Blockade of body weight gain and plasma corticosterone levels in Zucker fatty rats using an orally active neuropeptide Y Y1 antagonist

An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. Oral administration of the Y1 antagonist (30 and 100 mg kg−1, once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity. Keywords: Neuropeptide Y, a Y1 antagonist; body weight gain; plasma corticosterone levels; Zucker fatty rats; obesity; feeding behaviour Introduction Neuropeptide Y (NPY) is a highly conserved 36 amino acid peptide that has been shown to have potent, centrally-mediated orexigenic effects (Tatemoto et al., 1982; Clark et al., 1984; Stanley & Leibowitz, 1984). It is a member of a peptide family which also includes peptide YY (PYY), and pancreatic polypeptide (PP) (Tatemoto & Mutt, 1980; Tatemoto et al., 1982). Chronic administration of NPY into the brain results in hyperphagia and body weight gain, reduces energy expenditure, and increases lipogenic activity in the liver and adipose tissue (Stanley et al., 1986; Zarjevski et al., 1993). It has been also reported that concentrations of NPY and its mRNA in the hypothalamus are markedly increased during food deprivation and in some genetic models of obesity in rodents (Sanacora et al., 1990; White et al., 1990; Kesterson et al., 1997; Guan et al., 1998). Moreover, it was well known that NPY-deficient ob/ob mice are less obese than ob/ob mice with reduction of food intake (Erikson et al., 1996). From these data it is inferred that NPY may be one of the major regulators of energy homeostasis. Five distinct subtypes of NPY receptors (Y1, Y2, Y4, Y5 and Y6) have been cloned so far, and more than one receptor subtype seems to be involved in the NPY-mediated feeding (Blomqvist & Herzog, 1997). Among them, the Y1 receptor is considered to be one of the major feeding receptors, since Y1 antagonists with distinct chemical structures are reported to suppress feeding. This is also supported by a findings that mice lacking Y1 receptor showed a significantly diminished response to exogenously administered NPY (Kanatani et al., 2000b). Genetically obese Zucker fatty rat (fa/fa) is extensively used for the study of obesity. Hyperphagia, decreased energy expenditure, hyperinsulinaemia, and hypercorticosteronaemia based on a disfunction of leptin long-form receptors are characteristics of Zucker fatty rats (Bray, 1977). As a consequence, a large dys-regulation of leptin-controlled hypothalamic neuropeptides is observed, and NPY is thought to be one responsible factor for the abnormality (Beck et al., 1990; 1993). Levels of NPY (McKibbin et al., 1991) and its mRNA (Sanacora et al., 1990), and NPY secretion (Dryden et al., 1995) are increased in the hypothalamic nuclei involved in the regulation of feeding behaviour. In addition, hyperphagia, obesity and metabolic changes such as hyperinsulinaemia, hypercorticosteroidimia and hyperlipidaemia, which were seen in Zucker fatty rats, were mimicked by repeated administration of NPY in normal rats (Stanley et al., 1986). We previously demonstrated that a potent peptidic Y1 antagonist, 1229U91 more potently inhibited the spontaneous feeding in Zucker fatty rats than lean litter mates after intracerebroventricular (ICV) administration (Ishihara et al., 1998). Taken together, we hypothesized that Y1 receptor play a key role in the generation of obesity in Zucker fatty rats. Recently we reported that an orally-active and highly selective Y1 antagonist can suppress NPY-induced feeding in SD rats (Kanatani et al., 1999). To clarify the physiological role of the Y1 receptor in the development of obesity in Zucker fatty rats, here we further examined the chronic effect of the Y1 antagonist in this model animal.