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 language | English |
---|---|
Pages (from-to) | 940-950 |
Number of pages | 11 |
Journal | The Journal of Clinical Investigation |
Volume | 115 |
Publication status | Published - 2005 |
Keywords
- BODY-WEIGHT
- PANCREATIC-ISLETS
- ARCUATE NUCLEUS
- FOOD-INTAKE
- STEM-CELLS
- MICE
- GENE
- DISRUPTION
- RESISTANCE
- EXPRESSION
Cite this
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 journal › Article
}
TY - JOUR
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 -