Bezafibrate prolongs hypothermia induced by an A₁ adenosine receptor agonist in CBA/N mice

Understanding thermoregulation within the range of low body temperatures (Tb) in homeotherms is of special interest in various life science fields. Here, we report that mice exhibit long-lasting hypothermia induced by the administration of an A₁ adenosine receptor (A₁AR) agonist, N⁶-cyclohexyladenosine (CHA), in combination with pretreatment with bezafibrates (BZ), a peroxisome proliferator-activated receptor α (PPARα) agonist. Before the induction of hypothermia by CHA administration at a dose of 0.5 mg/kg, CBA/N mice were fed 0.5% BZ-supplemented food for 10 days at an ambient temperature of 23-24°C. Ten days after BZ treatment, intraperitoneal CHA administration induced low Tb (<33°C) lasting for 6 hr, while mice provided the control food without BZ supplementation experienced low Tb lasting for <1 hr after CHA administration. The combined administration of these drugs also marked decreased oxygen consumption, carbon dioxide output, and energy expenditure compared with those in control mice that received CHA injections alone. These findings demonstrate that BZ-induced PPARα activation enhanced the sensitivity of A₁AR, thereby prolonging low Tb. Both receptors are considered key factors in controlling torpor and/or hibernation; however, a synergistic relationship between these receptors has not been reported. Therefore, our findings suggest that metabolic activation of lipid catabolism via PPARα signaling may potentiate the hypothermic effects induced by A₁AR activation.