Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and Zucker diabetic fatty rats and effects of rosiglitazone

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep-wake cycle. To study their possible releva nce to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA le vels in obese, normoglycemic Zucker fatty (fa/fa) and in hyperglycemic, non -obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA co ncentrations in Zucker fatty rats were 31% lower than those in lean control s (0.69+/-0.06 vs. 1.00+/-0.10 arbitrary units, P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diab etic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while l eptin levels were 67% higher than in untreated ZDF rats (20.2+/-0.5 vs. 12. 1+/-2.5, P<0.001). Rosiglitazone treatment markedly enhanced weight gain co mpared with untreated ZDF rats (final weight 732+/-13 g vs. 409+/-13 g, P<0 .001) even though they were restricted to the same food intake. Rosiglitazo ne-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68+/-0.07 arbitrary units) than both non-diabetic lean controls (1.00+/-0.10, P=0.02) and untreated diabetics (1.03+/-0.14, P=0.03). Our da ta suggest that prepro-orexin gene expression may be suppressed by substant ial weight gain. Obesity-related signals that might mediate this effect hav e not been identified, but plasma leptin, insulin and glucose are not obvio usly involved. (C) 2000 Elsevier Science BN. All rights reserved.