title: The role of insulin receptor substrate 2 in hypothalamic and beta cell function.
abstract: Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.
authors.affiliation: Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, United Kingdom.
authors.forename: Agharul I
authors.initials: AI
authors.lastname: Choudhury
authors.forename: Helen
authors.initials: H
authors.lastname: Heffron
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Hind
authors.initials: H
authors.lastname: Al-Qassab
authors.forename: Allison W
authors.initials: AW
authors.lastname: Xu
authors.forename: Colin
authors.initials: C
authors.lastname: Selman
authors.forename: Marcus
authors.initials: M
authors.lastname: Simmgen
authors.forename: Melanie
authors.initials: M
authors.lastname: Clements
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
authors.forename: Gavin
authors.initials: G
authors.lastname: Maccoll
authors.forename: David C
authors.initials: DC
authors.lastname: Bedford
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hisadome
authors.forename: Ivan
authors.initials: I
authors.lastname: Diakonov
authors.forename: Vazira
authors.initials: V
authors.lastname: Moosajee
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Bell
authors.forename: John R
authors.initials: JR
authors.lastname: Speakman
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Batterham
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
mesh_terms: D000818:Animals; D001835:Body Weight; D004594:Electrophysiology; D004734:Energy Metabolism; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D011333:Pro-Opiomelanocortin; D011972:Receptor, Insulin; D005947:Glucose