A novel mechanism for UCP1‐independent thermogenesis

Nonshivering thermogenesis (NST) via uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is a well‐established mechanism for temperature homeostasis in many mammals. The recent findings that BAT function is limited in adult humans and UCP1‐deficient mice can be cold adapted indicated that alternative sites of NST must exist. Ongoing studies in our laboratory have established that sarcolipin (SLN), an inhibitor of the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), is involved in skeletal muscle‐based NST. Therefore, we hypothesized that SLN can compensate for UCP1 and that SLN and UCP1 play synergistic roles. To test this, we generated double knockout (DKO) mice deficient in both UCP1 and SLN and challenged them to acute cold (4°C). The DKO mice are severely cold‐intolerant, compared to UCP1‐KO and SLN‐KO. Furthermore, we show that SLN is upregulated in the skeletal muscle of UCP1‐KO mice and UCP1 is induced in SLN‐KO mice during cold adaptation. These data suggest that UCP1 and SLN play synergistic roles in cold adaptation and that they compensate for one another. Importantly, these data establish SLN as a critical component of NST and suggest that muscle‐based NST can replace BAT when BAT function is minimal as found in adult large mammals, including humans. Because NST mechanisms can be exploited to expend excess energy, these findings have novel implications for weight loss and obesity therapies. Research Support: NIH.