DIET-INDUCED OBESE MICE DEVELOP PERIPHERAL, BUT NOT CENTRAL, RESISTANCE TO LEPTIN

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 deter mine whether diet-induced obesity in mice produces resistance to perip heral and/or central leptin treatment. Obesity was induced in two stra ins of mice by exposure to a 45% fat diet. Serum leptin increased in p roportion to body weight (P <0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease i n food intake, leptin resistance developed after 16 d on high fat diet ; mice on 10% fat diet retained leptin sensitivity. In AKR mice, perip heral leptin significantly decreased food intake in both 10 and 45% fa t-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central a dministration of leptin to peripherally leptin-resistant AKR mice on 4 5% fat diet resulted in a robust response to leptin, with a dose-depen dent decrease in food intake (P <0.00001) and body weight (P <0.0001) after a single intracerebroventricular infusion. These data demonstrat e that, in a diet-induced obesity model, mice exhibit resistance to pe ripherally administered leptin, while retaining sensitivity to central ly administered leptin.