Autophagy‐Related Protein 16L1 (Atg16L1) Depletion Induces Insulin Resistance Through Decreased IRS Expression
Bibliographic record
Abstract
Autophagy is a degradation pathway persisting in all cells at basal levels and further activated by various stimuli, such as starvation. This cellular process is mediated by autophagy‐related (Atg) proteins, which govern cargo recognition and formation of a nascent organelle called the autophagosome. Several Atg proteins have been identified, including Atg3 and the Atg12‐Atg5‐Atg16L1 complex. Recently, connections between autophagy and insulin action have emerged. The insulin receptor (IR) and insulin‐like growth factor receptor (IGF1R) bind and phosphorylate insulin receptor substrate 1 (IRS1) leading to PI3K/Akt activation, which through downstream activation of mTORC1 inhibit autophagy. On the other hand, tissue‐specific, autophagy‐deficient mouse models have attenuated basal and insulin‐stimulated PI3K/Akt signalling. Similarly, expression of the dominant‐negative mutant ATG5K130R in L6 myoblasts reduces insulin‐induced Akt and IRS1 phosphorylation. As growth factor signalling reduces autophagy, these findings suggest a potential feedback mechanism whereby deficient autophagy acts to attenuate insulin signalling. However, the mechanism through which reduced autophagy feeds back onto insulin signalling remains unknown. We hypothesize that interfering with autophagy affects insulin and IGF1 signalling at different levels, including IR, IGF1R and IRS1, and we investigate the potential underlying mechanism. To examine the interplay between deficient autophagy and insulin action, we treated mouse embryonic fibroblasts (MEFs) depleted of Atg3, Atg5, Atg12 or Atg16L1 with 10nM insulin or 100ng/ml (13.3nM) IGF1. Atg depletion did not induce changes in IR content, its localization at the plasma membrane or insulin binding. Interestingly, Atg16L1‐KO MEFs have reduced IRS1 and IRS2 protein content and gene expression, which suggests that defective Atg16L1 affects IRS gene transcription. ER stress is known to reduce Foxo1 protein content, an important transcription factor of IRS, and we have found elevated ER stress in Atg16L1‐KO MEFs. Accordingly, Atg16L1‐ and Atg5‐KO MEFs exhibited attenuated insulin‐ and IGF1‐induced Akt phosphorylation at both S473 and T308 compared to WT. In contrast, insulin‐ and IGF1‐induced Akt phosphorylation was inhibited selectively at T308 in Atg3‐KO MEFs, and at S473 in Atg12 KO MEFs. In conclusion, Atg16L1 appears to induce insulin and IGF1 resistance through decreased IRS1 and IRS2 expression, while Atg3 Atg5 and Atg12 affect signalling at the level of Akt. Support or Funding Information SFC is funded by NSERC‐CGS. 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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.002 | 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".