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 (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). Here, we test the hypothesis that prolonged DR decreases T(b) by sensitizing adenosine A(1) receptors (A(1)AR) 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 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. 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. Evidence that diet can modulate purinergic signaling has implications for the treatment of stroke, brain injury, epilepsy, and aging.