Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis
Bibliographic record
Abstract
Monocyte-derived liver macrophages are critical in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, but their recruitment mechanisms remain unclear. Serotonin (5-hydroxytryptamine [5HT]) is a conserved monoamine synthesized by tryptophan hydroxylase 1 (Tph1) in peripheral tissues and Tph2 in the brain. We show that, in mice housed at thermoneutrality and fed a high-fat, high-fructose diet, inhibition of peripheral serotonin (pe5HT) through genetic deletion of Tph1 prevents MASH independent of reduction in body weight. Liver flow cytometry and single-nucleus sequencing showed reduced pro-inflammatory Ly6C high monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6C high monocytes. A single 5HT injection increased Ly6C high monocytes, while Tph1 KO mice had reduced monocytes without affecting bone marrow monocytes. Mechanistically, serotonin inhibition increases liver AMP-activated protein kinase (AMPK) activity, and this is important for reducing CCL2 and monocyte recruitment. These findings link two ancient energy sensors, 5HT and AMPK, with obesity-associated liver fibrosis.
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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".