NRG1-Fc improves metabolic health via dual hepatic and central action.
NRG1-Fc improves metabolic health via dual hepatic and central action.
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DOI：
10.1172/jci.insight.98522
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Peng Zhang;Henry Kuang;Yanlin He;Sharon O. Idiga;Si-ming Li;Zhimin Chen;Zhao Yang;Xing Cai;Kezhong Zhang;Matthew J. Potthoff;Yong Xu;Jiandie D. Lin
中科院分区：
文献类型：
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作者：
Peng Zhang;Henry Kuang;Yanlin He;Sharon O. Idiga;Si-ming Li;Zhimin Chen;Zhao Yang;Xing Cai;Kezhong Zhang;Matthew J. Potthoff;Yong Xu;Jiandie D. Lin
神经调节蛋白(NRGs)是一类重要的调节糖脂平衡的信号配体家族。NRG1降低肥胖小鼠的血糖水平，而富含棕色脂肪的分泌因子NRG4则保护小鼠免受高脂饮食诱导的胰岛素抵抗和肝脏脂肪变性。然而，考虑到天然配体的血浆半衰期很差，NRGs的治疗潜力仍然难以捉摸。在这里，我们利用人NRG1和人IgG1的Fc结构域(NRG1-Fc)设计了一种融合蛋白，该融合蛋白在循环中表现出更长的半衰期，并提高了受体信号的效力。我们评价了其改善代谢参数的效果，并对其作用机制进行了剖析。NRG1-FC治疗在肥胖小鼠的肝脏中触发了强大的AKT激活，降低了血糖，改善了胰岛素敏感性，并抑制了食物摄入。NRG1-FC是代谢激素FGF21的有效促分泌剂；然而，后者在很大程度上是不必要的，因为它的代谢作用。NRG1-Fc直接靶向下丘脑POMC神经元，促进膜去极化，增加放电频率。总之，NRG1-FC表现出改善的药代动力学特性，并通过双重抑制肝脏糖异生和热量摄入发挥代谢优势。
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.