AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus

Abstract

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.

AMP-activated protein kinase in the brain

“…Our results are consistent with those of Minokoshi et al, who injected the mediobasal hypothalamus with adenoviruses expressing constitutively active AMPK or dominant-negative AMPK. 5 Consistent with our AICAR data, constitutively active AMPK mice ate more and gained more weight than controls, and consistent with Compound C results, dominant-negative AMPK mice ate less, lost more weight after surgery and regained weight more slowly than controls. 5 Collectively, our data and those of Minokoshi et al indicate that alterations in hypothalamic AMPK activity are sufficient to drive feeding changes.…”

“…2,3 We and other laboratories have shown that hypothalamic AMPK plays a major role in the regulation of organism's energy balance. [4][5][6] Our interest in hypothalamic AMPK grew from our work with C75, a synthetic molecule that inhibits fatty acid synthase (FAS) 7 and stimulates carnitine palmitoyltransferase-1 (CPT-1) and beta-oxidation of fatty acids. [8][9][10] Fatty acid metabolic pathways are poised at a crossroads of energy deficit and energy surplus, with the potential to either use or make the high-energy molecule ATP.…”

“…2,31 Hormones and pharmacological agents modulate AMPK activity in muscle, liver and hypothalamus to promote fatty acid oxidation, glucose utilization and feeding responses. [4][5][6]36,37 Physiological stimuli can activate AMPK to promote tissue-specific responses such as skeletal muscle glucose uptake and glycolysis through glucose transporter translocation and 6-phosphofructo-2-kinase kinase activity, respectively, and fatty acid oxidation. 32,33,38 Liver AMPK inhibits fatty acid and cholesterol biosynthesis by phosphorylating and inactivating ACC and 3-hydroxy-3-methylglutaryl-coenzyme A reductase.…”

“…Once we knew that C75 altered pAMPK in neurons in vitro, 8 we altered the brain and hypothalamic AMPK in mice using well-known pharmacological tools, and fed and fasted states, to demonstrate that AMPK was a physiological mediator of C75's effects. 4 Other research groups also altered hypothalamic AMPK activity using genetic approaches 5 or peripheral hormones 5,6 to alter hypothalamic AMPK activity. These studies suggest that hypothalamic AMPK controls energy expenditure and fuel utilization as well.…”

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…Given the growing interest in brain adenosine monophosphate-activated protein kinase (AMPK) as a cellular fuel gauge that regulates energy balance, 60,61 as well as evidence from hypothalamic tissues that show leptin and refeeding (associated with GI stimulation) decrease the elevated AMPK activity induced by food deprivation, we have been pursuing the hypothesis that leptin and GI signals processed in NTS neurons combine to affect intracellular AMPK activity. Using western blots and activity assays we show that food deprivation elevates and refeeding reduces AMPK activity in NTS-enriched lysates.…”