Transgenic mice overexpressing leptin backcrossed to the C57BL/6J genetic background (LepTg) have a lean phenotype, characterized by a 95% reduction in adipose mass; reduced plasma levels of glucose, triglycerides, insulin, and IGF-1; and a 75% decrease in adipocyte size. High-fat diet treatment for 20 wk revealed that, compared with normal mice, the LepTg mice had an increased susceptibility to diet-induced obesity, as demonstrated by their rate of weight gain, higher accumulation of sc white adipose tissue mass, hypertrophy of adipocytes, and normalization of their reduced metabolic parameters. The stromal vascular fraction of white adipose tissue from the LepTg mice was highly cellular and contained cells capable of rapid lipid accumulation in primary cultures. The precipitous diet-induced obesity of the LepTg mice was accompanied with 10-fold and 1.6-fold elevations in insulin and IGF-1, respectively, suggesting that the trophic action of insulin and IGF-1 on the preadipocytes and small adipocytes may have caused them to rapidly differentiate and accumulate triacylglycerol stores. Other contributing factors may involve a shift in insulin sensitivity triggered by hyperleptinemia and a decrease in energy expenditure. These studies demonstrate that a chronic response to hyperleptinemia as in the LepTg mice is a predisposing factor to diet-induced obesity and suggest that individuals who are particularly lean because of increased leptin secretion may develop rapid obesity under conditions of a high-fat diet.