Tryptophan Hydroxylase 1 Regulates High-Fat Diet-Induced Hepatic Indian Hedgehog Expression and Secretion in Mice

Activation of hedgehog (Hh) signaling in the liver is implicated in the progression of chronic liver diseases. Here, we show that increases in the expression of hepatic Indian hedgehog (Ihh), a hepatokine, its transcriptional regulator TAZ, periostin, and lipogenesis-related genes, as well as in plasma Ihh levels, precede weight gain in C57BL6 mice fed a high-fat diet compared with a chow diet. Intake of whey protein isolate, a milk protein, significantly suppressed these high-fat diet-induced changes independently of body weight. In addition, despite increased tryptophan levels, whey protein intake markedly reduced colonic 5-HT levels in high-fat diet-fed mice. Moreover, genetic ablation of tryptophan hydroxylase 1 (Tph1), the enzyme responsible for gut-derived 5-HT synthesis from tryptophan, attenuated increases in hepatic TAZ and Ihh expression, and in plasma Ihh levels independently of body weight. These findings suggest that Tph1-mediated increases in hepatic Ihh expression and plasma Ihh levels occur at an early stage of high-fat diet-induced metabolic dysfunction. Whey protein intake suppresses these changes, potentially by inhibiting gut-derived serotonin.