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Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms

Nature Medicine volume 14, pages 667–675 (2008)Cite this article

Abstract

Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.

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Figure 1: MBH leptin regulates adipose tissue lipogenesis.
Figure 2: The regulation of adipose tissue lipogenesis by MBH leptin is STAT3 independent.
Figure 3: PI3K signaling is required for the central effects of leptin on WAT metabolism.
Figure 4: Leptin regulates adiposity and WAT anadamide independently of Stat3 signaling.
Figure 5: Control of WAT lipogenesis by MBH leptin requires intact autonomic innervation.
Figure 6: STAT3-dependent and STAT3-independent pathways of leptin signaling.

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Acknowledgements

We wish to thank B. Liu, S. Gaveda and C. Baveghems for technical assistance, S. Chua for helpful discussions and M. Myers (University of Michigan, Ann Arbor) for the s/s mice. Some of the db/db mice were a gift from R. Harris (University of Georgia, Athens). This work was supported by grants to L.R. (NIH DK048321), C.B. (NIH DK074873) and G.J.S. (NIH DK066618) from the US National Institutes of Health, the Skirball Institute for Nutrient Sensing and the New York Obesity Research Center (NIH DK026687). C.B. is the recipient of a Junior Faculty Award and E.D.M. is the recipient of a Physician Scientist Training Award, both from the American Diabetes Association.

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  1. Alessandro Pocai & Luciano Rossetti

    Present address: Current address: Merck, 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA.,

Authors and Affiliations

  1. Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1005, New York, 10029, New York, USA

    Christoph Buettner, Linghong Chen, Thomas Scherer, Kai Su & Bob Cheng

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park, Bronx, 10461, New York, USA

    Evan D Muse, Andrew Cheng & Luciano Rossetti

  3. Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park, Bronx, 10461, New York, USA

    Evan D Muse, Andrew Cheng, Alessandro Pocai, Xiasong Li, Gary J Schwartz & Luciano Rossetti

  4. Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park, Bronx, 10461, New York, USA

    Evan D Muse, Alessandro Pocai, Xiasong Li, Gary J Schwartz & Luciano Rossetti

  5. US National Institute on Alcohol Abuse & Alcoholism, US National Institutes of Health, 5625 Fishers Lane, Bethesda, 20892, Maryland, USA

    Judith Harvey-White & George Kunos

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Contributions

E.D.M performed qPCR (Fig. 2), A.C. performed qPCR and western blots (Fig. 2), L.C. assisted with western blots and qPCR (Figs. 4 and 5 and Supplementary Figs. 1,3 and 4), T.S. performed western blots (Figs. 5 and 6), A.P. performed and supervised clamp studies (Fig. 2), K.S. carried out MBH infusions and western blots (Fig. 3 and 5), B.C. performed some of the clamp studies (Fig. 5), J.H.-W. measured endocannabinoid and catecholamine levels, X.L. performed denervations, G.J.S. performed 6-OHDA injections, denervations and designed experiments (Fig. 5 and Supplementary Figs. 3 and 4), G.K. analyzed endocannabinoid and catecholamine levels and designed experiments (Fig. 4 and Supplementary Figs. 2 and 3), L.R. designed experiments (Figs. 1 – 3), and C.B. designed and performed experiments, supervised experimentation, analyzed the data, coordinated the project and wrote the manuscript.

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Correspondence to Christoph Buettner or Luciano Rossetti.

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Buettner, C., Muse, E., Cheng, A. et al. Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms. Nat Med 14, 667–675 (2008). https://doi.org/10.1038/nm1775

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