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Leptin receptor signaling and the regulation of mammalian physiology

International Journal of Obesity volume 32, pages S8–S12 (2008)Cite this article

Abstract

The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr1138 → STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr985 binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr1077, the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.

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Acknowledgements

This study was supported by NIH R01 DK57768 and R01DK56731 (to MGM).

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Authors and Affiliations

  1. Division of Metabolism, Department of Internal Medicine, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA

    E C Villanueva & M G Myers Jr

  2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    M G Myers Jr

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  1. E C Villanueva
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Correspondence to M G Myers Jr.

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Conflict of interest

Martin G Myers has received consulting fees from BMS and lecturing fees from Merck and Amylin, as well as royalties from Millipore Inc. for the development of antibodies for research. The remaining author has declared no financial interests.

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Villanueva, E., Myers, M. Leptin receptor signaling and the regulation of mammalian physiology. Int J Obes 32 (Suppl 7), S8–S12 (2008). https://doi.org/10.1038/ijo.2008.232

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