Tryptophan Hydroxylase 1 Regulates Tryptophan and Its Metabolites

Tryptophan hydroxylase (Tph), the rate-limiting enzyme of serotonin (5-hydroxytryptophan; 5-HT) synthesis, exists in two isoforms, Tph1 and Tph2. Tph1 upregulates peripheral 5-HT synthesis and blood 5-HT levels, whereas Tph2 upregulates brain 5-HT synthesis. Here, we show that plasma and brain levels of tryptophan and its metabolites, including 5-HT, 5-hydroxy indoleacetic acid, indolepropionic acid, indole-3-acetic acid, kynurenine, and xanthurenic acid, are decreased in young (8-week-old) Tph1-mutant mice compared with age-matched wild-type mice. In older (7-month-old) Tph1-mutants, the decreases in tryptophan and its metabolites outside the 5-HT pathway were diminished. Although single-housed Tph1 mutants displayed age-related alterations in food intake, body weight, and plasma FGF21 levels, blood glucose levels were lower in both young and older Tph1 mutants compared with age-matched wild-type mice. These findings suggest that Tph1 regulates tryptophan and its metabolites in the plasma and brain, as well as blood glucose homeostasis.