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
beta-cells,
glucose excitation of
neurons is driven by ATP-mediated closure of ATP-sensitive
potassium (K(ATP)) channels. Although beta-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 K(ATP) 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.
