Mori Hiroyuki, Hanada Reiko, Hanada Toshikatsu, Aki Daisuke, Mashima Ryuichi, Nishinakamura Hitomi, Torisu Takehiro, Chien Kenneth R, Yasukawa Hideo, Yoshimura Akihiko
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nat Med. 2004 Jul;10(7):739-43. doi: 10.1038/nm1071. Epub 2004 Jun 20.
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.
瘦素是一种由脂肪细胞分泌的激素，在能量平衡中起关键作用，但对瘦素的抵抗是人类和啮齿动物大多数肥胖病例的一个特征。体外分析表明，细胞因子信号转导抑制因子3（Socs3）是参与瘦素抵抗的瘦素信号的负反馈调节因子。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条件性敲除小鼠。与野生型同窝小鼠相比，Socs3缺陷型小鼠表现出瘦素诱导的下丘脑Stat3酪氨酸磷酸化增强以及阿黑皮素原（POMC）诱导增加，这导致体重减轻更多且食物摄入量受到抑制。此外，Socs3缺陷型小鼠对高脂饮食诱导的体重增加和高瘦素血症具有抗性，并且胰岛素敏感性得以保留。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是治疗肥胖症中瘦素抵抗的一种潜在疗法。
