The Development of Obesity, Hyperinsulinemia, and Hyperglycemia in Ob/ob Mice

The development of obesity, hyperglycemia, and hyperinsulinemia, was examined in obese-hyperglycemic (ob/ob) mice, their lean littermates, and homozygous lean mice (+/+) between 17 days and 8 wk of age. By 4 wk of age ob/ob mice displayed many of the metabolic characteristics that are typical of the syndrome in adult animals, including elevated systemic insulin and glucose levels, increased body weight, obesity, reduced skeletal growth, and in vivo evidence of insulin resistance. In addition, 4-wk-old lean littermates of obese mice had greater body weights, increased per cent carcass lipid, and higher insulin levels than did +/+ mice of the same age that were raised under identical conditions. At 17 or 21 days of age ob/ob mice, defined by either (1) elevated carcass fat content when compared to littermates at time of killing or (2) by phenotypic expression of obesity at 6 wk of age, exhibited moderate hyperinsulinemia, hypoglycemia, reduced skeletal growth, and "obesity", as expressed by the Lee index. The present results indicate that altered pancreatic beta-cell function, obesity, and abnormalities of somatic growth all precede the onset of hyperglycemia and insulin "resistance" in ob/ob mice. Furthermore, the occurrence of these characteristics before 17 days of age suggests that the transition to laboratory diet is not essential for the expression of the ob mutation. The present data also support recent studies that have described a small but reliable effect of the ob gene on the metabolism of heterozygous lean mice.