A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced-Obese Rats With Circadian Rhythm Change.
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.
Extra Value Generation & General Medicine Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Yasunori
Y
Nio
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Natsu
N
Hotta
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Minoru
M
Maruyama
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Kenichi
K
Hamagami
Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Toshimi
T
Nagi
Biomolecular Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Masaaki
M
Funata
Biomolecular Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Junichi
J
Sakamoto
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Masanori
M
Nakakariya
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Nobuyuki
N
Amano
Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Tomohiro
T
Okawa
Central Nervous System Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Yasuyoshi
Y
Arikawa
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Shinobu
S
Sasaki
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Shoki
S
Okuda
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
Shizuo
S
Kasai
Foods & Nutrients, Yamanashi Gakuin Junior College, Kofu, Yamanashi 400-8575, Japan.
Yugo
Y
Habata
CVM Marketing Japan Pharma Business Unit, Takeda Pharmaceutical Company Ltd, Chuo-ku, Tokyo 103-8686, Japan.
Yasutaka
Y
Nagisa
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018004:Receptors, Bombesin / Q000819:agonists*; D015431:Weight Loss / Q000187:drug effects
D019440:Anti-Obesity Agents; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; D003345:Corticosterone