The effect of moxonidine on feeding and body fat in obese Zucker rats: role of hypothalamic NPY neurones

1 The antihypertensive agent moxonidine, an imidazoline Ii-receptor agonist , also induces hypophagia and lowers body weight in the obese spontaneously hypertensive rat, but the central mediation of this action and the neurona l pathways that moxonidine may interact with are not known. We studied whet her moxonidine has anti-obesity effects in the genetically-obese and insuli n-resistant fa/fa Zucker rat, and whether these are mediated through inhibi tion of the hypothalamic neuropeptide Y (NPY) neurones. 2 Lean and obese Zucker rats were given moxonidine (3 mg kg(-1) day(-1)) or saline by gavage for 21 days. 3 Moxonidine decreased food intake throughout by 20%;in obese rats (P<0.001 ) and by 8% in lean rats (P<0.001), and reduced weight gain that final body weight was 15% lower in obese (P<0.001) and 7% lower in lean (P<0.01) rats than their untreated controls. Plasma insulin and leptin levels were decre ased in moxonidine-treated obese rats (P<0.01 and P<0.05), but unchanged in treated lean rats. Uncoupling protein-1 gene expression in brown adipose t issue was stimulated by 40-50% (P less than or equal to 0.05) in both obese and lean animals given moxonidine. Obese animals given moxonidine showed a 37% reduction in hypothalamic NPY mRNA levels (P= 0.01), together with sig nificantly increased NPY concentrations in the paraventricular nucleus (P<0 .05), but no changes in the arcuate nucleus or other nuclei; this is consis tent with reduced NPY synthesis in the arcuate nucleus and blocked release of NPY in the paraventricular nucleus. In lean animals, moxonidine did not affect NPY levels or NPY mRNA. 4 The hypophagic, thermogenic and anti-obesity effects of moxonidine in obe se Zucker rats may be partly due to inhibition of the NPY neurones, whose i nappropriate overactivity may underlie obesity in this model.