Sayler, A. L.; Hammond, J. R.

SLC43A3 encodes for a membrane transporter selective for purine nucleobases (equilibrative nucleoside transporter 1; ENBT1). Adenine, an endogenous substrate for ENBT1, plays an important role in many biochemical and physiological processes, including cellular energy metabolism. To investigate how the loss of ENBT1 impacts these processes, we generated a slc43a3-null (global; KO) mouse model. Metabolic function, physical activity, and food and water consumption were assessed in male and female wild-type (WT) and KO mice (age 10-12 weeks) for a 66-hour period (12 hr light/dark cycle). Blood pressure and heart rate of each group of mice were also assessed using a rodent tail cuff method. Female KO mice showed a significant decrease in oxygen consumption and carbon dioxide generation with no change in RER, relative to female WT mice. This was accompanied by a significant 4-hour negative phase-shift in circadian rhythm in the metabolic and activity measures in the female, but not male, KO mice. Male KO mice, in contrast, displayed a significant decrease in rearing activity and blood pressure, and an increase in metabolic expenditure relative to WT mice. It may be concluded that loss of slc43a3-encoded ENBT1 impacts numerous measures of activity in mice, with female mice impacted more significantly than male mice. This may reflect disruption of purinergic processes associated with energy metabolism coincident with changes in adenine availability. The results of this study also imply an interaction between estrogen and adenine metabolism in the regulation of circadian rhythms.