A308 HNF4A ORCHESTRATES PHYSIOLOGICAL REGULATIONS FROM THE INTESTINE THROUGH INCRETINS
Bibliographic record
Abstract
HNF4α is a transcription factor known to regulate the intestinal epithelium homeostasis. Since HNF4α is also involved in nutrient metabolism, we questioned its ability to regulate systemic physiology from its specific alteration in the intestine. Upon a conditional deletion of HNF4A from the intestinal epithelium, we evidenced a deficiency for incretins (GIP and GLP-1) that favors glycemic and fat metabolism improvements in a murine model. To demonstrate how sensitive is the physiology to intestinal changes in expression of the transcription factor HNF4α and enteroendocrine-derived incretins. Control and HNF4αΔIEC mice were fed with a chow diet or a high fat diet (HFD: 45% calories from fat) for 14 weeks. Effect of HNF4α on GIP transcription was assessed by luciferase-reporter assays. The endocrine system components were measured by ELISA. Physiological parameters were measured using metabolic cage and indirect calorimetry. Gross intestinal absorption of calories was estimated by measuring residual fecal calories using a calorimeter bomb. Glucose (GTT) and Insulin tolerance test (ITT) were performed intraperitoneally with 2 mg/g and 0.75 mUI/g doses, respectively. HNF4αΔIEC mice fed with either high fat or chow diet displayed lowered circulating GIP and GLP-1 levels as compared to controls. These observations were reminiscent to a reduction of GIP and GCG gene transcript levels in the intestine. Coincidently, HNF4α was able to regulate transcriptional activity of the GIP promoter. Despite incretins deficiency, HNF4αΔIEC mice harbored similar weight gain, feeding behavior, intestinal calories absorption and most intriguingly, similar GTT as compared to controls. However, ITT resulted in faster blood glucose clearance in HNF4αΔIEC mice suggesting better insulin sensitivity in this context. Since obesity links insulin resistance and type 2 diabetes, HNF4αΔIEC and control mice were fed with HFD to study their sensitivity to obesity. Once again, HNF4αΔIEC mice displayed similar feeding behavior and intestinal calories absorption, but significant reduced weight gains as compared to controls under HFD, indicative of a higher energy expenditure. In parallel, fat metabolism was investigated using indirect calorimetry and showed a higher lipid consumption profile occurring in HNF4αΔIEC mice during the dark cycle. These data are the first to link HNF4α as a common transcriptional regulator for incretins. Incretins downregulation following the intestinal epithelial loss of HNF4α improved native insulin sensitivity under chow diet and improved fat metabolism under HFD. Therefore, our study emphasizes on the key role of the intestinal epithelium and enteroendocrine function in nutrients metabolism following absorption and their impact on whole physiology. CIHR
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) | 0.002 | 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".