MSG Mediates Systemic Energy Homeostasis By Regulating Phosphatidylcholine Synthesis In Skeletal Muscle

Skeletal muscle is not only a vital metabolic organ but also an important secretory organ of the body,which plays pivotal roles in maintaining whole body metabolic homeostasis by secreting factors to crosstalk with other metabolic organs.In this study,we find that skeletal muscle communicates with white adipose tissue and mediates systemic energy homeostasis by secreting phosphatidylcholine.MSG,a skeletal muscle specific transcriptional factor,has higher expression level in glycolytic fibers than in oxidative fibers,suggesting that MSG might exert unappreciated functions in orchestrating metabolism in mature fibers.We take advantage of MSG knockout mice(MSG-/-mice)to investigate the role of MSG in skeletal muscle metabolism.We find that genes regulate glycolytic metabolism are down-regulated while genes regulate oxidative phosphorylation metabolism are up-regulated after deleting MSG in skeletal muscle.This result shows that MSG has the function of regulating skeletal muscle metabolism.Because skeletal muscle metabolism is very important for whole body energy metabolism,we further evaluate the energy metabolism of MSG-/-mice.Our results show that MSG-/-mice have higher metabolic rate and resist to HFD induced obesity.These results show that MSG regulates systemic energy homeostasis.In order to explore the mechanism for MSG regulating systemic metabolism,we carry out untargeted lipidomics analysis using conditioned medium(CM)of skeletal muscle from MSG-/-mice and wild type littermates fed on SD and HFD,respectively.We find that the secretion of phosphatidylcholine(PC)is significantly increased in skeletal muscle of MSG-/-mice compared to that in wild type littermates.The observations are further individually validated by ELISA.Furthermore,the level of PC in serum of MSG-/-mice is also significantly higher than that in wild type littermates.Next,we treat mature adipocytes with PC and find that PC significantly induce white adipocytes browning.The result suggests that skeletal muscle of MSG-/-mice regulate white adipose tissue browning and systemic energy homeostasis by secreting PC.Unsaturated fatty acids(USFA)can activate the activity of phosphocholine cytidylyltransferase a(CTa),a rate-limiting enzyme that regulates PC synthesis.Our ELISA results show that the content of USFA in skeletal muscle of MSG-/-mice was significantly higher than that of wild type littermates.What’s more,stearyl CoA desaturase 1(SCD1),an enzyme catalyzes the conversion of saturated fatty acids(SFA)to USFA,has a higher expression level in skeletal muscle of MSG-/-mice confirmed by real-time PCR and Western Blotting.The above results suggest that MSG mediates PC synthesis in skeletal muscle by regulating SCD1 expression.The mechanism for MSG regulating the expression of SCD1 is under studying now.In summary,our study find that MSG mediates wholebody energy homeostasis by regulating the synthesis of PC in skeletal muscle,which can induce browning of white adipose tissue.