title: IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02062, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sadagurski
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Leshan
authors.forename: Christa
authors.initials: C
authors.lastname: Patterson
authors.forename: Aldo
authors.initials: A
authors.lastname: Rozzo
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kuznetsova
authors.forename: Josh
authors.initials: J
authors.lastname: Skorupski
authors.forename: Justin C
authors.initials: JC
authors.lastname: Jones
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D003598:Cytoskeletal Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D009419:Nerve Tissue Proteins; D054411:Receptors, Leptin; C092069:activity regulated cytoskeletal-associated protein; D005947:Glucose