Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (Tb) is regulated in part by nutritional status, with a reduced Tb during fasting. We report that fed Brs3 knockout mice have a lower Tb, which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased Tb, more so when the baseline Tb was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the Tb increase attenuated despite continued weight loss efficacy. The increase in Tb was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a β-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting Tb reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, β3-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted Tb and the fasted, resting metabolic rates. The Tb assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery.
A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Diet-Induced–Obese Rats With Circadian Rhythm Change
