Abstract 17217: Brown Adipose Tissue Promotes Exercise Capacity Through Sirtuin-3

It is well recognized that increased white adipose tissue impairs exercise performance. However, little is known about regulation of exercise performance by brown adipose tissue (BAT). The Regulator of G Protein Signaling 14 (RGS 14) knockout (KO) mouse is a model of enhanced longevity and improved metabolism through a novel BAT mechanism. The RGS14 KO mice also exhibit enhanced exercise performance. Accordingly, the goal of this investigation was to determine if BAT from RGS14 KO mice transplanted into their wild type littermates (WTL) recapitulated the enhanced exercise performance of the RGS14 KO mice. To accomplish this, BAT was extracted from the RGS14 KO mice and transplanted into their WTL and exercise was performed 3 days later. When BAT was transplanted from the RGS14 KO mice to WTL, a reversal of phenotype was observed, i.e., WTL with the transplanted BAT ran for a longer distance (565 ± 18m vs. 386 ± 17m) and performed 52% more work to exhaustion, p<0.05, and showed significant increases in maximum VO 2 (21%), VCO 2 (27%), and energy expenditure (23%), and hind limb blood flow (62%), measured ultrasonically with the Vevo 3100, than was observed in the RGS14 KO BAT donor mice. Interestingly, BAT transplanted from WTL to other WTL also recapitulated the enhanced exercise performance, but not at 3 days after transplantation, but rather after 8 weeks of transplantation. Since mitochondrial numbers and cross sectional area were enhanced both in RGS14 KO and BAT recipients, we examined whether blocking Sirtuin-3 (SIRT3), a master regulator of mitochondria, would eliminate the improved exercise performance in the mice with BAT transplants. To accomplish this, we crossed the mice with BAT transplants from RGS14 KO mice with SIRT3 KO mice, which abolished the enhanced exercise capacity in mice with BAT transplants. In conclusion, in contrast to increased white adipose tissue, which impairs exercise performance, brown adipose tissue enhances exercise performance, through a SIRT3 mechanism, suggesting that brown adipose tissue could be a potential mechanism for improving exercise capacity in patients with exercise intolerance.