Zumbaugh, Morgan D.Yen, Con-NingBodmer, Jocelyn S.Shi, HaoGerrard, David E.2022-04-082022-04-082021-07-131664-042X682052http://hdl.handle.net/10919/109612Besides its roles in locomotion and thermogenesis, skeletal muscle plays a significant role in global glucose metabolism and insulin sensitivity through complex nutrient sensing networks. Our previous work showed that the muscle-specific ablation of O-GlcNAc transferase (OGT) led to a lean phenotype through enhanced interleukin-15 (IL-15) expression. We also showed OGT epigenetically modified and repressed the Il15 promoter. However, whether there is a causal relationship between OGT ablation-induced IL-15 secretion and the lean phenotype remains unknown. To address this question, we generated muscle specific OGT and interleukin-15 receptor alpha subunit (IL-15r alpha) double knockout mice (mDKO). Deletion of IL-15r alpha in skeletal muscle impaired IL-15 secretion. When fed with a high-fat diet, mDKO mice were no longer protected against HFD-induced obesity compared to wild-type mice. After 22 weeks of HFD feeding, mDKO mice had an intermediate body weight and glucose sensitivity compared to wild-type and OGT knockout mice. Taken together, these data suggest that OGT action is partially mediated by muscle IL-15 production and provides some clarity into how disrupting the O-GlcNAc nutrient signaling pathway leads to a lean phenotype. Further, our work suggests that interfering with the OGT-IL15 nutrient sensing axis may provide a new avenue for combating obesity and metabolic disorders.application/pdfenCreative Commons Attribution 4.0 InternationalO-GlcNAc signalinginterleukin-15tissue cross-talkinsulin sensitivitymyokinesArticle - Refereedhttps://doi.org/10.3389/fphys.2021.6820521234326778