SAT653 Conditional Knockout Of Neural Sarm1 Improves Body Mass And Metabolic Health With High Fat Diet

Abstract

Abstract Disclosure: L. Dabill: None. I. Shen: None. X. Zhang: None. A. DiAntonio: None. E. Scheller: None. Sterile alpha and TIR motif containing 1 (Sarm1) is a toll-like receptor, highly expressed in the nervous system, that is activated with injury, inflammation, and oxidative stress to promote axon degeneration and dysfunction. Previous findings with global knockout of Sarm1 showed evidence of metabolic improvements in high-fat diet (HFD) induced type 2 diabetes (T2D) as well as reduced peripheral axon degeneration. We hypothesize that this is due to the actions of Sarm1 in the nervous system. To test this hypothesis, we used Baf53b-Cre to knock out Sarm1 in all neurons throughout the body (Sarm1-cKO). Both control and Sarm1-cKO mice were fed HFD for 24 weeks, starting at 4-6 weeks of age. Quantitative PCR (qPCR) analysis confirmed high Sarm1 expression in the dorsal root ganglia (DRG) with a significant decrease in Sarm1-cKO mice; no significant difference in Sarm1 expression was observed in bone, testis, liver, iWAT, or brain tissue between control and Sarm1-cKO mice. Over the 24-week study period, Sarm1-cKO mice fed HFD gained 20% less body mass than controls (20.8g mass gain on average in cKO vs 26g mass gain in control mice). Furthermore, subcutaneous inguinal fat, but not visceral gonadal fat, was preferentially reduced by 26% in Sarm1-cKO mice. Sarm1-cKO mice on HFD also showed evidence of metabolic rescue with smaller livers and less steatosis. Lastly, insulin tolerance testing (ITT) results suggest that Sarm1-cKO mice on HFD were more sensitive to insulin than controls. Sarm1 inhibitors are currently under clinical development for the treatment of neurodegenerative disease. These results show that inhibition of Sarm1-dependent neurometabolic regulatory pathways also has the potential to support metabolic health in settings of obesity and T2D. Presentation: Saturday, June 17, 2023