Skeletal muscle non-shivering thermogenesis as an attractive strategy to combat obesity

Obesity is a chronic disease derived from disequilibrium between energy intake and energy expenditure and evolving as a challenging epidemiological disease in the 21st century. It is urgently necessary to solve this issue by searching for effective strategies and safe drugs. Skeletal muscle could be a potential therapeutic target for the prevention and treatment of obesity and its associated complications due to non-shivering thermogenesis (NST) function. Skeletal muscle NST is based dominantly on futile sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) pump cycling that leads to a rise in cytosolic Ca²⁺, increased adenosine triphosphate (ATP) hydrolysis and heat production. This review will highlight the mechanisms of skeletal muscle NST, including SLN mediated SERCA pump futile cycling, SR-mitochondrial crosstalk and increased mitochondrial biogenesis, and thermogenesis induced by uncoupling proteins 3 (UCP3). We then summarize natural products targeting the pathogenesis of obesity via skeletal muscle NST, offering new insights into pharmacotherapy and potential drug candidates to combat obesity.