PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
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DOI：
10.1172/jci39620
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Bence, Kendra K.
中科院分区：
文献类型：
--
作者：
Banno, Ryoichi;Zimmer, Derek;Bence, Kendra K.
蛋白酪氨酸磷酸酶1B（PTP 1B）和含SH 2结构域的蛋白酪氨酸磷酸酶-2（SHP 2）已被证明在小鼠中通过中枢神经系统调节代谢，但介导这些作用的特定神经元尚不清楚。在这里，我们已经表明，前阿黑皮素（POMC）神经元特异性缺乏PTP 1B或SHP 2在小鼠中的结果在体重增加，肥胖和能量平衡的高脂肪饮食诱导的相互影响。编码PTP 1B基因的POMC神经元特异性缺失小鼠与野生型小鼠相比，POMC-Ptp 1b（-/-）小鼠（本文称为POMC-Ptp 1b（-/-）小鼠）具有减少的肥胖、改善的瘦素敏感性和增加的能量消耗，而具有编码SHP 2的基因的POMC神经元特异性缺失的小鼠（本文称为POMC-Sbp 2（-/-）小鼠）具有升高的肥胖、降低的瘦素敏感性和降低的能量消耗。POMC-Ptp 1b（-/-）小鼠在高脂饮食中显示出显著改善的葡萄糖稳态，高胰岛素-正葡萄糖钳夹研究显示，在没有任何体重差异的情况下，这些小鼠的胰岛素敏感性在标准食物饮食中得到改善。相比之下，POMC-Sbp 2（-/-）小鼠显示出仅继发于其增加的体重增加的葡萄糖耐量受损。有趣的是，POMC-Sbp 2（-/-）小鼠的下丘脑Pomc mRNA和α-黑素细胞刺激激素（α MSH）肽水平显著降低。这些研究暗示PTP 1B和SHP 2作为POMC神经元调节能量平衡的重要组成部分，并指出我们认为SHP 2在黑皮质素系统的正常功能中的新作用。
Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b(-/-) mice) had reduced adiposity improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Sbp2(-/-) mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b(-/-) mice showed substantially improved glucose homeo-stasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Sbp2(-/-) mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and alpha-melanocyte-stimulating hormone (alpha MSH) peptide levels were markedly reduced in POMC-Sbp2(-/-) mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system.