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.

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve

“…The BW of rats fed HFD (D12451) kept increasing after HFD feeding, and took over 16 weeks to reach a plateau [38] . In addition, several anti-obese compounds have been tested using DIO rats fed HFD for long term (27–46 weeks) [39, 40] . To precisely evaluate weight-reducing effects of T-3601386, we selected DIO rats fed HFD for long term especially in multiple dosing study.…”

Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake

“…Targeted deletion of Brs3 in mice causes obesity, mediated both by a decrease in energy expenditure and an increase in food intake, with a reduced resting body temperature (Tb) and resting heart rate 7–11 . Concordantly, BRS3 agonists increase resting Tb, energy expenditure, heart rate, blood pressure, activate brown adipose tissue (BAT) and decrease food intake 4,12–15 . The global BRS3 null phenotype is replicated by selective loss of Brs3 in neurons expressing vesicular glutamate transporter 2 (Vglut2) 16 .…”

Bombesin-like receptor 3 ( Brs3 ) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism

“…Because receptors often have different functions in different brain regions, even if complete molecular target selectivity is achieved with a drug, multiple drug effects are likely. To avoid this problem, there has been a hope that BRS-3 agonists might have anti-obesity effects via pharmacologic actions outside of the brain, avoiding some side effects [28] , [31] , [43] . However, our results strongly indicate that BRS-3 agonists achieve anti-obesity efficacy via activating glutamatergic neurons, likely chiefly in the brain.…”

“…The development of potent and selective ligands has expanded our knowledge of BRS-3 ( [15] , reviewed in [28] , [29] ). Treatment with a BRS-3 antagonist increased food intake and body weight, while agonists reduced food intake, increased resting metabolic rate, body temperature, and heart rate [15] , [27] , [30] , [31] . One BRS-3 agonist, MK-5046, reached initial human studies but increased blood pressure and was discontinued [32] .…”