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Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase

Author

Listed:
  • Yasuhiko Minokoshi

    (Diabetes and Metabolism, Harvard Medical School)

  • Young-Bum Kim

    (Diabetes and Metabolism, Harvard Medical School)

  • Odile D. Peroni

    (Diabetes and Metabolism, Harvard Medical School)

  • Lee G. D. Fryer

    (The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital)

  • Corinna Müller

    (Diabetes and Metabolism, Harvard Medical School)

  • David Carling

    (The Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital)

  • Barbara B. Kahn

    (Diabetes and Metabolism, Harvard Medical School)

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 α2 catalytic subunit of AMPK (α2 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.

Suggested Citation

  • Yasuhiko Minokoshi & Young-Bum Kim & Odile D. Peroni & Lee G. D. Fryer & Corinna Müller & David Carling & Barbara B. Kahn, 2002. "Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase," Nature, Nature, vol. 415(6869), pages 339-343, January.
  • Handle: RePEc:nat:nature:v:415:y:2002:i:6869:d:10.1038_415339a
    DOI: 10.1038/415339a
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    Cited by:

    1. King Hang Tommy Mau & Donja Karimlou & David Barneda & Vincent Brochard & Christophe Royer & Bryony Leeke & Roshni A. Souza & Mélanie Pailles & Michelle Percharde & Shankar Srinivas & Alice Jouneau & , 2022. "Dynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Mark Almond & Hugo A. Farne & Millie M. Jackson & Akhilesh Jha & Orestis Katsoulis & Oliver Pitts & Tanushree Tunstall & Eteri Regis & Jake Dunning & Adam J. Byrne & Patrick Mallia & Onn Min Kon & Ken, 2023. "Obesity dysregulates the pulmonary antiviral immune response," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Ying Yang & Michael A. Reid & Eric A. Hanse & Haiqing Li & Yuanding Li & Bryan I. Ruiz & Qi Fan & Mei Kong, 2023. "SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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