1713-P: Adipocyte O-GlcNAc Transferase Regulate Adipogenesis through De Novo Lipogenesis in Mice

O-linked N-acetylglucosamine (O-GlcNAc) modification is one of the post-translational modifications which modulates protein fate and function, and it is mediated by O-GlcNAc transferase (OGT). The substrate of OGT, UDP-GlcNAc, is biosynthesized through the branch of glycolysis. Thus O-GlcNAcylation has been regarded as a nutrient sensor. Metabolic regulation in white adipose tissues (WAT) is dramatically changed in the process of obesity. We previously reported that the deletion of Ogt in adipose tissues (Ogt-FKO) decrease WAT mass without affecting glucose tolerance in mice under normal condition. However, the role of O-GlcNAcylation in WAT in the process of being obesity remains unknown. In this study, we investigated the role of O-GlcNAcylation in WAT under diet induced obesity. Despite no significant differences in food intake, body weight gain by high-fat diet was suppressed in Ogt-FKO mice along with the significant decrease of WAT mass. However, Ogt-FKO mice were severely impaired glucose tolerance and decreased insulin sensitivity in liver, which was confirmed by hyper-insulinemic euglycemic clamp. Histologically, we observed smaller adipocytes and fibrosis in WAT of Ogt-FKO mice. In addition, gene expression of F4/80, CD11c, MCP-1 and Col1a1 were significantly higher in Ogt-FKO mice, suggesting increased inflammation and fibrosis. Also, the expression of genes associated to fatty acid synthesis such as SREBP-1c, FAS, SCD1 and SCD2 were reduced in Ogt-FKO mice. Furthermore, Ogt-FKO mice showed lower serum concentration of adiponectin and leptin (46.43 ± 3.62 vs. 8.42 ± 1.53ng/ml) along with their gene expression, which is consistent with severe atrophy of WAT in Ogt-FKO mice. In conclusion, loss of O-GlcNAcylation in WAT exhibited obesity resistance and impaired glucose tolerance because of lipoatrophy under diet induced obesity, and the results suggest that O-GlcNAcylation in WAT plays important role for fatty acid synthesis and functional adipocyte formation. Disclosure K. Morino: None. A. Tsuji: None. N. Ohashi: None. S. Ida: None. R.J. Perry: Research Support; Self; AstraZeneca. S. Ugi: None. Y. Fujita: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, LLC, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Consultant; Self; Novo Nordisk A/S. Consultant; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Self; Gilead Sciences, Inc., iMetabolic Biopharma Corporation. Other Relationship; Spouse/Partner; iMetabolic Biopharma Corporation. Other Relationship; Self; Maze Therapeutics. H. Maegawa: Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science (18K16226)