Human SH2B1 mutations are associated with maladaptive behaviors and obesity
Human SH2B1 mutations are associated with maladaptive behaviors and obesity
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DOI：
10.1172/jci62696
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Farooqi, I. Sadaf
中科院分区：
文献类型：
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作者：
Doche, Michael E.;Bochukova, Elena G.;Farooqi, I. Sadaf
Src同源性2 B衔接蛋白1（SH2B1）通过结合受体酪氨酸激酶或JAK相关细胞因子受体（包括瘦素、胰岛素、生长激素（GH）和神经生长因子（NGF））的多种配体调节信号传导。靶向缺失Sh2Blm小鼠导致食物摄入增加、肥胖和胰岛素抵抗，在高脂肪饮食的杂合无效小鼠中观察到中间表型。我们在大量患有严重早发性肥胖症的患者中鉴定了SH2B1功能丧失突变。突变携带者表现出摄食过多、儿童期肥胖、不成比例的胰岛素抵抗和成年后最终身高降低。出乎意料的是，突变携带者表现出一系列在对照组中没有报道的行为异常，包括社交孤立和攻击性。我们的结论是，SH2B1起着至关重要的作用，在控制人类的食物摄入量和体重，并在适应不良的人类行为有牵连。
Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 m Mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high fat diet We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early onset obesity, Mutation carriers exhibited hyperphagia, childhood onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, Mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and-is implicated in maladaptive human behavior.