Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice
Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice
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DOI：
10.1016/j.cmet.2005.07.004
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发表时间：
2005-08-01
期刊：
影响因子：
29
通讯作者：
Rui, LY
中科院分区：
文献类型：
--
作者：
Ren, DC;Li, MH;Rui, LY
瘦素通过激活其受体LEPR和多个下游信号通路来调节能量平衡和体重，包括STAT3和下丘脑中的IRS2/PI 3-激酶途径。瘦素刺激LEPRB相关的JAK2的激活，该JAK2引发了细胞信号。在这里，我们将SH2-B（一种JAK2相互作用的蛋白质）确定为瘦素灵敏度，能量平衡和体重的关键调节剂。 SH2-B纯合子零小鼠严重倍增和肥胖，并发展出一种代谢综合征，其特征是高血治，高胰岛素血症，高脂血症，肝脂肪变性和高血糖。在SH2-B - / - 小鼠中，下丘脑原性NPY和AGRP的表达增加。在SH2-B - / - 小鼠中，下丘脑JAK2和下丘脑STAT3和IRS2的磷酸化激活以及下丘脑STAT3和IRS2的磷酸化的激活显着受损。此外，SH2-B的过表达对培养细胞中瘦素信号传导的抑制作用。我们的数据表明，SH2-B是瘦素敏感性的内源性增强子，是维持小鼠正常能量代谢和体重所必需的。
Leptin regulates energy balance and body weight by activating its receptor LEPRb and multiple downstream signaling pathways, including the STAT3 and the IRS2/PI 3-kinase pathways, in the hypothalamus. Leptin stimulates activation of LEPRb-associated JAK2, which initiates cell signaling. Here we identified SH2-B, a JAK2-interacting protein, as a key regulator of leptin sensitivity, energy balance, and body weight. SH2-B homozygous null mice were severely hyperphagic and obese and developed a metabolic syndrome characterized by hyperleptinemia, hyperinsulinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. The expression of hypothalamic orexigenic NPY and AgRP was increased in SH2-B-/- mice. Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hypothalamic STAT3 and IRS2 were significantly impaired in SH2-B-/- mice. Moreover, overexpression of SH2-B counteracted PTP1B-mediated inhibition of leptin signaling in cultured cells. Our data suggest that SH2-B is an endogenous enhancer of leptin sensitivity and required for maintaining normal energy metabolism and body weight in mice.