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Endocrinology. 2017 May 1;158(5):1298-1313. doi: 10.1210/en.2016-1825.

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

Author information

1
Extra Value Generation & General Medicine Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
2
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
3
Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
4
Biomolecular Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
5
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
6
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
7
Foods & Nutrients, Yamanashi Gakuin Junior College, Kofu, Yamanashi 400-8575, Japan.
8
CVM Marketing Japan Pharma Business Unit, Takeda Pharmaceutical Company Ltd, Chuo-ku, Tokyo 103-8686, Japan.

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.

PMID:
28324017
DOI:
10.1210/en.2016-1825
[Indexed for MEDLINE]
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