Suppression of circadian secretion of glucagon‐like peptide‐1 by the saturated fatty acid, palmitate
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Bibliographic record
Abstract
Abstract Aim Glucagon‐like peptide‐1 is an incretin hormone secreted by the intestinal L‐cell with a circadian rhythm that parallels expression of the core clock gene, Bmal1 . Although feeding rats a high‐fat/high‐sucrose Western diet impairs rhythmic glucagon‐like peptide‐1 release, the mechanisms underlying this effect remain unclear. Therefore, the aim of this study was to determine the pathway(s) by which the saturated fat, palmitate, a major component of the Western diet, impairs circadian glucagon‐like peptide‐1 secretion. Methods Murine mGLUT ag L‐cells were synchronized, and the effects of palmitate pre‐treatment on gene expression and glucagon‐like peptide‐1 secretion were determined, in addition to metabolite quantification, mitochondrial function analysis and enzyme inhibition and activation assays. Glucagon‐like peptide‐1 secretion was also analysed in ileal crypt cultures from control and Bmal1 knockout mice. Results Pre‐treatment with palmitate dampened Bmal1 mRNA and protein expression and glucagon‐like peptide‐1 secretion at 8 but not 20 hours after cell synchronization ( P < .05‐.001). Glucagon‐like peptide‐1 release was also impaired in Bmal1 knockout cultures as compared to wild‐type controls ( P < .001). Palmitate pre‐treatment reduced expression of the Bmal1 downstream target, nicotinamide phosphoribosyltransferase, the rate‐limiting enzyme in the synthesis of NAD + . This was paralleled by dampening of total NAD + levels, as well as impaired mitochondrial function and ATP production ( P < .05‐.001). Whereas direct inhibition of nicotinamide phosphoribosyltransferase also decreased glucagon‐like peptide‐1 release, activation of this enzyme restored glucagon‐like peptide‐1 secretion in the presence of palmitate. Conclusion Palmitate impairs L‐cell clock function at the peak of Bmal1 gene expression, thereby impairing mitochondrial function and ultimately rhythmic glucagon‐like peptide‐1 secretion.
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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 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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