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

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.

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Figure 1: Leptin activates α2 AMPK in skeletal muscle.
Figure 2: Leptin activates α2 AMPK in soleus muscle through two different mechanisms.
Figure 3: Leptin inhibits acetyl-CoA carboxylase (ACC) activity and activates fatty-acid oxidation in red muscle in vivo.
Figure 4: Dominant-negative AMPK inhibits leptin-induced AMPK activation and ACC phosphorylation in H-2Kb cells.

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Acknowledgements

We thank N. D. Oakes for the gift of [9,10-3H]-(R)-2-bromopalmitate, and B. B. Lowell and L. A. Witters for helpful advice. This work was supported by NIH grants (B.B.K.), the Boston Obesity Nutrition Research Center (Y.-B.K.), and The Kato Memorial Trust for Nambyo Research and Mitsui Life Social Welfare Foundation (Y.M.).

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Correspondence to Barbara B. Kahn.

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Minokoshi, Y., Kim, YB., Peroni, O. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002). https://doi.org/10.1038/415339a

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