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Letters to Nature
Nature 415, 339-343 (17 January 2002) | doi:10.1038/415339a; Received 28 August 2001; Accepted 12 October 2001
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Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
Yasuhiko Minokoshi1, Young-Bum Kim1, Odile D. Peroni1, Lee G. D. Fryer2, Corinna Müller1, David Carling2 & Barbara B. Kahn1
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
- The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, UK
Correspondence to: Barbara B. Kahn1 Correspondence and requests for materials should be addressed to B.B.K. (e-mail: Email: bkahn@caregroup.harvard.edu).
Abstract
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function1. Leptin stimulates the oxidation of fatty acids2 and the uptake of glucose3, 4, and prevents the accumulation of lipids in nonadipose tissues, which can lead to functional impairments known as "lipotoxicity"5. The signalling pathways that mediate the metabolic effects of leptin remain undefined. The 5'-AMP-activated protein kinase (AMPK) potently stimulates fatty-acid oxidation in muscle by inhibiting the activity of acetyl coenzyme A carboxylase (ACC)6, 7. AMPK is a heterotrimeric enzyme that is conserved from yeast to humans and functions as a 'fuel gauge' to monitor the status of cellular energy6. Here we show that leptin selectively stimulates phosphorylation and activation of the
2 catalytic subunit of AMPK (
2 AMPK) in skeletal muscle, thus establishing a previously unknown signalling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Our data identify AMPK as a principal mediator of the effects of leptin on fatty-acid metabolism in muscle.
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
- The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, UK
Correspondence to: Barbara B. Kahn1 Correspondence and requests for materials should be addressed to B.B.K. (e-mail: Email: bkahn@caregroup.harvard.edu).
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