AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine.
Skeletal muscle plays important roles in whole-body energy homeostasis. Excessive skeletal muscle lipid accumulation is associated with some metabolic diseases such as obesity and Type 2 Diabetes. The energy sensor AMPK (AMP-activated protein kinase) is a key regulator of skeletal muscle lipid metabolism, but the precise regulatory mechanism remains to be elucidated. Here, we provide a novel mechanism by which AMPK regulates skeletal muscle lipid accumulation through fat mass and obesity-associated protein (FTO)-dependent demethylation of N6-methyladenosine (m6A). We confirmed an inverse correlation between AMPK and skeletal muscle lipid content. Moreover, inhibition of AMPK enhanced lipid accumulation, while activation of AMPK reduced lipid accumulation in skeletal muscle cells. Notably, we found that mRNA m6A methylation levels were inversely correlated with lipid content in skeletal muscle. Furthermore, AMPK positively regulated the m6A methylation levels of mRNA, which could negatively regulate lipid accumulation in C2C12. At the molecular level, we demonstrated that AMPK regulated lipid accumulation in skeletal muscle cells by regulating FTO expression and FTO-dependent demethylation of m6A. Together, these results provide a novel regulatory mechanism of AMPK on lipid metabolism in skeletal muscle cells and suggest the possibility of controlling skeletal muscle lipid deposition by targeting AMPK or using m6A related drugs.
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Weiche
W
Wu
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Jie
J
Feng
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Denghu
D
Jiang
Institute of Subtropical Agriculture, The Chinese Academy of Science, Changsha, Hunan 410125, P. R. China.
Xihong
X
Zhou
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Qin
Q
Jiang
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Min
M
Cai
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Xinxia
X
Wang
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Tizhong
T
Shan
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition &Feed Sciences, Ministry of Agriculture; Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.
Yizhen
Y
Wang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000073398:Demethylation; D015870:Gene Expression; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; C010223:N-methyladenosine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D055372:AMP-Activated Protein Kinases; D000241:Adenosine