Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis

Cell Metab. 2005 Mar;1(3):169-78. doi: 10.1016/j.cmet.2005.02.001.


Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Body Composition
  • Body Weight
  • Caloric Restriction
  • DNA-Binding Proteins / physiology*
  • Glucose / physiology*
  • Homeostasis*
  • Hyperglycemia / etiology
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Mutant Strains
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators / physiology*


  • DNA-Binding Proteins
  • Receptors, Cell Surface
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • leptin receptor, mouse
  • Glucose