The effects of genetic background and adrenalectomy on the obese phenotype and hypothalamic neuropeptide expression in corpulent (cp) rats and agouti (Avy) mice.

摘要

Understanding the physiology of energy intake and expenditure is a first step in developing an effective set of programs that are needed to prevent and treat obesity. Although clinical studies have been helpful to meet this goal, the use of animal models of obesity is both time- and cost-effective. The popularity of genetic models has resulted in the adoption of an implicit assumption: the obese mutation would affect any strain in the same manner. The primary aim of this dissertation was to test whether strain interacts with obesity in two different animal obesity models: agouti mice and corpulent rats. Using a single experimental design in both rat and mouse model we tested whether genetic background could alter the expression of the obese phenotype. The corpulent gene was inserted in the LAN rat, the Spontaneously Hypertensive Rat (SHR) and the Dahl Salt Sensitive (DSS) rat using congenic breeding. In addition a mouse model using the viable yellow agouti mutation (Avy) was congenically bred into C57BL/6 and BALB/c mice.; The second hypothesis tested in this dissertation is whether the obesity in each model would be altered by adrenal status. Adult male obese and lean animals were either bilaterally adrenalectomized (ADX) or sham operated and given ad libitum access to pelleted rat chow and water (sham) or 0.9% saline (ADX). Food intake, corrected for spillage, and body weight measurements were then recorded for 30 days. Animals were sacrificed on day 30 and plasma corticosterone, insulin and leptin were measured by radioimmunoassay. The brains were flash frozen and the carcasses were prepared for gravimetric analyses. The brains were serially sliced using a cryostat and stored in a biological freezer (−80°C) until hybridized. We selected a neuropeptide receptor in each model that may be altered in the obese animal and measured its hypothalamic expression. In that way we manipulated adrenal status and measured receptors in the hypothalamus. The MC4 receptor was measured in agouti mice and the neuropeptide Y5 receptor was measured in corpulent rats. The results confirmed our initial hypothesis: background strain interacts with phenotype and adrenal status in both corpulent rats and agouti mice.