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

Abstract

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 Ͻ 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 Ͻ 0.00001) and body weight ( P Ͻ 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.( J. Clin.Invest.1997.99:385-390.)Key words: leptin resistance • high fat diet • food intake • C57BL/6 • AKR MethodsAnimals and diets.4-wk-old male C57BL/6 and AKR mice were obtained from Charles River Laboratories (Wilmington, MA) or Jackson Labs (Bar Harbor, ME).Animals were housed individually in a reverse light cycle room (dark cycle from 10:00 to 22:00) and were