TY - JOUR
T1 - IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action
AU - Sadagurski, Marianna
AU - Leshan, Rebecca L.
AU - Patterson, Christa
AU - Rozzo, Aldo
AU - Kuznetsova, Alexandra
AU - Skorupski, Josh
AU - Jones, Justin C.
AU - Depinho, Ronald A.
AU - Myers, Martin G.
AU - White, Morris F.
N1 - Funding Information:
The authors thank Dr. A. Parlow, National Hormone and Pituitary Program for recombinant mouse leptin. We also thank Dr. K.R. Vella for help with brain microdissections. This project was supported by NIH grants DK38712 and DK55326 (to M.F.W.) and DK056731 and DK057768 (to M.G.M.), and by the Ellison Foundation (to M.F.W. and M.S.). R.L.L. was supported by a grant from the American Heart Association, and C.P. was supported by T32HL007853.
PY - 2012/5/2
Y1 - 2012/5/2
N2 - 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 (Lepr ΔIrs2). 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.
AB - 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 (Lepr ΔIrs2). 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.
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U2 - 10.1016/j.cmet.2012.04.011
DO - 10.1016/j.cmet.2012.04.011
M3 - Article
C2 - 22560222
AN - SCOPUS:84860451500
SN - 1550-4131
VL - 15
SP - 703
EP - 712
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -