AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons

Beth Ann Murphy, Kurt A. Fakira, Zhentao Song, Annie Beuve, Vanessa H. Routh

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

The mechanisms by which glucose regulates the activity of glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH) are largely unknown. We have previously shown that AMP-activated protein kinase (AMPK) increases nitric oxide (NO) production in VMH GI neurons. We hypothesized that AMPK-mediated NO signaling is required for depolarization of VMH GI neurons in response to decreased glucose. In support of our hypothesis, inhibition of neuronal nitric oxide synthase (nNOS) or the NO receptor soluble guanylyl cyclase (sGC) blocked depolarization of GI neurons to decreased glucose from 2.5 to 0.7 mM or to AMPK activation. Conversely, activation of sGC or the cell-permeable analog of cGMP, 8-bromoguanosine 3′,5′-cyclic monophosphate (8-Br-cGMP), enhanced the response of GI neurons to decreased glucose, suggesting that stimulation of NO-sGC-cGMP signaling by AMPK is required for glucose sensing in GI neurons. Interestingly, the AMPK inhibitor compound C completely blocked the effect of sGC activation or 8-Br-cGMP, and 8-Br-cGMP increased VMH AMPKα2 phosphorylation. These data suggest that NO, in turn, amplifies AMPK activation in GI neurons. Finally, inhibition of the cystic fibrosis transmembrane regulator (CFTR) Cl- conductance blocked depolarization of GI neurons to decreased glucose or AMPK activation, whereas decreased glucose, AMPK activation, and 8-Br-cGMP increased VMH CFTR phosphorylation. We conclude that decreased glucose triggers the following sequence of events leading to depolarization in VMH GI neurons: AMPK activation, nNOS phosphorylation, NO production, and stimulation of sGC-cGMP signaling, which amplifies AMPK activation and leads to closure of the CFTR.

Original languageEnglish (US)
Pages (from-to)C750-C758
JournalAmerican Journal of Physiology - Cell Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Keywords

  • Cystic fibrosis transmembrane regulator
  • Glucose-sensing neurons
  • Guanosine 3′,5′-cyclic monophosphate
  • Membrane potential sensitive dye
  • Soluble guanylyl cyclase

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