The role of insulin receptor substrate 2 in hypothalamic and β cell function
| Autor: | Mark A. Smith, Helen Heffron, Allison W. Xu, John R. Speakman, Michael L.J. Ashford, Gavin MacColl, Agharul I. Choudhury, Vazira Moosajee, Jimmy D. Bell, Marcus Simmgen, David C. Bedford, Gregory S. Barsh, Rachel L. Batterham, Ivan Diakonov, Marc Claret, Hind Al-Qassab, Kazunari Hisadome, Melanie Clements, Colin Selman, Dominic J. Withers |
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| Rok vydání: | 2005 |
| Předmět: |
Leptin
Male medicine.medical_specialty Pro-Opiomelanocortin Genotype Recombinant Fusion Proteins medicine.medical_treatment Population Hypothalamus 030209 endocrinology & metabolism Article Energy homeostasis Islets of Langerhans Mice 03 medical and health sciences 0302 clinical medicine Proopiomelanocortin Internal medicine medicine Animals Homeostasis Insulin Glucose homeostasis education 030304 developmental biology Mice Knockout Neurons 0303 health sciences education.field_of_study biology Body Weight digestive oral and skin physiology Intracellular Signaling Peptides and Proteins General Medicine Phosphoproteins Receptor Insulin IRS2 Electrophysiology Mice Inbred C57BL Glucose Endocrinology nervous system Insulin Receptor Substrate Proteins biology.protein Melanocortin Energy Metabolism hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Clinical Investigation. 115:940-950 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci24445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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