Type 2 diabetic mice enter a state of spontaneous hibernation-like suspended animation following accumulation of uric acid

Abstract

Hibernation is an example of extreme hypometabolic behavior. How mammals achieve such a state of suspended animation remains unclear. Here we show that several strains of type 2 diabetic mice spontaneously enter into hibernation-like suspended animation (HLSA) in cold temperatures. Nondiabetic mice injected with ATP mimic the severe hypothermia analogous to that observed in diabetic mice. We identified that uric acid, an ATP metabolite, is a key molecular in the entry of HLSA. Uric acid binds to the Na+ binding pocket of the Na+/H+ exchanger protein and inhibits its activity, acidifying the cytoplasm and triggering a drop in metabolic rate. The suppression of uric acid biosynthesis blocks the occurrence of HLSA, and hyperuricemic mice induced by treatment with an uricase inhibitor can spontaneously enter into HLSA similar to that observed in type 2 diabetic mice. In rats and dogs, injection of ATP induces a reversible state of HLSA similar to that seen in mice. However, ATP injection fails to induce HLSA in pigs due to the lack of their ability to accumulate uric acid. Our results raise the possibility that nonhibernating mammals could spontaneously undergo HLSA upon accumulation of ATP metabolite, uric acid.