[HTML][HTML] The role of insulin receptor substrate 2 in hypothalamic and β cell function

AI Choudhury, H Heffron, MA Smith… - The Journal of …, 2005 - Am Soc Clin Investig
AI Choudhury, H Heffron, MA Smith, H Al-Qassab, AW Xu, C Selman, M Simmgen…
The Journal of clinical investigation, 2005Am Soc Clin Investig
Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated
mice lacking Irs2 in β 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 β cell. RIPCreIrs2KO mice displayed impaired
glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells
escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and …
Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β 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 β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β 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 β 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 β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.
The Journal of Clinical Investigation