Agouti-related protein is a mediator of diabetic hyperphagia

To explore the role of agouti-related protein (AGRP) in diabetic hyperphagi a changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (bl ood glucose 456.0+/-8.4 mg/dl versus 71.8+/-1.9 mg/dl) and hyperphagia (36. 9+/-1.0 g/day versus 22.0+/-0.4 g/day), that was associated with a 286.6+/- 4.4% increase in hypothalamic AGRP mRNA and a 178.9+/-13.5% increase in hyp othalamic NPY mRNA. Insulin treatment of diabetic rats partially corrected blood glucose (147.4+/-13.1 mg/dl) and ameliorated hyperphagia (26.6+/-2.0 g/day). Insulin replacement was also associated with a return of hypothalam ic AGRP mRNA (111.7+/-8.3% of controls) and NPY mRNA (125.0+/-8.9% of contr ols) from the elevated levels that were observed in untreated diabetic rats . In contrast to insulin treated rats, sodium orthovanadate treated diabeti c rats remained significantly hyperglycemic (361.5+/-12.5 mg/dl). However, despite their persistent hyperglycemia, orthovanadate treated diabetic rats were still observed to have a significant reduction of hypothalamic AGRP m RNA (138.7+/-11.4%) and NPY mRNA (129.9+/-9.8%). Simultaneous measurement o f serum leptin revealed suppressed levels in both untreated diabetic (0.5+/ -0.1 ng/ml) and sodium orthovanadate treated rats (0.5+/-0.1 ng/ml) compare d to non-diabetic controls (2.1+/-0.1 ng/ml). These data indicate that AGRP is a mediator of diabetic hyperhpagia and suggest that insulin can directl y influence hypothalamic AGRP and NPY mRNA expression. (C) 2001 Elsevier Sc ience B.V. All rights reserved.