Leptin receptor signaling: pathways to leptin resistance

Front Biosci (Landmark Ed). 2011 Jun 1;16:2771-93. doi: 10.2741/3885.


The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research. Leptin, an adipocyte-derived hormone, mirrors the body's fat stores and thereby informs the brain about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations, like POMC and AgRP/NPY neurons, and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin is also involved in the regulation of other physiological processes including reproduction, bone homeostasis and immune function. Here, we review the pathways that are activated upon ObR activation, how ObR expression is controlled and the molecular mechanisms leading to leptin resistance, i.e. the inability to adequately respond to elevated leptin levels and therefore a primary risk factor for obesity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Blood-Brain Barrier
  • Endoplasmic Reticulum / physiology
  • Humans
  • Janus Kinases / physiology
  • Leptin / genetics
  • Leptin / physiology*
  • MAP Kinase Signaling System
  • Models, Biological
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / physiopathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
  • Receptors, Leptin / genetics
  • Receptors, Leptin / physiology*
  • STAT Transcription Factors / physiology
  • Signal Transduction
  • Stress, Physiological
  • TOR Serine-Threonine Kinases / physiology


  • Leptin
  • Receptors, Leptin
  • STAT Transcription Factors
  • TOR Serine-Threonine Kinases
  • Janus Kinases
  • AMP-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11