Atg16L1 Knockout Induces Insulin Resistance through Proteasomal IRS1 Degradation, Mediated by the Induction of ER Stress
Bibliographic record
Abstract
Insulin resistance is a defining feature of type 2 diabetes, yet our understanding of the progression and development of insulin resistance is incomplete. Recently, deficient autophagy, a bulk degradation pathway, was associated with the induction of insulin resistance, although the causative mechanism remains unknown. We sought to investigate the underlying signals responsible for how deficient autophagy induces insulin resistance. We report that knockout of an essential autophagy protein, Autophagy Related 16L1 (Atg16L1), in mouse embryonic fibroblasts (MEFs) markedly decreases insulin and insulin‐like growth factor 1 (IGF1)‐stimulated Akt recruitment to the cellular membrane and phosphorylation on S473 and T308, as well as cortical actin remodelling. Atg16L1 KO did not adversely affect insulin receptor (IR) or IGF1 receptor content, cell surface IR localization or 125 I‐insulin binding. However, Atg16L1 KO MEFs and Atg16L1 depleted HeLa cells displayed reduced protein content of Insulin Receptor Substrates (IRS1 and IRS2), pivotal proximal signals in insulin signaling known to be dysregulated in insulin resistant and diabetic states. Corroborating these findings, visceral adipose tissue of high fat‐fed mice displayed lower Atg16L1 mRNA and IRS1 protein content. Expression of IRS1myc recovered insulin‐stimulated Akt phosphorylation in KO MEFs. Treatment of KO MEFs with the proteasome inhibitor MG132restored IRS1 protein content and insulin‐stimulated Akt phosphorylation. Moreover, ER stress, which induces insulin resistance at the level of IRS1, was upregulated in Atg16L1 KO MEFs. Alleviating ER stress with the chemical chaperone phenylbutyrate increased IRS1 protein expression and insulin stimulated Akt phosphorylation similar to MG132. Together, we show that Atg16L1 KO induces insulin and IGF1 resistance through the induction of ER stress, leading to targeted proteasomal degradation of IRS1. Support or Funding Information S.F.C was supported by an NSERC Alexander Graham Bell Canada Graduate Scholarship‐Doctoral (CGS D), as well as Restracomp and a 2018 Pricewaterhouse Coopers Student Bursary from the Hospital for Sick Children. This abstract is from the Experimental Biology 2019 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) | 0.000 | 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) | 0.002 | 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".