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The role of insulin receptor substrate 2 in hypothalamic and beta cell function
Agharul I Choudhury1, Helen Heffron, Mark A Smith
1Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, United Kingdom.
The Journal of Clinical Investigation
|April 21, 2005
Summary
Insulin receptor substrate 2 (Irs2) is vital for beta cell function and energy balance. Its absence in specific neurons impacts appetite, obesity, and growth, revealing new roles in the hypothalamus.
Area of Science:
- Neuroscience
- Endocrinology
- Metabolism
Background:
- Insulin receptor substrate 2 (Irs2) is implicated in energy homeostasis.
- Understanding Irs2's specific roles in the central nervous system (CNS) and beta cells is crucial.
Purpose of the Study:
- To investigate the function of Irs2 in beta cells and distinct neuronal populations within the CNS.
- To elucidate the role of Irs2 in regulating glucose metabolism, body weight, and growth.
Main Methods:
- Generated genetically modified mice with Irs2 deletion in beta cells (RIPCreIrs2KO), all neurons (NesCreIrs2KO), and proopiomelanocortin (POMC) neurons (POMCCreIrs2KO).
- Assessed glucose tolerance, beta cell mass, body weight, body length, and neuronal responses to various stimuli (insulin, leptin, melanocortin agonist).
Main Results:
- Mice lacking Irs2 in beta cells (RIPCreIrs2KO) showed impaired glucose tolerance and reduced beta cell mass, with compensatory islet repopulation.
- Mice with Irs2 deletion in beta cells or all neurons (RIPCreIrs2KO, NesCreIrs2KO) exhibited hyperphagia, obesity, and increased body length, suggesting altered melanocortin signaling.
- These CNS Irs2-deficient mice remained leptin-sensitive, indicating Irs2 pathways are not essential for leptin action.
- RIPCre neurons, distinct from POMC neurons, responded to insulin and a melanocortin agonist but not leptin, highlighting their unique role.
Conclusions:
- Irs2 plays a critical role in both pancreatic beta cell function and hypothalamic regulation of energy homeostasis.
- RIPCre neurons represent a distinct neuronal population involved in growth and energy balance, independent of POMC neurons.
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