Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Laura E. Parton, Chian Ping Ye, Roberto Coppari, Pablo J. Enriori, Brian Choi, Chen Yu Zhang, Chun Xu, Claudia R. Vianna, Nina Balthasar, Charlotte E. Lee, Joel K. Elmquist, Michael A. Cowley, Bradford B. Lowell

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464 Scopus citations

Abstract

A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic β-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (KATP) channels. Although β-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of KATP channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)228-232
Number of pages5
JournalNature
Volume449
Issue number7159
DOIs
StatePublished - Sep 13 2007

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    Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C. Y., Xu, C., Vianna, C. R., Balthasar, N., Lee, C. E., Elmquist, J. K., Cowley, M. A., & Lowell, B. B. (2007). Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature, 449(7159), 228-232. https://doi.org/10.1038/nature06098