282-OR: Nod1 Plays a Causal Role in Western-Diet–Induced Insulin Resistance and Glucose Intolerance in Microbiota-Deficient Conditions

Introduction & Objective: Recent studies revealed that nucleotide-binding oligomerization domain 1 (Nod1), an innate immunity receptor, mediates high fat diet (HFD) effects to induce insulin resistance and glucose intolerance. Circulating free fatty acids, acting as damage-associated molecular patterns (DAMPs), activate Nod1, which also senses gut microbiota-derived pathogen-associated molecular patterns (PAMPs), which are thought to be absorbed into the circulation as HFD changes gut permeability. While Nod1-null mice showed protection from HFD-induced insulin resistance, it remains unclear if this is driven by PAMPs or DAMPs. To investigate whether the protective effect of Nod1 deficiency is abolished without PAMPs, we studied Nod1 knockout (KO) in germ-free (GF) conditions, minimizing PAMP influence to reveal DAMP-induced Nod1 activation's role in insulin resistance and T2D.

Methods: We subjected GF or conventionally maintained C57BL/6 Nod1 KO and wild type (WT) mice to an 8-week high-fat, high-sucrose diet (HFSD) starting at 5 weeks of age to mimic Western diet-induced glucose intolerance and early diabetes. At 13 weeks, mice underwent intraperitoneal insulin tolerance tests (IPITT) and glucose tolerance tests (IPGTT) three days apart to assess insulin sensitivity and glucose tolerance.

Results: HFSD-induced insulin resistance in WT mice was alleviated by Nod1 deficiency in both non-GF and GF KO groups, as demonstrated by IPITT. In IPGTT, calculated insulin sensitivity and disposition index revealed HFSD-induced insulin resistance and attenuated β-cell function in WT mice, which was improved in Nod1KO mice, regardless of GF conditions.

Conclusion: Our data suggest DAMP mediated Nod1 activation as displayed by protection from HFSD induced insulin resistance and glucose intolerance in the absence of microbial PAMPs. These findings indicate that Western diet exerts its diabetogenic effects via Nod1 independent of gut microbiota.