Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat.
The melanocortin-4 receptor (MC4-R) appears to be an important downstream mediator of the action of leptin. We examined to what extent the anorectic effects of cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1) and corticotrophin releasing factor (CRF) might be mediated 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 effect 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 magnitude as 1 nmol alpha-MSH. Agrp (83-132) (1 nmol) administered ICV did not block the anorectic effects of CART (55-102) (1 h food intake, 0.2 nmol CART (55-102), 2.7+/-0.8 g vs. CART (55-102)+Agrp (83-132), 2.6+/-0.6 g, P=0.87; saline 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.
Edwards
C M
CM
ICSM Endocrine Unit, Hammersmith Hospital, W12 0NN, London, UK.
Abbott
C R
CR
Sunter
D
D
Kim
M
M
Dakin
C L
CL
Murphy
K G
KG
Abusnana
S
S
Taheri
S
S
Rossi
M
M
Bloom
S R
SR
D054369:Agouti-Related Protein; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D000521:alpha-MSH / Q000494:pharmacology; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000521:alpha-MSH; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D003346:Corticotropin-Releasing Hormone