Altered metabolism in RGS2 KO mice

Regulator of G‐protein signaling 2 (RGS2) is known to inhibit Gq‐ and Gs‐mediated GPCR signalling. We have previously reported that RGS2 knock out mice (rgs2−/−) exhibit a lean phenotype compared to their wildtype (WT) counterparts, with significantly reduced fat deposits, leptin levels, and serum lipids. The objective of this study is to further elucidate the role of RGS2 in metabolism. CLAMS metabolic cages were used to measure various indices in 1 month‐, 3 month‐, and 12 month‐old rgs2−/− and WT mice. Animals were acclimatised in metabolic cages for 24 hours (12‐hour light and dark cycles), followed by another 24 hours of metabolic recordings. At both 3 months and 12 months, rgs2−/− mice displayed increased rates of respiratory intake (vO 2 ) and expiratory output (vCO 2 ), particularly during the dark cycle, suggesting increased metabolic activity in the knockouts. Furthermore, calculated respiratory exchange ratios (RER) suggest an increase in carbohydrate rather than fat or protein metabolism in rgs2−/− mice of all three age groups compared to WT. Hyperphagia, as well as increased water intake, were also observed in the knockouts at 3 and 12 months. Even with significantly increased food and water intake, 3 and 12 month‐old rgs2−/− mice maintained lower body weights compared to WT, and displayed comparable ambulatory activity. In addition, a 30% diet restriction study in which 3 month‐old mice were fed once daily, followed by metabolic cage measurements, was performed to determine possible alterations in metabolism following changes in food intake. Compared to our previous ad libitum studies, the difference in vO 2 and vCO 2 between WT and rgs2−/− mice was further exacerbated. In addition, RERs were significantly higher in rgs2−/− mice, and allude to the possibility of elevated carbohydrate metabolism in rgs2−/− mice. Ambulatory activity remained comparable to WT. Interestingly, diet restriction appears to have exacerbated the hyperphagic phenotype of rgs2−/−mice – although body weights remained stable, rgs2−/−mice consumed 50% of their daily food amounts at a 4 times higher rate than WT, and displayed hoarding behaviour. The lack of changes in overall activity between genotypes in both ad libitum and diet restricted mice suggests that weight loss in rgs2−/− mice is due to internal energy metabolism rather than overt physical activity. These results suggest that RGS2 may play an important role in the regulation of body metabolism. Support or Funding Information Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario

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