Hyperleptinemia precipitates diet-induced obesity in transgenic mice overexpressing leptin.

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.

Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes.

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes.

Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age.

Sensitivity to leptin is associated with a normal regulation of the adipose mass, whereas decreased leptin sensitivity results in elevated adipose tissue stores. To address whether the effects of chronic hyperleptinemia are sustained with age, we generated transgenic mice that overexpress leptin under the control of the fat specific aP2 promoter/enhancer. At 6-9 weeks of age, transgenic mice overexpressed 5-fold more human leptin than endogenous mouse levels and had consistently low body weights, with reduced brown and white fat depots characterized by adipocytes either devoid of or containing minute lipid droplets. However, at 33-37 weeks, despite continuous secretion of human leptin, the transgenic mice showed a rebound effect characterized by an increase in body weight, accumulation of adipose mass, and lipid-filled adipocytes. Thus, this mouse model exhibits a two-stage phenotype, with respect to fat accumulation. In addition, plasma glucose, triglycerides, and cholesterol levels were markedly depressed in young, but not older, transgenic mice. A detrimental consequence of early hyperleptinemia was a failure of the transgenic mice to acclimatize to the cold, as a result of depleted fat stores within their brown adipocytes. Cold exposure was tolerated after a 2-week high-fat diet or at an older age when fat depots had naturally accumulated. Treatment of the older transgenic mice with large doses of leptin stimulated weight loss, demonstrating that the leptin pathway still responds to pharmacological levels of leptin. Overall, these studies show that moderate hyperleptinemia in normal mice results in a sensitivity of the adipose mass to leptin at a younger (but not older) age. The mechanisms that lead to the accumulation of fat at an older age remain largely unknown, and this hyperleptinemic mouse model will allow the uncovering of at least some of these mechanisms.