Mice homozygous for the obese spontaneous mutation, (Lepob commonly referred to as ob or ob/ob) exhibit obesity hyperphagia, a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing, and an increase in hormone production from both pituitary and adrenal glands. They are also hypometabolic and hypothermic. The obesity is characterized by an increase in both number and size of adipocytes. Although hyperphagia contributes to the obesity, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal weight maintenance in lean mice. Hyperinsulinemia does not develop until after the increase body weight and is probably the result of it. Homozygotes do have an abnormally low threshold for stimulation of pancreatic islet insulin secretion even in very young preobese animals. As is the case with mice carrying the diabetes mutation (Leprdb), manifestation of the diabetic syndrome is strikingly dependent on genetic background. Lepob homozygotes on the BTBR background develop diabetes at six weeks (males), and eight weeks (females). Hyperglycemia is severe and progressive with a fasting plasma glucose of 400 mg/dl at 10 weeks (Stoehr et al., 2000). In contrast to homozygotes on the C57BL/6 background, BTBR homozygotes develop extreme obesity (Stoehr et al., 2004) and progressive hypertriglyceridemia (Lan et al., 2003). Hepatic lipogenesis is not increased and homozygotes do not develop hepatic steatosis (Lan et al., 2003). Males remain hyperinsulinemic although insulin levels and islet mass are much reduced (Stoehr personal communication). Two modifier loci (Mobe1, Mobe2, formerly, Moo1 and Moo2) regulate total fat mass. BTBR alleles of these loci semi-dominantly increase body mass (Stoehr et al., 2004).
