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 Leprcre together with Irs2L/L to ablate Irs2 expression in LepR-b neurons (LeprΔIrs2). LeprΔIrs2 mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young LeprΔIrs2 mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in LeprΔIrs2 mice. Indeed, deletion of Foxo1 from LepR-b neurons in LeprΔIrs2 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.
Highlights
► Deletion of Irs2 in LEPR-B neurons causes obesity and hyperglycemia ► Deletion of Irs2 in LEPR-B neurons impairs energy homeostasis ► Irs2 is not required for LEPR-B signaling or leptin action ► Irs2 controls energy homeostasis by regulating FoxO1 activity in LEPR-B neurons