Chemosensation: Sensing sugar in the brain

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Glucose sensitivity is dictated by the closure of neuronal ATP-sensitive potassium channels; uncoupling protein 2 (UCP2) activity, which lowers ATP yield and thus decreases glucose sensitivity, is thought to be important in glucose homeostasis.

Some hypothalamic neurons can be activated by glucose, but the functional significance of this capacity was unclear. Parton et al. now show that glucose-sensing pro-opiomelanocortin (POMC) neurons in the hypothalamus play a part in the regulation of systemic glucose levels, and that this function is impaired in obesity.


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Approximately 50% of POMC neurons in the hypothalamic arcuate nucleus, which has a role in appetite regulation, depolarize and increase their firing rate in response to increases in extracellular glucose levels. This excitability is caused by a closure of ATP-sensitive potassium (K_ATP) channels that is induced by ATP yielded from the breakdown of glucose. To elucidate the physiological function of these glucose-sensitive neurons, the authors created mice in which the K_ATP channel was mutated specifically in POMC neurons. This greatly decreased the neurons' sensitivity to glucose.

The authors showed that the mutation produced systemic effects: when given a dose of glucose, mutant mice took longer than wild-type mice to bring blood glucose levels back to baseline, indicating that hypothalamic POMC neurons might have a role in glucose homeostasis. The glucose intolerance of the mutant mice resembled that of obese individuals, in whom it often develops into type 2 diabetes. The authors therefore tested whether obesity alters the glucose sensitivity of hypothalamic POMC neurons. They found that mice that had been maintained on a high-fat diet and become obese had POMC neurons that were less sensitive to glucose.

What causes this reduced glucose sensitivity? In pancreatic beta -cells, glucose sensing is regulated by uncoupling protein 2 (UCP2). This protein lowers the yield of ATP from glucose breakdown, reducing the closure of K_ATP channels and thus decreasing glucose sensitivity. As UCP2 is also expressed in POMC neurons in the arcuate nucleus, the authors proposed that it might control glucose sensing here as well, and moreover, that this regulation might be disturbed in obese animals.

Indeed, mice that had eaten high-fat food had increased UCP2 mRNA levels in the hypothalamus. Moreover, inhibiting UCP2 in these mice restored their glucose sensitivity, and knocking out the Ucp2 gene prevented its loss altogether, indicating that increased UCP2 activity underlies the reduced glucose sensitivity of POMC neurons that is induced by a high-fat diet.

This study provides further evidence that the brain has a role in glucose homeostasis and, possibly, in the development of obesity-induced diabetes. Further research will be needed to establish the relative contribution of glucose-sensing neurons to the regulation of blood glucose levels and to determine whether this central regulation of glucose homeostasis might provide a target for the treatment of type 2 diabetes.

Leonie Welberg

References

Parton, L. E. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007) | Article | PubMed |