Possible involvement of melanocortin-4-receptor and AMP-activated protein kinase in the interaction of glucagon-like peptide-1 and leptin on feeding in rats

• Published in: Biochemical and biophysical research communications 2012-03, Vol.420 (1), p.36-41
• Main Authors: Poleni, Paul-Emile, Akieda-Asai, Sayaka, Koda, Shuichi, Sakurai, Maya, Bae, Cho-Rong, Senba, Kazuyo, Cha, Youn-Soo, Furuya, Mayumi, Date, Yukari
• Format: Article
• Language: English
• Subjects: alpha-MSH - metabolism; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Drug Interactions; Eating - drug effects; Feeding; Feeding Behavior - drug effects; GLP-1; Glucagon-Like Peptide 1 - administration & dosage; Leptin; Leptin - administration & dosage; Male; MC4-R; Melanocyte-Stimulating Hormones - pharmacology; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4 - antagonists & inhibitors; Receptor, Melanocortin, Type 4 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.02.109

► We investigate the interaction of GLP-1 and leptin on feeding. ► Coinjection of subthreshold of these two hormones significantly decreases feeding. ► Coinjection of these two hormones dramatically decreases AMPK in the hypothalamus. ► Coinjection of these two hormones significantly increases POMC mRNA. ► Blockade of POMC/MC4-R cancels feeding reduction induced by GLP-1+leptin. Glucagon-like peptide-1 (GLP-1) and leptin are anorectic hormones produced in the small intestine and white adipose tissue, respectively. Investigating how these hormones act together as an integrated anorectic signal is important to elucidate a mechanism to maintain energy balance. In the present study, coadministration of subthreshold GLP-1 and leptin dramatically reduced feeding in rats. Although coadministration of GLP-1 with leptin did not enhance leptin signal transduction in the hypothalamus, it significantly decreased phosphorylation of AMP-activated protein kinase (AMPK). In addition, coadministration of GLP-1 with leptin significantly increased proopiomelanocortin (POMC) mRNA levels. Considering that α-melanocortin stimulating hormone (α-MSH) is derived from POMC and functions through the melanocortin-4-receptor (MC4-R) as a key molecule involved in feeding reduction, the interaction of GLP-1 and leptin on feeding reduction may be mediated through the α-MSH/MC4-R system. As expected, the interaction of GLP-1 and leptin was abolished by intracerebroventricular preadministration of the MC4-R antagonists agouti-related peptide and SHU9119. Taken together, GLP-1 and leptin cooperatively reduce feeding at least in part via inhibition of AMPK following binding of α-MSH to MC4-R.