Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3
Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3
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DOI：
10.1038/nm1072
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发表时间：
2004-07-01
期刊：
影响因子：
82.9
通讯作者：
Flier, JS
中科院分区：
文献类型：
--
作者：
Howard, JK;Cave, BJ;Flier, JS
瘦素是一种脂肪细胞来源的激素，主要通过作用于特定的下丘脑通路来调节能量平衡和神经内分泌功能（1，2）。对瘦素的减肥作用的抵抗是大多数人类和啮齿动物肥胖病例的特征（1，2），然而瘦素抵抗的分子基础知之甚少。我们先前已经鉴定了细胞因子信号传导抑制因子-3（Socs 3）作为瘦素诱导的瘦素受体信号传导的负调节因子和瘦素抗性的潜在介体（3-5）。然而，由于靶向破坏Socs 3的小鼠的非存活性（参考文献6），Socs 3在体内瘦素作用中的重要性尚不清楚。为了确定Socs 3在体内能量平衡中的功能意义，我们在具有杂合Socs 3缺陷（Socs 3（+/-））的小鼠中进行了研究。我们在这里报告说，Socs 3（+/-）小鼠表现出更大的瘦素敏感性比野生型对照小鼠：Socs 3（+/-）小鼠表现出增强的体重减轻和增加下丘脑瘦素受体信号转导响应外源性瘦素管理。此外，Socs 3（+/-）小鼠被显著保护免于饮食诱导的肥胖和相关代谢并发症的发展。因此，Socs 3表达水平是体内瘦素敏感性和肥胖易感性的关键决定因素，并且该分子是治疗干预的潜在靶标。
Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways(1,2). Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity(1,2), yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance(3-5). However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3(+/-)). We report here that Socs3(+/-) mice display greater leptin sensitivity than wild-type control mice: Socs3(+/-) mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.