TISSUE‐SPECIFIC GENETIC TARGETING OF INOS REVEALS AN UNEXPECTED ROLE OF ADIPOCYTE INOS IN THE DEVELOPMENT OF INSULIN RESISTANCE, DYSLIPIDEMIA AND ALTERED ENERGY METABOLISM IN DIET‐INDUCED OBESE MICE
Bibliographic record
Abstract
Nitric oxide (NO) is synthesized from L‐arginine by NO synthase (NOS) enzymes. The expression of the inducible member of the NOS family, iNOS, is markedly enhanced in adipose, skeletal muscle and liver tissues in response to bacterial endotoxins (LPS), inflammatory cytokines, and diet‐induced obesity. We have previously showed that mice lacking iNOS are protected from insulin resistance induced by high‐fat feeding; acute exposure to LPS or lipid infusion, providing genetic evidence that iNOS is a key inflammatory mediator in these settings. It is believed that in immune cells within adipose tissue of obese animals mainly contribute to iNOS expression and the immunometabolic perturbances of obesity. To clarify the specific role of iNOS induction in adipocytes, muscle and liver in the development of insulin resistance and altered energy metabolism of obese animals, mice containing flox sites flanking Exon 2 of nos2 were created. Myocyte‐specific (MuKO), hepatocyte‐specific (HeKO) and adipocyte‐specific (AdKO) iNOS knockout mice were generated on a C57BL/6J background by crossing mice homozygous for floxed iNOS (nos2 f/f ) with Ckmm‐cre, Alb‐Cre and Adipoq‐Cre, respectively. KO mice and their respective wild‐type controls were fed regular chow or a high‐fat/high sucrose (HFHS) diet for 8 weeks and then extensively phenotyped for metabolic outcomes. We found that AdKO mice were partially protected from HFHS‐diet insulin resistance as compared to WT littermates on the same diet, and that this beneficial effect was associated with increased energy expenditure as measured by indirect calorimetry. These effects were observed despite no differences in body weight gain and adiposity. Adipocyte‐specific iNOS KO was also associated with a reduction in circulating triglyceride levels upon HFHS feeding. However, disrupting iNOS selectively in skeletal muscle and liver did not improve metabolic phenotypes after 2 months of HFHS feeding. Our results reveal an unexpected role of iNOS specifically expressed in adipocytes in the development of systemic insulin resistance, dyslipidemia and altered energy metabolism in diet‐induced obesity, suggesting an important role of adipocyte NO release in the metabolic complications of obesity. The role of muscle and liver iNOS appears limited after 2 months of HFHS diet but studies are underway to document their potential impact after longer‐term feeding experiments. Support or Funding Information Canadian Institutes of Health Research This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".