Agouti-related protein is a mediator of diabetic hyperphagia

To explore the role of agouti-related protein (AGRP) in diabetic hyperphagia changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (blood 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 hypothalamic 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 hypothalamic AGRP mRNA (111.7±8.3% of controls) and NPY mRNA (125.0±8.9% of controls) from the elevated levels that were observed in untreated diabetic rats. In contrast to insulin treated rats, sodium orthovanadate treated diabetic 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 mRNA (138.7±11.4%) and NPY mRNA (129.9±9.8%). Simultaneous measurement of 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) compared 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 directly influence hypothalamic AGRP and NPY mRNA expression.