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Sci. STKE, 18 September 2007
Vol. 2007, Issue 404, p. tw337
[DOI: 10.1126/stke.4042007tw337]


Metabolism Regulating Glucose

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Increased extracellular glucose stimulates firing of a subset of proopiomelanocortin (POMC)-containing neurons in the hypothalamus through a mechanism thought to depend, like insulin secretion in pancreatic beta cells, on the adenosine 5'-triphosphate (ATP)-dependent closure of ATP-sensitive potassium (KATP) channels in the plasma membrane. Parton et al. generated transgenic mice (POMC-mut-Kir6.2 mice) that expressed a mutant KATP Kir6.2 subunit under the transcriptional control of the POMC promoter, so that relatively ATP-insensitive KATP channels were selectively expressed in hypothalamic POMC neurons (and in the pituitary). Although the body weight of POMC-mut-Kir6.2 mice was normal, glucose homeostasis was impaired so that they showed an exaggerated increase in blood glucose after intraperitoneal glucose injection. Whereas the firing rate of about half the POMC neurons in wild-type mice was stimulated by physiologically relevant increases in glucose concentration, only 1 of 27 POMC neurons in POMC-mut-Kir6.2 mice was glucose-sensitive. Glucose stimulated release of {alpha}-melanocyte–stimulating hormone ({alpha}-MSH) from hypothalamic slices from wild-type, but not POMC-mut-Kir6.2, mice. Moreover, it failed to stimulate the release of {alpha}-MSH from hypothalamic slices of wild-type mice fed a high-fat diet, and its effect on the firing rate of their POMC neurons was severely attenuated. Expression of the mRNA encoding uncoupling protein 2 (UCP2, a mitochondrial protein that decreases ATP production from glucose) was increased in the hypothalami of obese mice, and pharmacological inhibition of UCP with genipin stimulated firing in glucose-sensitive POMC neurons from wild-type mice. Genipin had little effect on POMC neuronal firing in POMC-mut-Kir6.2 mice, but it restored glucose-dependent release of hypothalamic {alpha}-MSH in mice fed a high-fat diet. Furthermore, although mice lacking UCP2 became obese when fed a high-fat diet, the ability of glucose to elicit release of their hypothalamic {alpha}-MSH was intact. Thus, the authors conclude that glucose sensing by hypothalamic POMC neurons is implicated in systemic glucose homeostasis, a sensitivity that is lost through a mechanism involving UCP2 in obese mice fed a high-fat diet. They further note that these findings may be pertinent to the pathogenesis of type 2 diabetes.

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

Citation: E. M. Adler, Regulating Glucose. Sci. STKE 2007, tw337 (2007).

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