A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change

• Published in: Endocrinology (Philadelphia) 2017-05, Vol.158 (5), p.1298-1313
• Main Authors: Nio, Yasunori, Hotta, Natsu, Maruyama, Minoru, Hamagami, Kenichi, Nagi, Toshimi, Funata, Masaaki, Sakamoto, Junichi, Nakakariya, Masanori, Amano, Nobuyuki, Okawa, Tomohiro, Arikawa, Yasuyoshi, Sasaki, Shinobu, Okuda, Shoki, Kasai, Shizuo, Habata, Yugo, Nagisa, Yasutaka
• Format: Article
• Language: English
• Subjects: Activation; Agonists; Animal tissues; Animals; Anti-Obesity Agents - pharmacology; Blood levels; Blood pressure; Body weight; Body Weight - drug effects; Body weight loss; Bombesin; c-Fos protein; Circadian rhythm; Circadian Rhythm - drug effects; Circadian rhythms; Control centres; Corticosterone; Corticosterone - blood; Diet; Diet, High-Fat; Endocrinology; Energy expenditure; Energy metabolism; Energy Metabolism - drug effects; Gene expression; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Male; Males; Metabolism; Nervous system; Obesity; Obesity - drug therapy; Obesity - metabolism; Obesity - physiopathology; Oral administration; Phenotypes; Pituitary; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Pressure effects; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors; Receptors, Bombesin - agonists; Ribonucleic acid; RNA; Rodents; Side effects; Stimulation; Suprachiasmatic nucleus; Sympathetic nervous system; Weight loss; Weight Loss - drug effects; Weight reduction
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1825

Bombesin receptor subtype 3 (BRS-3) is an orphan G protein–coupled receptor. Based on the obese phenotype of male BRS-3–deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced–obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic–pituitary–adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.We identified a novel BRS-3 agonist, compound-A, and possible mechanism of antiobesity effects modulating circadian rhythm and activation of the HPA axis via SCN.