Abstract 244: The Flavonoids Naringenin and Nobiletin Stimulate the AMPKinase Pathway in Primary Mouse Hepatocytes
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Bibliographic record
Abstract
Dyslipidemia associated with insulin resistance and obesity are core features of the metabolic syndrome and type 2 diabetes, which contribute significantly to atherosclerosis. In mouse models of diet-induced metabolic dysregulation, the citrus flavonoids naringenin and nobiletin prevent obesity, hepatic steatosis, apoB100 overproduction, dyslipidemia, insulin resistance and atherosclerosis. To elucidate the mechanism of action in liver we assessed flavonoid-induced activation of AMP-activated protein kinase (AMPK), the major regulator of cellular energy homeostasis, in primary mouse hepatocytes. Stimulated AMPK activity promotes catabolic, ATP-generating processes such as fatty acid (FA) oxidation while inhibiting anabolic processes such as FA synthesis. In primary C57BL/6 (WT) hepatocytes, naringenin and nobiletin increased phosphorylation (P) of AMPK and its downstream target acetyl-CoA carboxylase (ACC) in a time- and dose-dependent manner. This was associated with decreased apoB100 secretion. Phosphorylation of ACC by AMPK inhibits the formation of malonyl-CoA reducing substrate for FA synthesis in the cytosol while relieving inhibition of mitochondrial FA oxidation by malonyl-CoA. Under insulin resistant conditions stimulated by high glucose media, reduced pAMPK and pACC were reversed by flavonoid treatment in WT hepatocytes, whereas these effects were lost in Ampkβ1-/- hepatocytes. Sterol receptor element binding protein-1c, which stimulates lipogenesis, was also phosphorylated (inhibited) by flavonoid-induced AMPK activation. BAPTA, a calcium chelator or STO609, an inhibitor of Ca2+/calmodulin-dependent protein kinase kinase-beta (CaMKKβ), did not block flavonoid-induced pACC, suggesting that CaMKKβ is not required for AMPK activation by flavonoids. In chow-fed Ldlr-/- mice, acute i.p. injection of nobiletin following a fasting-refeeding protocol, depressed the respiratory exchange ratio indicative of a switch to FA oxidation. Freeze-clamped liver samples from these mice sacrificed 90 min. post injection showed marked induction of pAMPK and pACC. These results suggest that naringenin and nobiletin attenuate hepatic steatosis and metabolic dysregulation, in part, through activation of hepatic AMPK.
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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 | 0.001 | 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