IRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action

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• 作者：Marianna Sadagurski¹ ; Rebecca  ; L. Leshan² ; Christa Patterson² ; Aldo Rozzo¹ ; Alexandra Kuznetsova¹ ; Josh Skorupski² ; Justin  ; C. Jones² ; Ronald  ; A. Depinho³ ; Martin  ; G. Myers Jr.² ; Morris  ; F. White¹ ; ^{morris.white@childrens.harvard.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：703-712
• 文件大小：1188 K

摘要

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Summary

Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lepr^cre together with Irs2^L/L to ablate Irs2 expression in LepR-b neurons (Lepr^螖Irs2). Lepr^螖Irs2 mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr^螖Irs2 mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr^螖Irs2 mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr^螖Irs2 mice normalized energy balance, glucose homeostasis, and arcuate nucleus gene expression. Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism.