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 gene s(1,2) and the environment(3,4), demonstrated, for example, by the var iable susceptibility of inbred strains of mice to obesity when offered a high-fat diets. The identification of the gene responsible for obes ity in the ob/ob mouse(6) provides a new approach to defining links be tween diet and genetics in the regulation of body weight. The ob gene protein product, leptin(7), is an adipocyte-derived circulating protei n(6,8). Administration of recombinant leptin reduces food intake and i ncreases energy expenditure in ob/ob mice(7,9,10), suggesting that it signals to the brain the magnitude of fat stores. Information on the r egulation of this protein is limited. In several rodent models of obes ity including db/db(6,8,11), fa/fa(12), yellow (Ay/a)(13) VMH-lesioned (14) and those induced by gold thioglucose(11), monosodium glutamate(8 ), and transgenic ablation of brown adipose tissues, leptin mRNA expre ssion(6,8,11-14) and the level of circulating leptin(6,8) are increase d, suggesting resistance to one or more of its actions. We have assess ed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue(15,16). We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, wit h leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, a nimals fed a high-fat diet became obese without decreasing their calor ic 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.