Altered thermoregulation via sensitization of A1 adenosine receptors in dietary-restricted rats

Abstract

Evidence links longevity to dietary restriction (DR). A decrease in body temperature (Tb) is thought to contribute to enhanced longevity because lower Tb reduces oxidative metabolism and oxidative stress. It is as yet unclear how DR decreases Tb. Here, we test the hypothesis that prolonged DR decreases Tb by sensitizing adenosine A1 receptors (A1AR) and adenosine-induced cooling. Sprague–Dawley rats were dietary restricted using an every-other-day feeding protocol. Rats were fed every other day for 27 days and then administered the A1AR agonist, N6-cyclohexyladenosine (CHA; 0.5 mg/kg, i.p.). Respiratory rate (RR) and subcutaneous Tb measured using IPTT-300 transponders were monitored every day and after drug administration. DR animals displayed lower RR on day 20 and lower Tb on day 22 compared to animals fed ad libitum and displayed a larger response to CHA. In all cases, RR declined before Tb. Contrary to previous reports, a higher dose of CHA (5 mg/kg, i.p.) was lethal in both dietary groups. We next tested the hypothesis that sensitization to the effects of CHA was due to increased surface expression of A1AR within the hypothalamus. We report that the abundance of A1AR in the membrane fraction increases in hypothalamus, but not cortex of DR rats. These results suggest that every-other-day feeding lowers Tb via sensitization of thermoregulatory effects of endogenous adenosine by increasing surface expression of A1AR. Evidence that diet can modulate purinergic signaling has implications for the treatment of stroke, brain injury, epilepsy, and aging.