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


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-cells1, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (KATP) channels2,3,4,5. 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) neurons5 via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of KATP channels6,7. 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 production8. 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.

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Figure 1: Glucose sensing is lost in POMC-mut-Kir6.2 neurons.
Figure 2: Glucose-sensing is lost in POMC neurons of mice on a high-fat diet.
Figure 3: Genipin activates glucose-excited POMC neurons.
Figure 4: Acute inhibition or genetic deletion of UCP2 restores or prevents loss of glucose sensing in POMC neurons as a result of obesity induced by a high-fat diet.

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We would like to thank J. Koster and C. Nichols for donation of the Kir6.2[ΔN2–30,K185Q]–GFP construct; Z. Yang, L. Christiansen, M. Kramer and S. Skowronek for animal care and technical assistance; and B. Bean for discussions, guidance with electrophysiological experiments and for critical reading of this manuscript. This work was supported by NIH grants (B.B.L., J.K.E., M.A.C., P.J.E.); a Smith Family Pinnacle Award from the American Diabetes Association (J.K.E.); a National Natural Science Foundation of China Outstanding Young Scientist Award; the National Basic Research Program of China (973 Program); the ‘111’ Project; and the Natural Science Foundation of Jiangsu Province (C.-Y.Z.).

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Correspondence to Michael A. Cowley or Bradford B. Lowell.

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Supplementary information

Supplementary Information

This file contains Supplementary Data with a full description of studies used to characterize the ATP sensitivity of both wild-type and mutKir6.2 POMC neurons in addition to whole-cell recordings showing effects of glucose, genipin and leptin. Also, Supplementary Figure S1 displays RT-PCR results showing tissue specific expression of mutKir6.2 and characterization of KATP channels in mutKir6.2 POMC neurons; and Supplementary Figure S2 displays whole cell electrophysiological recordings of wild-type and mutKir6.2 POMC neurons showing effects of glucose, genipin and leptin. (PDF 692 kb)

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Parton, L., Ye, C., Coppari, R. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007).

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