1. A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change
- Author
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Shoki Okuda, Yasuyoshi Arikawa, Tomohiro Okawa, Junichi Sakamoto, Nobuyuki Amano, Shinobu Sasaki, Masanori Nakakariya, Yugo Habata, Shizuo Kasai, Natsu Hotta, Kenichi Hamagami, Masaaki Funata, Yasutaka Nagisa, Minoru Maruyama, Toshimi Nagi, and Yasunori Nio
- Subjects
Male ,0301 basic medicine ,Agonist ,Hypothalamo-Hypophyseal System ,endocrine system ,Sympathetic nervous system ,medicine.medical_specialty ,medicine.drug_class ,Pituitary-Adrenal System ,Diet, High-Fat ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Weight Loss ,medicine ,Animals ,Obesity ,Circadian rhythm ,business.industry ,Suprachiasmatic nucleus ,Body Weight ,Lipid Metabolism ,Rats, Inbred F344 ,Circadian Rhythm ,Rats ,Receptors, Bombesin ,030104 developmental biology ,medicine.anatomical_structure ,Hypothalamus ,Anorectic ,Bombesin Receptor Subtype-3 ,Anti-Obesity Agents ,Corticosterone ,Energy Metabolism ,business ,Diet-induced obese ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - 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.
- Published
- 2017