title: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.forename: Noboru
authors.initials: N
authors.lastname: Furukawa
authors.forename: Yong-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Lee
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.forename: James
authors.initials: J
authors.lastname: Mu
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Bettina J
authors.initials: BJ
authors.lastname: Stuck
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D006728:Hormones; D007328:Insulin; D020738:Leptin; D012333:RNA, Messenger; D044101:Receptors, Melanocortin; D000263:Adenylate Kinase; D005947:Glucose