The role of insulin receptor substrate 2 in hypothalamic and beta cell function

A I Choudhury, H Heffron, M A Smith, H Al-Qassab, A W Xu, C Selman, M Simmgen, M Clements, M Claret, G MacColl, D C Bedford, K Hisadome, I Diakonov, V Moosajee, J D Bell, J R Speakman, R L Batterham, G S Barsh, M L J Ashford, D J Withers

Research output: Contribution to journalArticle

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 P 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.

Original languageEnglish
Pages (from-to)940-950
Number of pages11
JournalThe Journal of Clinical Investigation
Volume115
Publication statusPublished - 2005

Keywords

  • BODY-WEIGHT
  • PANCREATIC-ISLETS
  • ARCUATE NUCLEUS
  • FOOD-INTAKE
  • STEM-CELLS
  • MICE
  • GENE
  • DISRUPTION
  • RESISTANCE
  • EXPRESSION

Cite this

Choudhury, A. I., Heffron, H., Smith, M. A., Al-Qassab, H., Xu, A. W., Selman, C., ... Withers, D. J. (2005). The role of insulin receptor substrate 2 in hypothalamic and beta cell function. The Journal of Clinical Investigation, 115, 940-950.

The role of insulin receptor substrate 2 in hypothalamic and beta cell function. / Choudhury, A I ; Heffron, H ; Smith, M A ; Al-Qassab, H ; Xu, A W ; Selman, C ; Simmgen, M ; Clements, M ; Claret, M ; MacColl, G ; Bedford, D C ; Hisadome, K ; Diakonov, I ; Moosajee, V ; Bell, J D ; Speakman, J R ; Batterham, R L ; Barsh, G S ; Ashford, M L J ; Withers, D J .

In: The Journal of Clinical Investigation, Vol. 115, 2005, p. 940-950.

Research output: Contribution to journalArticle

Choudhury, AI, Heffron, H, Smith, MA, Al-Qassab, H, Xu, AW, Selman, C, Simmgen, M, Clements, M, Claret, M, MacColl, G, Bedford, DC, Hisadome, K, Diakonov, I, Moosajee, V, Bell, JD, Speakman, JR, Batterham, RL, Barsh, GS, Ashford, MLJ & Withers, DJ 2005, 'The role of insulin receptor substrate 2 in hypothalamic and beta cell function', The Journal of Clinical Investigation, vol. 115, pp. 940-950.
Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C et al. The role of insulin receptor substrate 2 in hypothalamic and beta cell function. The Journal of Clinical Investigation. 2005;115:940-950.
Choudhury, A I ; Heffron, H ; Smith, M A ; Al-Qassab, H ; Xu, A W ; Selman, C ; Simmgen, M ; Clements, M ; Claret, M ; MacColl, G ; Bedford, D C ; Hisadome, K ; Diakonov, I ; Moosajee, V ; Bell, J D ; Speakman, J R ; Batterham, R L ; Barsh, G S ; Ashford, M L J ; Withers, D J . / The role of insulin receptor substrate 2 in hypothalamic and beta cell function. In: The Journal of Clinical Investigation. 2005 ; Vol. 115. pp. 940-950.
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T1 - The role of insulin receptor substrate 2 in hypothalamic and beta cell function

AU - Choudhury, A I

AU - Heffron, H

AU - Smith, M A

AU - Al-Qassab, H

AU - Xu, A W

AU - Selman, C

AU - Simmgen, M

AU - Clements, M

AU - Claret, M

AU - MacColl, G

AU - Bedford, D C

AU - Hisadome, K

AU - Diakonov, I

AU - Moosajee, V

AU - Bell, J D

AU - Speakman, J R

AU - Batterham, R L

AU - Barsh, G S

AU - Ashford, M L J

AU - Withers, D J

PY - 2005

Y1 - 2005

N2 - 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 P 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.

AB - 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 P 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.

KW - BODY-WEIGHT

KW - PANCREATIC-ISLETS

KW - ARCUATE NUCLEUS

KW - FOOD-INTAKE

KW - STEM-CELLS

KW - MICE

KW - GENE

KW - DISRUPTION

KW - RESISTANCE

KW - EXPRESSION

M3 - Article

VL - 115

SP - 940

EP - 950

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

SN - 0021-9738

ER -