Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge
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Bibliographic record
Abstract
Background and Aims Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon‐like peptide 1 (GLP‐1)–based diabetes drugs. As GLP‐1 receptor (GLP‐1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP‐1R, and clarify whether FGF21 mediates certain functions of the GLP‐1R agonist liraglutide. Approach and Results Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high‐fat diet (HFD)‐fed mice and compared with the effects of the dipeptidyl‐peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r−/− mice and liver‐specific FGF21‐knockout ( lFgf21‐KO ) mice. In wild‐type mouse liver that underwent RNA sequencing and quantitative reverse‐transcription PCR, we observed liraglutide‐stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21 . In mice with HFD‐induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body‐weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide‐treated mice but was not observed in sitagliptin‐treated mice. In HFD‐fed Glp1r−/− mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21‐KO mice undergoing dietary challenge, the body‐weight‐gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. Conclusions We suggest that liraglutide‐stimulated hepatic Fgf21 expression may require GLP‐1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP‐1–based drugs in NAFLD.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it