Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action

To understand the role of agouti-related protein (AGRP), an endogenous anta gonist of hypothalamic melanocortin receptor, in leptin action, we produced a full-length recombinant AGRP and examined its effect on the satiety effe ct of leptin. We also studied leptin's regulation of hypothalamic AGRP mRNA expression. A single intracerebroventricular (ICV) injection of AGRP signi ficantly increased cumulative food intake and body weight in a dose-depende nt manner in rats. The leptin-induced inhibition of food intake and body we ight was reversed by co-injection of AGRP in a dose-dependent manner. Hypot halamic AGRP mRNA expression a-as upregulated in leptin-deficient ob/ob mic e and leptin receptor-deficient db/db mice and downregulated in lethal yell ow agouti mice (KKA(y) mice) with hyperleptinemia. A single ICV injection o f leptin reversed the increased AGRP mRNA levels in ob/ob mice but not in d b/db, mice. In control mice and KKA(y) mice, AGRP mRNA expression was upreg ulated during fasting, when plasma. leptin concentrations were decreased. N o significant increase in AGRP mRNA expression was noted during fasting in control mice and KKA(y) mice treated with leptin. This study provides the f irst direct evidence that AGRP is a negative regulator of leptin action, an d leptin downregulates hypothalamic AGRP production. Because leptin is show n to increase hypothalamic ol-melanocyte stimulating hormone (alpha-MSH) pr oduction, our data suggest that its action via the hypothalamic melanocorti n system is determined by the balance between the levels of its agonist and antagonist, alpha-MSH and AGRP.