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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 1;99(3):385–390. doi: 10.1172/JCI119171

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

M Van Heek 1, D S Compton 1, C F France 1, R P Tedesco 1, A B Fawzi 1, M P Graziano 1, E J Sybertz 1, C D Strader 1, H R Davis Jr 1
PMCID: PMC507810  PMID: 9022070

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 < 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.

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Selected References

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