Diet-induced obese mice develop peripheral, but not central, resistance to leptin

J Clin Invest. 1997 Feb 1;99(3):385-90. doi: 10.1172/JCI119171.


Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.

Publication types

  • Clinical Trial

MeSH terms

  • Animals
  • Appetite Regulation / drug effects
  • Body Weight / drug effects
  • Dietary Fats / administration & dosage
  • Dietary Fats / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Eating / drug effects
  • Feeding Behavior / drug effects
  • Leptin
  • Longitudinal Studies
  • Male
  • Mice
  • Mice, Inbred AKR
  • Mice, Inbred C57BL
  • Obesity / blood
  • Obesity / drug therapy*
  • Proteins / administration & dosage*
  • Proteins / analysis
  • Proteins / therapeutic use*
  • Time Factors


  • Dietary Fats
  • Leptin
  • Proteins