Neuronal SH2B1 is essential for controlling energy and glucose homeostasis
Neuronal SH2B1 is essential for controlling energy and glucose homeostasis
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DOI：
10.1172/jci29417
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发表时间：
2007-02-01
影响因子：
15.9
通讯作者：
Rui, Liangyou
中科院分区：
文献类型：
--
作者：
Ren, Decheng;Zhou, Yingjiang;Rui, Liangyou
SH2B1（先前称为SH2-B）是一种细胞质衔接蛋白，通过其SRC同源性2（SH2）结构域结合了各种蛋白质酪氨酸激酶，包括JAK2和胰岛素受体。 SH2B1缺陷小鼠肥胖和糖尿病患者。在这里，我们证明了SH2B1（Alpha，Beta，Gamma和/或Delta）的多种同工型在许多组织中表达，包括大脑，下丘脑，肝脏，肌肉，肌肉，脂肪组织，心脏和胰腺。大鼠SH2B1β在SH2B1-转基因（SH2B1（TG））小鼠中的神经组织中特异性表达。将SH2B1（TG）小鼠与SH2B1-敲除（SH2B1（KO））小鼠交叉，以生成仅在神经组织中但在其他组织中表达SH2B1的SH2B1（TGKO）小鼠。 SH2B1基因的全身缺失导致SH2B1（KO）小鼠的代谢性疾病，包括高脂血症，瘦素耐药性，心晶状体，肥胖，高血糖，胰岛素耐药性和葡萄糖不耐症。 SH2B1β的神经元特异性恢复不仅纠正了SH2B1（TGKO）小鼠中的代谢性疾病，而且还改善了下丘脑中原质神经肽表达的JAK2介导的瘦素信号传导和瘦素调节。此外，SH2B1剂量的神经元特异性过表达依赖性地依赖于高脂饮食诱导的瘦素耐药性和肥胖症。这些观察结果表明，神经元SH2B1调节能量平衡，体重，周围胰岛素敏感性和葡萄糖稳态至少在某种程度上通过增强下丘脑瘦素敏感性来调节。
SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1 beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1 beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved-JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.