Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Abstract

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 (T(b)) is regulated in part by nutritional status, with a reduced T(b) during fasting. We report that fed Brs3 knockout mice have a lower T(b), which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) increase attenuated despite continued weight loss efficacy. The increase in T(b) 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 T(b) 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 T(b) and the fasted, resting metabolic rates. The T(b) 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.