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Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action


The regulation of body weight and composition involves input from genes1,2 and the environment3,4, demonstrated, for example, by the variable susceptibility of inbred strains of mice to obesity when offered a high-fat diet5. The identification of the gene responsible for obesity in the ob/ob mouse6 provides a new approach to defining links between diet and genetics in the regulation of body weight. The ob gene protein product, leptin7, is an adipocyte-derived circulating protein6,8. Administration of recombinant leptin reduces food intake and increases energy expenditure in ob/ob mice7,9,10, suggesting that it signals to the brain the magnitude of fat stores. Information on the regulation of this protein is limited. In several rodent models of obesity including db/db6,8,11, fa/fa12, yellow (Ay/a)13 VMH-lesioned14, and those induced by gold thioglucose11, monosodium glutamate8, and transgenic ablation of brown adipose tissue8, leptin mRNA expression6,8,11–14 and the level of circulating leptin68 are increased, suggesting resistance to one or more of its actions. We have assessed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue15,16. We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, with leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, animals fed a high-fat diet became obese without decreasing their caloric intake, suggesting that a high content of dietary fat changes the ‘set point’17 for body weight, at least in part by limiting the action of leptin.

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Frederich, R., Hamann, A., Anderson, S. et al. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nat Med 1, 1311–1314 (1995).

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