Hypothalamic NPY status during positive energy balance and the effects of the NPY antagonist, BW1229U91, on the consumption of highly palatable energy-rich diet

We have studied the hypothalamic activity of the neuropeptide Y (NPY) syste m in dietary-induced obese male Wistar rats and examined whether the NPY an tagonist, BW1229U91, can inhibit the hyperphagia during positive energy bal ance associated with feeding rats an energy-rich, highly palatable diet. Ra ts given a highly palatable, high-fat diet became obese after 8 weeks and e xhibited hyperinsulinemia and hyperleptinemia, as compared to lean rats fed on standard pellet laboratory diet. Hypothalamic NPY mRNA concentrations w ere significantly reduced by approximately 70% in dietary-obese rats compar ed with lean controls, and the former were hypersensitive to intracerebrove ntricular injections of NPY, possibly as a result of NPY receptor up-regula tion. Intracerebroventricular injections of BW1229U91, that inhibits food i ntake in starved rats, did not alter food intake in either control or obese rats fed either standard pellet diet or the highly palatable diet, respect ively. We conclude that dietary-obese rats have underactive hypothalamic NP Yergic neurons compared to lean controls, possibly as a result of increased plasma concentrations of leptin and/or insulin that directly inhibit the N PY neuronal activity. The lack of effect of BW1229U91 on the increased calo ric intake of dietary-obese rats suggests that the hyperphagia is not NPY-d riven and supports the data indicating reduced synaptic activity of the hyp othalamic NPY system. (C) 1999 Elsevier Science Inc. All rights reserved.