The role of insulin receptor substrate 2 in hypothalamic and beta cell function.
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.
Choudhury
Agharul I
AI
Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, United Kingdom.
Heffron
Helen
H
Smith
Mark A
MA
Al-Qassab
Hind
H
Xu
Allison W
AW
Selman
Colin
C
Simmgen
Marcus
M
Clements
Melanie
M
Claret
Marc
M
Maccoll
Gavin
G
Bedford
David C
DC
Hisadome
Kazunari
K
Diakonov
Ivan
I
Moosajee
Vazira
V
Bell
Jimmy D
JD
Speakman
John R
JR
Batterham
Rachel L
RL
Barsh
Gregory S
GS
Ashford
Michael L J
ML
Withers
Dominic J
DJ
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
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