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

Abstract

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.

• Authors: Yasunori Nio, Natsu Hotta, Minoru Maruyama, Kenichi Hamagami, Toshimi Nagi, Masaaki Funata, Junichi Sakamoto, Masanori Nakakariya, Nobuyuki Amano, Tomohiro Okawa, Yasuyoshi Arikawa, Shinobu Sasaki, Shoki Okuda, Shizuo Kasai, Yugo Habata, Yasutaka Nagisa
• Journal: Endocrinology (Endocrinology) Vol. 158 Issue 5 Pg. 1298-1313 (05 01 2017) ISSN: 1945-7170 [Electronic] United States
• PMID: 28324017 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Endocrine Society.

Chemical References

• Anti-Obesity Agents
• Receptors, Bombesin
• bombesin receptor subtype 3
• Corticosterone

Topics

• Animals
• Anti-Obesity Agents (pharmacology)
• Body Weight (drug effects)
• Circadian Rhythm (drug effects)
• Corticosterone (blood)
• Diet, High-Fat
• Energy Metabolism (drug effects)
• Hypothalamo-Hypophyseal System (drug effects, metabolism)
• Lipid Metabolism (drug effects)
• Male
• Obesity (drug therapy, metabolism, physiopathology)
• Pituitary-Adrenal System (drug effects, metabolism)
• Rats
• Rats, Inbred F344
• Rats, Sprague-Dawley
• Receptors, Bombesin (agonists)
• Weight Loss (drug effects)