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Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α – published online 13/01/2024

Liu graphical abstract

Beibei Liu, Di Xie, Xinmei Huang, Sungho Jin, Yangyang Dai, Xiaoli Sun, Da Li, Anton M. Bennett, Sabrina Diano, Yingqun Huang

Skeletal muscle insulin resistance is a critical component of the pathogenesis of type 2 diabetes. Decreased expression of PGC-1α is among the many mechanisms implicated in insulin resistance; however, how this dysregulation occurs is yet to be elucidated. In this issue Liu, Xie, Huang et al ( report increased expression of ten-eleven translocation 3 (TET3) in skeletal muscle of individuals with type 2 diabetes as compared with individuals without diabetes. They show that TET3 interacts with and reduces the abundance of PGC-1α in myocytes. Specifically, TET3 was found to form protein complexes with PGC-1α, preventing its phosphorylation on sites known to promote protein stability and activity. It is proposed that this results in decreased mitochondrial respiration and insulin sensitivity in myocytes. Consistent with this theory, the authors showed that mice with skeletal muscle-specific TET3 deficiency exhibited increased PGC-1α abundance, and enhanced muscle and whole-body insulin sensitivity. Moreover, these animals remained insulin sensitive under high-fat diet challenge. The authors conclude that these findings hold promise for developing novel, TET3-targeting therapeutic agents for insulin resistance and type 2 diabetes.

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