Two Mechanisms Mediating Enhanced Glucose Tolerance with Regulator of GS Protein 14 Disruption; Increased Exercise Capacity and Increased Brown Adipose Tissue

The goal of this investigation was to examine glucose tolerance and exercise capacity in the regulator of the G protein signaling 14 knock out (RGS14 KO) mouse. Exercise capacity, which affects glucose tolerance, was improved in the RGS14 KO compared to their wild type littermates (WTL), as reflected by a 64 ± 8%, p<0.05, increase in total distance run on a treadmill. Glucose tolerance was also increased in the RGS14 KO, compared with their WTL, as reflected by a 40 ± 11%, p<0.05, reduction in the area under the glucose curve after administration of 2g of glucose and monitoring blood glucose over the next 3 hours. The insulin tolerance test showed similar improvement in RGS14 KO. The RGS14 KO is also a model of obesity protection, as reflected by 44% less white adipose tissue in the inguinal fat pad, compared with WTL. However, brown adipose tissue (BAT) is increased in the RGS14 KO, as reflected by a 47% increase in the BAT index. To determine if BAT mediated the salutary effects of exercise and glucose tolerance in the RGS14 KO, we simulated a BAT KO, by removing it from the RGS14 KO and transplanting the BAT to their WTL. This resulted in a reversal of phenotype, where the WTL with transplanted BAT behaved like RGS14 KO and the RGS14 KO behaved like WTL; i.e., the WTL with transplanted BAT from RGS14 KO exhibited improved exercise capacity by 36 ± 5%, p<0.05, compared with the RGS14 KO donors. Glucose tolerance showed the same pattern, where WTL with the RGS14 KO BAT transplants exhibited a 39 ± 6% reduction in area under the glucose curve, p<0.05, compared with the RGS14 KO BAT donors. The insulin tolerance test showed similar improvement in the WTL mice with BAT transplant. Thus, there are two mechanisms by which glucose tolerance is enhanced in RGS14 KO: 1. Improved exercise capacity; and 2. Increased BAT, suggesting that either inhibiting RGS14 or increasing BAT would be novel therapeutic approaches to protect against diabetes and obesity.