Restoration of hepatic TDAG51 expression improves insulin signaling and reduces weight gain in mouse models of non‐alcoholic fatty liver disease
Bibliographic record
Abstract
The absence of T‐cell death‐associated gene 51 (TDAG51) in mice results in late‐onset insulin resistance (IR), obesity and hepatic steatosis. In support of these findings, mice fed a high fat diet, which leads to IR and obesity, as well as the leptin‐deficient mouse model, a well‐established genetic model of type 2 diabetes and obesity, show significantly diminished hepatic TDAG51 protein levels. Here we report that hepatic TDAG51 protein levels are reduced in multiple mouse models of liver injury and in liver biopsies from patients with non‐alcoholic steatohepatitis. Given that hepatic TDAG51 protein levels decrease under conditions of fatty liver and correlate with IR, we investigated whether restoring hepatic TDAG51 protein levels would reverse hepatic IR. Hepatic expression of a TDAG51‐GFP fusion protein was increased via a liver‐specific adeno‐associated virus (AAV) in both TDAG51 knockout and leptin‐deficient mice. Restoration of hepatic TDAG51 protein increased insulin sensitivity and reduced weight gain compared to mice injected with a control AAV vector encoding only GFP. Specifically, TDAG51 knockout mice expressing ectopic TDAG51 demonstrated: 1) improved Akt 473 phosphorylation, 2) reduced expression of diacylglycerol O‐acyltransferase, which catalyzes the final step in triglyceride biosynthesis, and 3) reduced expression of the SREBP‐1c target genes, fatty acid synthase and stearoyl‐CoA desaturase‐1. These findings demonstrate that restoring hepatic TDAG51 in mouse models of metabolic disease and fatty liver improves hepatic insulin signaling and reduces weight gain. However, this protective effect is lost over time, correlates with fatty liver progression and is accompanied by diminished hepatic TDAG51 protein stability. Taken together, these studies suggest that hepatic TDAG51 is an important factor that mediates insulin signaling and weight gain. Future studies aimed at increasing hepatic TDAG51 protein levels and/or stability may represent a new therapeutic opportunity for the amelioration of obesity and augmentation of insulin sensitivity in non‐alcoholic fatty liver disease. Support or Funding Information R.C.A is supported by grants from the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research. Financial support from St. Joseph's Healthcare Hamilton is also acknowledged. R.C.A. is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Amgen Canada Research Chair in Nephrology. K.N.M acknowledges financial support from the William R. Hummel Homocystinuria Research Fund and holds the Ehst‐Hummel‐Kaufmann Family Endowed Chair in Inherited Metabolic Disease. G.R.S is supported by a Canada Research Chair in Metabolism and Obesity, the J. Bruce Duncan Endowed Chair in Metabolic Diseases and grants from the Canadian Institutes of Health Research and Diabetes Canada. 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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".