282-OR: Nod1 Plays a Causal Role in Western-Diet–Induced Insulin Resistance and Glucose Intolerance in Microbiota-Deficient Conditions
Bibliographic record
Abstract
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. Disclosure S. Rahman: None. N. Tsakiridis: None. M.A. Garcia: None. J. Park: None. Y. Tan: None. A. Giacca: None. Funding Canadian Institutes of Health Research (CIHR 507485)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".