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

Rationale Evidence links longevity to dietary restriction (DR). A decrease in body temperature (T b ) is thought to contribute to enhanced longevity because lower T b reduces oxidative metabolism and oxidative stress. It is as yet unclear how DR decreases T b . Objective Here, we test the hypothesis that prolonged DR decreases T b by sensitizing adenosine A 1 receptors (A 1 AR) and adenosine-induced cooling. Methods and results 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 A 1 AR agonist, N 6 -cyclohexyladenosine (CHA; 0.5 mg/kg, i.p.). Respiratory rate (RR) and subcutaneous T b measured using IPTT-300 transponders were monitored every day and after drug administration. DR animals displayed lower RR on day 20 and lower T b on day 22 compared to animals fed ad libitum and displayed a larger response to CHA. In all cases, RR declined before T b . 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 A 1 AR within the hypothalamus. We report that the abundance of A 1 AR in the membrane fraction increases in hypothalamus, but not cortex of DR rats. Conclusion These results suggest that every-other-day feeding lowers T b via sensitization of thermoregulatory effects of endogenous adenosine by increasing surface expression of A 1 AR. Discussion Evidence that diet can modulate purinergic signaling has implications for the treatment of stroke, brain injury, epilepsy, and aging.