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

Abstract

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.

Effect of different glycaemic conditions on gene expression of neuropeptides involved in control of food intake in rainbow trout; interaction with stress

“…In the only study carried out in fish regarding changes in NPY expression in response to changes in glucose, an increase rather than a decrease was observed in the preoptic area (but no changes were observed in the hypothalamus) of goldfish (Narnaware and Peter, 2002) and in the whole brain of tilapia (Riley et al, 2009) when glucose levels rose. However, a decreased expression of NPY is known to occur in the mammalian hypothalamus when glucose levels rise either in vivo (Lynch et al, 2000;Mobbs et al, 2005) or in vitro (Lee et al, 2005) or in the starved-to-fed transition, when circulating glucose levels are also known to increase (Stolarczyk et al, 2010). Considering that, in several mammalian hypothalamic nuclei (such as the arcuate nucleus), NPY neurons appear to be GI (DunnMeynell et al, 2002), we suggest that an increase in glucose levels in rainbow trout hypothalamus induces decreased synthesis of NPY as a result of the activation of the glucosensor mechanism (enhanced GK expression) in a way similar to that observed in mammals but in contrast to that observed in other fish species.…”

AMP-activated protein kinase pathway and bone metabolism

“…Fasting and orexigenic signals increase AMPK activity in several hypothalamic regions, while feeding and anorectic signals inhibit it (Kola et al 2005, Gao et al 2007. Nutrient-and hormone-induced alterations in AMPK hypothalamic activity have been shown to correlate with changes in neuropeptide expression in hypothalamic nuclei, indicating that AMPK activation in the hypothalamus links whole-body energy balance with neurotransmitter signaling pathways (Lee et al 2005. A possible role for hypothalamic AMPK in the control of obesity is the focus of increasing interest.…”

Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway

“…To test this possibility, we examined the biochemical and behavioral consequences of intrahippocampal administration of the AMPK activator AICAR. Numerous studies have used AICAR as a specific activator of AMPK (Sullivan et al, 1994;Corton et al, 1995;Bolster et al, 2002;McCrimmon et al, 2004;Lee et al, 2005). AICAR (260 ng) was infused into one hippocampus, and an equal volume of vehicle was infused into the contralateral hippocampus of the same animal (n ϭ 4).…”