Differential Hypothalamic Arginine Vasopressin Response to Glucocorticoid Receptor Antagonism in Lean and Obese Zucker Rats

The obese Zucker rat (fa/fa) is an animal model for genetic obesity characterized by hyperphagia, hyperinsulinemia, and severe insulin resistance in peripheral tissues. Adrenal steroids seem to play an important role in the onset of fatty syndrome in these animals. There is strong evidence of abnormal regulation of the hypothalamic-pituitary-adrenal axis in obese Zucker rats. Considering the physiological function of arginine vasopressin (AVP) as an adrenocorticotropic hormone secretagogue, the present study was carried out to investigate the role of glucocorticoids in the control of hypothalamic AVP systems in lean and obese Zucker rats. In the first experiment, mifepristone (RU 38486), a glucocorticoid receptor antagonist, was administered for 4 days (10 mg/kg orally twice daily), and the expression of AVP mRNA in hypothalamic paraventricular and supraoptic nuclei was measured using in situ hybridization, and the concentrations of AVP in the pituitary gland and in the median eminence were quantified. Plasma corticosterone levels were also analyzed. Mifepristone treatment resulted in a threefold increase in plasma corticosterone levels in lean Zucker rats, but it did not change corticosterone secretion in obese animals. Mifepristone treatment decreased AVP mRNA levels in lean animals in the supraoptic nuclei, while in obese animals the AVP mRNA content was increased in the paraventricular nuclei. Mifepristone treatment significantly increased the concentration of AVP in the median eminence in lean rats and decreased it in obese animals. Mifepristone treatment did not change concentrations of AVP in the pituitary gland. In the second experiment, mifepristone was given for 4 days (10 mg/kg orally twice daily), and its effects on 24-hour food intake and plasma AVP concentrations were measured. Mifepristone treatment significantly increased the plasma AVP concentrations in lean animals, while in obese rats the plasma AVP levels remained unchanged. Basal plasma AVP levels were significantly higher in obese as compared with lean rats. The food intake was not changed by mifepristone. Our results suggest that blockade of glucocorticoid receptors, not resulting in complete adrenal insufficiency like adrenalectomy, differentially modulates hypothalamic AVP systems in lean and obese Zucker rats. This may be associated with the inability of mifepristone to activate the hypothalamic-pituitary-adrenal axis in obese animals which may be due to aberrant glucocorticoid receptor regulation in established genetic obesity.