SAT-183 Activating Transcription Factor 4 (ATF4) As A Possible Mediator Of Gluconeogenic And Lipogenic Actions Of Fat Mass And Obesity Associated (FTO) In Liver
Bibliographic record
Abstract
Hepatic metabolism is critical for the maintenance of whole body glucose and lipid metabolism. Excessive hepatic glucose production and de novo lipogenesis contributes to fasting hyperglycemia in diabetes and hepatic steatosis, respectively. Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. However, the role of FTO in the regulation of hepatic metabolism is not well understood. We have demonstrated that increased FTO level leads to an increase in gluconeogenic glucose-6-phosphatase (G6Pase) mRNA expression in hepatic cells. Conversely, reduced FTO level or inhibition of FTO activity caused a reduction of G6Pase mRNA expression. The transcription factor activating transcription factor 4 (ATF4) is a positive regulator of the expression of gluconeogenic and lipogenic genes in hepatocytes. These findings led to the hypothesis that increased hepatic FTO expression or activity leads to an increase expression of not only gluconeogenic genes but also lipogenic genes by activating ATF4, while reduced hepatic FTO expression or activity produces opposite effects. To address this hypothesis, we examined the effect of altered FTO expression on ATF4 and lipogenic stearoyl-CoA desaturase (SCD1) mRNA levels in alpha mouse liver 12 (AML12) immortalized hepatic cell line. We also treated AML12 cells with a small molecule FTO inhibitor rhein and measured the expression level of these genes. FTO overexpression resulted in increased ATF4 and SCD1 mRNA levels. FTO knockdown resulted in a reduction of SCD1 mRNA levels. Similarly, rhein treatment (1 μM) for 24 h reduced levels of ATF4 and SCD1 mRNA without causing cytotoxicity. These data support the hypothesis that FTO acts to shift hepatic metabolism toward anabolism, leading to increased gluconeogenesis and de novo lipogenesis and ATF4 is a possible mediator of this action. Our data also suggest that reduced activity of hepatic signaling pathways involving FTO and ATF4 may be effective in reversing hyperglycemic and hepatic steatosis partly by reducing gluconeogenesis and de novo lipogenesis in the liver. Sources of Research Support: Supported by University Research Grants Program (URGP) from University of Manitoba.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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".