Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity
Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity
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DOI：
10.1038/nm1071
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发表时间：
2004-07-01
期刊：
影响因子：
82.9
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Mori, H;Hanada, R;Yoshimura, A
瘦素是一种脂肪细胞衍生的激素，在能量稳态中发挥着关键作用，但对瘦素的抵抗是大多数人类和啮齿动物肥胖病例的一个特征。体外分析表明细胞因子信号传导抑制因子 3 (Socs3) 是参与瘦素抵抗的瘦素信号传导的负反馈调节因子。为了确定 Socs3 在体内的功能意义，我们使用 Cre-loxP 系统生成了神经细胞特异性 SOCS3 条件敲除小鼠。与野生型同窝小鼠相比，Socs3缺陷小鼠表现出瘦素诱导的下丘脑Stat3酪氨酸磷酸化以及阿黑皮素原（POMC）诱导增强，这导致了更大的体重减轻和食物摄入抑制。此外，Socs3缺陷的小鼠对高脂肪饮食引起的体重增加和高瘦素血症具有抵抗力，并且保留了胰岛素敏感性。这些数据表明 Socs3 是饮食诱导的瘦素以及胰岛素抵抗的关键调节因子。我们的研究证明了 Socs3 在体内瘦素信号传导中的负调节作用，因此抑制大脑中的 Socs3 是治疗肥胖症瘦素抵抗的潜在疗法。
Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.