DECREASED CENTRAL AND PERIPHERAL CATECHOLAMINERGIC ACTIVATION IN OBESE ZUCKER RATS

The Zucker rat is an animal model of autosomal recessive obesity chara cterized by excessive hypothalamic-pituitary-adrenal (HPA) axis and pa rasympathetic activities and deficient sympathetic outflow. Alteration s in norepinephrine (NE) release, reuptake, and metabolism in the hypo thalamic paraventricular nucleus (PVN) could also contribute to dysreg ulation of the HPA axis in obese Zucker rats via effects on corticotro pin-releasing hormone neurons or could be secondary to some other prim ary defect. The present study assessed whether the obese phenotype (fa /fa) compared to the lean phenotype (Fa/?) of this strain was also ass ociated with alterations in basal and immobilization (IMMO) stress-ind uced noradrenergic activation in the PVN, using in vivo microdialysis. To evaluate concurrent activity of the peripheral sympathetic nervous system and the HPA axis, we also measured plasma concentrations of ca techolamines, ACTH, and corticosterone. IMMO-induced increases in PVN NE levels were significantly lower in obese Zucker rats, as were eleva tions in plasma concentrations of dihydroxyphenylglycol and epinephrin e. Basal and IMMO-stimulated plasma ACTH concentrations were similar i n obese and lean rats. Basal plasma corticosterone concentrations were also similar in obese and lean rats; however, IMMO-stimulated cortico sterone levels were significantly greater in obese than in lean animal s. Basal plasma free corticosterone levels, measured by ultrafiltratio n, were significantly higher in obese than in lean rats, confirming th e state of chronic hypercorticosteronism in these animals. These findi ngs indicate that obese Zucker rats have diminished central noradrener gic and peripheral sympathetic nervous system responses to IMMO stress along with a chronically hyperactive HPA axis. We suggest that defect ive regulation of PVN NE reflects and contributes to the development a nd/or maintenance of obesity in Zucker rats via central hypoactivity o f the sympathetic system. The hypercorticosteranism of these animals, apparently sustained by some nonadrenergic stimulatory input, might pa rticipate in the suppression of the sympathetic system.