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Adipose Tissue_Appetite_and Obesity

ORF51-03 - Conditional Knockout of Neural Sarm1 Prevents Diet-Induced Weight Gain and Metabolic Dysfunction by Mechanisms Independent of Energy Expenditure

Monday, June 15, 2026
1:55 PM - 2:00 PM CT
Location: Room W181AB
Disclosure(s):
Lila Dabill, B.A.: No financial relationships to disclose

Sterile alpha and TIR motif containing 1 (Sarm1) is an inducible NADase, 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 partially prevented weight gain as well as metabolic improvements in high-fat diet (HFD) induced type 2 diabetes (T2D) in males. We hypothesized that this was due to the actions of Sarm1 in the nervous system. To test this hypothesis, we used Baf53b-Cre to knock out Sarm1 pan-neuronally (Sarm1-cKO). Both control and Sarm1-cKO mice were fed HFD for 24 weeks, starting at 5-7 weeks of age. Quantitative PCR (qPCR) analysis confirmed high Sarm1 expression in the dorsal root ganglia with a significant decrease in Sarm1-cKO mice; no significant difference in Sarm1 expression was observed in bone, gonads, liver, or iWAT tissue. Over the 24-week study period, conditional ablation of neural Sarm1 partially prevented weight gain and fat expansion in male HFD-fed mice with an even greater prevention of weight gain in female mice. Both male and female Sarm1-cKO mice on HFD also had evidence of metabolic rescue with less liver steatosis and improved insulin sensitivity based on insulin tolerance testing (ITT). Additionally, Sarm1-cKO HFD mice showed decreased food intake compared to controls (22% less food intake in females and 5% less in males). Assessments through metabolic caging show that the prevented weight gain in Sarm1-cKO mice is not through increased energy expenditure, locomotor activity, or respiratory exchange ratio (RER). We are currently investigating whether Sarm1 neural knockout may prevent excess weight gain via protection against enteric neuropathy thus stabilizing gut function and hunger cues. Currently, Sarm1 inhibitors are 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.