Neuropeptidergic characterization of the leptin receptor mutated obese Koletsky rat

Leptin regulates energy homeostasis and reproduction as evidenced by dysfunctions characterized in several genetic models of leptin pathway deficiency, such as the ob/ob and db/db mice and fa/fa Zucker rat. An additional model, the obese (f/f) Koletsky rat with a nonsense leptin receptor mutation has not been fully characterized. These rats are obese, hyperphagic, diabetic, and infertile; however, little else is known about the effects of the mutation. We have characterized alterations in hypothalamic appetite regulating neuropeptides as well as energy expenditure, metabolic hormones, and the reproductive axis of obese f/f rats. As expected, obese rats of both sexes were hyperinsulinemic, hyperglycemic, and hyperleptinemic. They exhibited reduced uncoupling protein-1 mRNA expression in brown fat, indicating reduced energy expenditure. In addition, hypothalamic expression of orexigenic neuropeptide Y and agouti-related peptide mRNA levels was upregulated while the anorexigenic cocaine and amphetamine regulated transcript and proopiomelanocortin mRNA levels were reduced. We also observed reproductive axis perturbations including reduced hypothalamic luteinizing hormone releasing hormone, serum estradiol and testosterone, and increased serum progesterone levels. In conclusion, obese Koletsky rats are phenotypically similar to other leptin pathway deficiency models with reduced energy expenditure and hypothalamic neuropeptidergic alterations that could account for their obesity and infertility.