| Popis: |
Thermogenic mechanisms are well known to influence body temperature maintenance as well as energy balance, including body mass and composition. Uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is a substantial component of cold-induced thermogenesis, and loss of UCP1 in mice results in severe diet-induced obesity. However, UCP1-knockout (UCP1-KO) mice can readily adapt to cold by gradual acclimatization, and under certain conditions, UCP1-KO mice do not develop diet-induced obesity. Furthermore, BAT function is either absent (birds and marsupials) or is minimally present as in adult mammals, including humans, yet these organisms maintain thermogenesis, suggesting other components are involved. Sarcolipin (SLN), a regulator of the sarcoplasmic reticulum Ca2+ transport ATPase (SERCA) in muscle, was recently identified as a significant contributor to cold-induced thermogenesis and diet-induced energy expenditure. When bound to SERCA, SLN has been shown to uncouple Ca2+ transport from ATP hydrolysis and increase heat production. However, the mechanistic basis for SLN in thermogenesis has not been fully elucidated. The studies here sought to further our understanding of how SLN contributes to both cold-induced thermogenesis and diet-induced thermogenesis. The major goals were: 1) to demonstrate that SLN-based heat production in muscle is a major mechanism for thermogenesis especially when BAT function is minimal and 2) to demonstrate that SLN is involved in diet-induced thermogenesis. Because BAT is a dominant contributor to thermogenesis in mice, we utilized the UCP1-KO mouse model and a double knockout (DKO) mouse for SLN and UCP1 to uncover the role of SLN. Our data showed that the DKO mice are severely cold-sensitive, indicating both SLN and UCP1 are important for cold-induced thermogenesis. Importantly, we also found that UCP1 and SLN compensate for the loss of one another during cold adaptation, suggesting muscle and BAT play complementary thermogenic roles. Surprisingly, the DKO mice were able to survive gradual cold exposure, though at an extremely high energetic cost, with significant weight loss and depletion of fat stores. Together, these studies suggest that UCP1 and SLN are required to maintain optimal thermogenesis and loss of both systems compromises survival of mice under cold stress. We next sought to determine how the DKO mice would respond to diet-induced obesity by feeding a high fat diet (HFD). After 12 weeks of HFD-feeding UCP1-KO and SLN-KO mice became obese and had similar weight gains and metabolic efficiencies. Surprisingly, the DKO mice gained weight equally, but no more than, the single knockout mice. These data suggest that while SLN and UCP1 play additive roles in cold-induced thermogenesis, they do not appear to compensate for one another in response to diet. That is, both SLN and UCP1 are required for diet-induced thermogenesis, while either SLN or UCP1 is sufficient for body temperature maintenance. The studies performed here establish that SLN is a significant contributor to thermogenesis and has broader implications in our overall understanding of muscle metabolism, energy expenditure, and obesity in animals where BAT content is limited, including humans. |
