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Am J Physiol Regul Integr Comp Physiol (December 14, 2006). doi:10.1152/ajpregu.00216.2006
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Submitted on March 28, 2006
Accepted on December 3, 2006

Glucose, insulin and leptin signaling pathways modulate nitric oxide (NO) synthesis in glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH)

Debra D Canabal1, Zhentao Song1, Joseph G Potian1, Annie Beuve1, Joseph J McArdle1, and Vanessa H. Routh1*

1 Pharmacology & Physiology, New Jersey Medical School (UMDNJ), Newark, New Jersey, United States

* To whom correspondence should be addressed. E-mail: routhvh{at}umdnj.edu.

Glucose sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucose sensing neurons alter their action potential frequency in response to physiological changes in extracellular glucose, insulin and leptin. Glucose-excited (GE) neurons decrease, while glucose-inhibited (GI) neurons increase their action potential frequency when extracellular glucose is reduced. Central nitric oxide (NO) synthesis is regulated by changes in local fuel availability, as well as insulin and leptin. NO is involved in the regulation of food intake and is altered in obesity and diabetes. Thus, this study tests the hypothesis that NO synthesis is a site of convergence for glucose, leptin and insulin signaling in VMH glucose sensing neurons. Using the NO sensitive dye, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM), in conjunction with the membrane potential sensitive dye, FLIPR, we found that glucose and leptin suppress, while insulin stimulates neuronal nitric oxide synthase (nNOS) - dependent NO production in cultured VMH GI neurons. The effects of glucose and leptin were mediated by suppression of AMP-activated protein kinase (AMPK). The AMPK activator 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR) increased both NO production and neuronal activity in GI neurons. In contrast, the effects of insulin on NO production were blocked by the phosphoinositide-3 kinase (PI3K) inhibitors, wortmannin and LY294002. Furthermore, decreased glucose, insulin and AICAR increase the phosphorylation of VMH nNOS while leptin decreases it. Finally, VMH neurons express soluble guanylyl cyclase (sGC), a downstream mediator of NO signaling. Thus, NO may mediate, in part, glucose, leptin and insulin signaling in VMH glucose sensing neurons.




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