Abstract 684: Nobiletin Corrects Intestinal Lipid Metabolism in <i>Ldlr</i> <sup>-/-</sup> Mice Fed a High-fat Diet
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Bibliographic record
Abstract
Supplementation of the citrus flavonoid nobiletin to a high-fat, high-cholesterol (HFHC) diet in Ldlr -/- mice prevents obesity, insulin resistance, hepatic steatosis, dyslipidemia and atherosclerosis, in part, through enhanced hepatic fatty-acid (FA) oxidation. Intriguingly, Ldlr -/- mice fed a HFHC diet, but not chow, retain lipids in the jejunum of the small intestine, even in the fasted state. Addition of nobiletin to the HFHC diet prevents this lipid accumulation, which may contribute to the metabolic and athero-protection. To determine the mechanisms through which nobiletin prevents jejunal lipid accumulation, Ldlr -/- mice were fed HFHC (42% kcal fat, 0.2% cholesterol), or HFHC + nobiletin (0.3%w/w; n=16/group) for 10 weeks. A fasting/2 hr-refeeding protocol revealed that nobiletin increased intestinal FoxO1 phosphorylation and decreased mTOR phosphorylation, indicating improved insulin sensitivity. Jejunal FA-synthesis and triglyceride (TG) synthesis were decreased, whereas jejunal FA-oxidation was unchanged. HFHC increased fasting (6 hr) plasma levels of total TG 2.5-fold (7.45 vs 2.9 mmol/L), chylomicron TG 1.6-fold (0.56 vs 0.36 mmol/L) and apoB48 1.4-fold (3.9 vs 2.8 AU) compared to nobiletin + HFHC. Postprandial experiments employing a poloxamer-407 injection ( i.p .) and a 3 H-TG-containing olive oil gavage showed that nobiletin increased secretion of TG mass and radioactivity into plasma compared to HFHC alone. Additionally, nobiletin increased the secretion of chylomicron-TG 1.3-fold (2.2 vs 1.4 mmol/L/hr), although apoB48 secretion was unchanged, suggesting that nobiletin increases chylomicron TG content. Electron micrographs reveal that nobiletin prevents HFHC-diet induced cytoplasmic lipid droplet formation within jejunal enterocytes 2 hours post-gavage. Nobiletin prevents HFHC-diet induced shortening of the small intestine and increases plasma levels of GLP-1, and likely GLP-2, in both fasting and post-prandial states. We conclude that nobiletin attenuates intestinal lipid accumulation through decreased de novo lipogenesis and increased chylomicron-TG secretion, where the former is achieved through improved intestinal insulin sensitivity and the latter through a possible GLP-2-dependent mechanism.
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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) | 0.001 | 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 it