1656-P: In Vivo Downregulation of Transglutaminase 2 in High Fat Diet (HFD)-Induced Obese Mice Reduces Metabolic Syndrome–Associated Factors

Introduction and Objective: Metabolic syndrome (MetS) in obesity increases the risk for type 2 diabetes, stroke, and heart disease. Fundamental gaps in the field remain to establish specific molecular targets to counteract MetS. Transglutaminase 2 (TGM2), a multifunctional enzyme known to crosslink proteins important for GTPase, cell adhesion, and scaffold activities has been implicated in adipose tissue growth and functioning. The objective of this study was to investigate TGM2 effects in MetS in a diet-induced obese mouse model. Methods: C57BL/6 mice were placed on HFD for 10 weeks and silenced for TGM2 via in vivo RNAi silencing or received a scramble sequence control. Readout indices to evaluate MetS included glucose and insulin tolerance tests, body weight and food consumption monitoring, body DEXA scan, excised tissue phenotyping via histology, qPCR, RNAseq and western blot. Serum was assessed for adiponectin, leptin, free fatty acids and inflammatory parameters. Results: Successful TGM2 silencing was found predominantly in epididymal white adipose tissue (eWAT) and liver. Diet-induced obese mice silenced for TGM2 had lower total body weight that was accompanied with improved glucose sensitivity, lower serum leptin and free fatty acid concentrations, reduced mean adipocyte size and increased adipocyte number in eWAT, along with reduced expression of molecular pathways associated with adipose tissue growth. Furthermore, there was an observed reduction in liver weight and hepatic steatosis and increased total lean mass. Conclusion: Results suggest that reducing TGM2 expression reduced obesity and improved glucose homeostasis, making TGM2 modulation in obesity a promising therapeutic approach targeting MetS. Disclosure D. Elizondo: None. M. Hollis: None. T.P. Patel: None. R. Roberson: None. J. Chen: None. J.A. Yanovski: Research Support; Rhythm Pharmaceuticals, Inc., Soleno Pharmaceuticals, Inc, Versanis Bil, Hikma Pharmaceuticals, Inc., National Institutes of Health. Funding National Institute of Child Health and Human Development (ZIAHD00641); National Institute of Diabetes and Digestive and Kidney Diseases (1K99DK136921)