Leptin, an adipocyte-derived
hormone, has well-established anorexigenic effects but is also able to regulate
glucose homeostasis independent of
body weight. Until recently, the ob/ob mouse was the only animal model of global
leptin deficiency. Here we report the effects of
leptin deficiency on
glucose homeostasis in male and female
leptin knockout (KO) rats.
Leptin KO rats developed
obesity by 6 to 7 weeks of age, and
lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age.
Hyperinsulinemia and
insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting
hyperglycemia between 14 and 25 weeks of age, but thereafter fasting
glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting
glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more
insulin when stimulated than islets from WT littermates.
Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated
weight gain, normalized
glucose tolerance, and improved
glucose-stimulated insulin secretion and
insulin sensitivity. Together, these data demonstrate that the absence of
leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of
hyperinsulinemia,
obesity, and
insulin resistance.