Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 andcorticotrophin releasing factor inhibit feeding via agouti-related proteinindependent pathways in the rat

The melanocortin-4 receptor (MC4-R) appears to be an important downstream m ediator of the action of leptin. We examined to what extent the anorectic e ffects of cocaine- and amphetamine-regulated transcript (CART), glucagon-li ke peptide-1 (GLP-1) and corticotrophin releasing factor (CRF) might be med iated via MC4-R. alpha-Melanocyte stimulating hormone (alpha-MSH), the MC4- R agonist, administered intracerebroventricularly (ICV) at a dose of 1 nmol reduced food intake by approximately half. Agouti-related protein (Agrp) ( 83-132), a biologically active fragment of the endogenous MC4-R antagonist, administered ICV at a dose of 1 nmol completely blocked the anorectic effe ct of 1 nmol alpha-MSH. CART (55-102) (0.2 nmol), GLP-1 (3 nmol) and CRF (0 .3 nmol) produced a reduction in feeding of approximately the same magnitud e as 1 nmol alpha-MSH. Agrp (83-132) (1 nmol) administered ICV did not bloc k the anorectic effects of CART (55-102) (1 h food intake, 0.2 nmol CART (5 5-102), 2.7+/-0.8 g vs. CART (55-102)+Agrp (83-132), 2.6+/-0.6 g, P=0.87; s aline control 5.4+/-0.3 g, P<0.001 vs. both groups). Agrp (83-132) also did not block the anorectic effects of GLP-1 or CRF (1 h food intake, 0.3 nmol CRF, 0.7+/-0.3 g vs. CRF+Agrp (83-132), 0.7+/-0.3 g, P=0.91; 3 nmol GLP-1, 1.9+/-0.4 g vs. GLP-1+Agrp (83-132), 1.1+/-0.5 g, P=0.23; saline control 5 .0+/-0.6 g, P<0.001 vs. all four groups). Thus, as previous data suggests, GLP-1 and CRF do not appear to reduce food intake predominantly via MC4-R, we here demonstrate for the first time that CART, in addition to GLP-1 and CRF primarily acts via Agrp independent pathways. (C) 2000 Elsevier Science B.V. All rights reserved.