The role of leptin in leptin resistance and obesity

Physiol Behav. 2006 Jun 30;88(3):249-56. doi: 10.1016/j.physbeh.2006.05.038. Epub 2006 Jun 16.


Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. This article summarizes some recent work from our laboratory supporting the concept that leptin, in and of itself, promotes leptin resistance and such resistance compounds the metabolic impact of diet-induced obesity. Results from multiple studies demonstrate that (1) chronically elevated central leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling; (2) leptin resistance and obesity are associated with reduced leptin receptors and diminished maximal leptin signaling capacity; and (3) leptin resistance confers increased susceptibility to diet-induced obesity. In essence, the augmented leptin accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic devastation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Age Factors
  • Animals
  • Body Weight / physiology
  • Dietary Fats / metabolism
  • Energy Metabolism / physiology*
  • Humans
  • Hypothalamus / metabolism
  • Leptin / blood*
  • Mice
  • Mice, Transgenic
  • Obesity / blood*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Leptin
  • Signal Transduction / physiology


  • Dietary Fats
  • LEPR protein, human
  • Leptin
  • Receptors, Cell Surface
  • Receptors, Leptin
  • leptin receptor, mouse