Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity

J Neurosci. 2010 Dec 1;30(48):16180-7. doi: 10.1523/JNEUROSCI.3202-10.2010.


Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

Publication types

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

MeSH terms

  • Adipose Tissue / enzymology
  • Adipose Tissue / physiopathology
  • Animals
  • Blood Glucose / metabolism
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / physiology
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Class Ib Phosphatidylinositol 3-Kinase / physiology
  • Glucose / metabolism*
  • Homeostasis / genetics
  • Homeostasis / physiology*
  • Hypothalamus / enzymology
  • Hypothalamus / metabolism*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Isoenzymes / genetics
  • Isoenzymes / physiology
  • Leptin / deficiency*
  • Leptin / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Obesity / enzymology
  • Obesity / genetics
  • Obesity / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Blood Glucose
  • Isoenzymes
  • Leptin
  • Class Ia Phosphatidylinositol 3-Kinase
  • Class Ib Phosphatidylinositol 3-Kinase
  • Glucose