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

Sep 18, 2004Endocrinology

How Brain Cell Energy Levels May Influence Energy-Regulating Proteins, Appetite Signals, and Eating Behavior

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Abstract

Low ATP levels in neuronal cells are associated with increased AgRP expression.

Low glucose and ATP synthesis inhibition lead to higher phosphorylation of AMPK and increased expression of the neuropeptide AgRP.
High ATP conditions, such as those created by high glucose, result in decreased AMPK phosphorylation and lower AgRP expression.
Inhibition of AMPK activity reduces the AgRP expression induced by low-glucose or ATP-depleting conditions.
High glucose concentrations in ex vivo hypothalamus cultures decrease both AMPK activity and the expression of AgRP and neuropeptide Y.
Pyruvate supplementation suppresses AgRP expression induced by ATP depletion.
In vivo, administering pyruvate delays food intake triggered by low-energy conditions.

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

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