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

Yasuhiko Minokoshi, Thierry Alquier, Noboru Furukawa, Young-Bum Kim, Anna Lee, Bingzhong Xue, James Mu, Fabienne Foufelle, Pascal Ferré, Morris J. Birnbaum, Bettina J. Stuck and Barbara B. Kahn ()
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Yasuhiko Minokoshi: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Thierry Alquier: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Noboru Furukawa: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Young-Bum Kim: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Anna Lee: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Bingzhong Xue: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
James Mu: University of Pennsylvania Medical School
Fabienne Foufelle: Unit 465 INSERM, Centre de Recherches Biomedicales des Cordeliers
Pascal Ferré: Unit 465 INSERM, Centre de Recherches Biomedicales des Cordeliers
Morris J. Birnbaum: University of Pennsylvania Medical School
Bettina J. Stuck: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Barbara B. Kahn: Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School

Nature, 2004, vol. 428, issue 6982, 569-574

Abstract: 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 status1. 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 anorexigen2, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen2, 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.

Date: 2004
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DOI: 10.1038/nature02440

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