Loss of Otopetrin 1 affects thermoregulation during fasting in mice

OBJECTIVE: Otopetrin 1 (OTOP1) is a proton channel that is highly expressed in brown adipose tissue. We examined the physiology of Otop1(-/-) mice, which lack functional OTOP1. METHODS: Mice were studied by indirect calorimetry and telemetric ambulatory body temperature monitoring. Mitochondrial function was measured as oxygen consumption and extracellular acidification. RESULTS: Otop1(-/-) mice had similar body temperatures as control mice at baseline and in response to cold and hot ambient temperatures. However, in response to fasting the Otop1(-/-) mice exhibited an exaggerated hypothermia and hypometabolism. Similarly, in ex vivo tests of Otop1(-/-) brown adipose tissue mitochondrial function, there was no change in baseline oxygen consumption, but the oxygen consumption was reduced after maximal uncoupling with FCCP and increased upon stimulation with the β(3)-adrenergic agonist CL316243. Mast cells also express Otop1, and Otop1(-/-) mice had intact, possibly greater hypothermia in response to mast cell activation by the adenosine A(3) receptor agonist MRS5698. No increase in insulin resistance was observed in the Otop1(-/-) mice. CONCLUSIONS: Loss of OTOP1 does not change basal function of brown adipose tissue but affects stimulated responses.