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

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 ΔIrs2 ). Lepr ΔIrs2 mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr ΔIrs2 mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr ΔIrs2 mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr ΔIrs2 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.