中年小鼠胰岛素敏感性降低神经元AR通过抑制核因子-κB（NF-κB）介导的蛋白酪氨酸磷酸酶1 B（PTP 1 B）诱导来调节下丘脑胰岛素信号传导。下丘脑胰岛素抵抗导致肝脏胰岛素抵抗、脂质积聚和内脏肥胖。雄性小鼠下丘脑中AR的功能缺陷导致其更容易受到高脂饮食消耗对PTP 1 B表达和NF-κB活化的影响。这些结果表明，在接受ADT的PCa男性中，大脑中AR功能的降低可能导致胰岛素抵抗和内脏肥胖。可能开发靶向神经元AR和NF-κB的药物治疗，以对抗接受ADT的男性和患有年龄相关性性腺功能减退症的老年男性的代谢综合征。
Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)–mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.
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