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Role of Neuronal Energy Status in the Regulation of Adenosine 5'-Monophosphate-Activated Protein Kinase, Orexigenic Neuropeptides Expression, and Feeding Behavior

Department of Animal Sciences (K.L.), The Ohio State University, Columbus, Ohio 43210; Neurobehavioral Laboratory (B.L., X.X., Y.S., R.J.M.) Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; and School of Human Ecology (B.L., R.J.M.), Louisiana State University AgCenter and College of Agriculture, Baton Rouge, Louisiana 70803

Address all correspondence and requests for reprints to: Dr. Kichoon Lee, Department of Animal Sciences, The Ohio State University, Columbus, Ohio 43210. E-mail: lee.2626{at}osu.edu; or Roy J. Martin, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808. E-mail: MartinRJ{at}pbrc.edu.

Nutrient sensing in the hypothalamus is tightly related to food intake regulation. However, the mechanisms by which the nutrient-sensing cells of the brain translate this signal of energy need into feeding behavior via regulation of neuropeptide expression are not known. To address this issue, we investigated two neuronal cell lines expressing agouti-related protein (AgRP), ex vivo hypothalamic tissues, and in vivo whole animals. Maintaining cells in a low cellular ATP concentration generated by low glucose, 2-deoxyglucose (2-DG), ATP synthesis inhibitor, and 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside increased phosphorylation of AMP-activated protein kinase (AMPK) and increased AgRP expression, whereas maintaining cells in high ATP status by high glucose and pyruvate supplementation in 2-DG-treated cells decreased phosphorylation of AMPK and decreased AgRP expression. Overexpression of a dominant-inhibitory mutant of AMPK significantly decreased low-glucose- or 2-DG-induced AgRP expression. Furthermore, ex vivo hypothalamus culture in high glucose concentrations decreased both expression and phosphorylation of AMPK and expression of both AgRP and neuropeptide Y, whereas pyruvate supplementation suppressed a 2-DG-induced AgRP expression. Finally, our in vivo studies clearly show that central administration of pyruvate dramatically delayed 2-DG-induced food intake. These data indicate that modulation of ATP levels in neuronal cells triggers a cascade of events via AMPK that modulate feeding behavior to restore energy status of cells.

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