Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis

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 Ly6Chigh monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6Chigh monocytes. A single 5HT injection increased Ly6Chigh 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.