Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance.
Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance.
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作者：
Briancon N;McNay DE;Maratos-Flier E;Flier JS
脂肪因子激素瘦素在大脑中触发信号，最终导致进食减少和能量消耗增加。然而，肥胖最常与血浆瘦素水平升高和瘦素抵抗相关。细胞因子信号转导抑制因子（SOCS）-3和蛋白酪氨酸磷酸酶1B（PTP-1B）是两种内源性酪氨酸激酶信号转导抑制因子，通过不同的分子机制抑制胰岛素和瘦素信号转导。在小鼠中，这些基因的大脑特异性失活部分地防止了饮食诱导的肥胖症（DIO）和胰岛素抵抗。本研究的目的是调查这两个基因之间可能的遗传相互作用，以确定是否在这些抑制活性的协同作用，上位性，或添加剂的效果控制能量平衡的结果相结合的减少。我们产生了在脑细胞中编码SOCS-3和PTP-1B的基因联合失活的小鼠，检查了它们对激素作用的敏感性，并分析了每个基因对所得表型的贡献。令人惊讶的是，用于介导基因失活的Nestin-Cre小鼠显示出表型。尽管如此，脑中SOCS-3和PTP-1B的联合失活揭示了对几个参数的累加效应，包括对DIO的部分抗性和相关的葡萄糖耐受不良。此外，观察到的体长和体重的协同效应，这表明可能的补偿机制，没有任何抑制剂。此外，在标准饮食中发现了SOCS-3特异性瘦肉表型。这些结果表明，SOCS-3和PTP-1B的生物学作用并不完全重叠，靶向这两种因子可能会改善其抑制肥胖和2型糖尿病的治疗效果。
The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control. We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype. Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3–specific lean phenotype was revealed on the standard diet. These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.
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