20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

    1. Martin G Myers Jr
    1. Departments of Internal Medicine, and Molecular and Integrative Physiology, University of Michigan, 1000 Wall Street, 6317 Brehm Tower, Ann Arbor, Michigan 48105, USA
    1. Correspondence should be addressed to M G Myers; Email: mgmyers{at}umich.edu


    Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling proteins and protein tyrosine phosphatases also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models that have been used to elucidate these functions in vivo.

    • Received in final form 5 August 2014
    • Accepted 8 August 2014
    | Table of Contents