Decreased orexigenic response to neuropeptide Y in rats with obstructive cholestasis

Neuropeptide Y (NPY) is a key factor in the neurochemical control of food i ntake, and obstructive cholestasis can be associated with disturbances in f ood intake. Our aim in this study was to determine whether obstructive chol estasis in the rat is associated with defective central responsiveness to N PY. Cholestasis was induced in rats by surgical bile duct resection. Rats w ith obstructive cholestasis exhibited a 20% reduction in food intake 2 days after laparotomy (compared with sham-resected controls) that had resolved by 4 days after surgery. Responsiveness to the orexigenic action of NPY was tested by measuring food intake after intracerebroventricular injection of NPY. In sham-resected rats, NPY infusion strikingly increased food intake, whereas bile duct-resected (BDR) rats showed a consistent significantly im paired feeding response to NPY at postlaparotomy days 2, 4, and 7. Separate experiments measured specific binding of [H-3] NPY to hypothalamic recepto rs. Fos protein expression was measured in the hypothalamic paraventricular nucleus (PVN) as a marker of NPY-induced neuronal activation. The decrease d orexigenic responsiveness to NPY was not caused by altered NPY binding at hypothalamic receptors or its ability to activate neurons in the PVN. Ther efore, cholestatic rats demonstrate an attenuated NPY-induced orexigenic dr ive that occurs early after biliary obstruction, when cholestatic rats exhi bit reduced food intake, and persists despite the return of food intake to normal levels and the presence of intact central NPY-related neuronal pathw ays.