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A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Author(s): Katsunori Nonogaki, Takao Kaji, Mari Murakami


Background:  Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone, and circulating FGF21 levels are elevated in mice with diet-induced obesity and an insulin-resistant state. The aim of our study was to determine the role of serotonin (5-HT) in the regulation of hepatic FGF21 production and circulating FGF21 levels in relation to insulin resistance in mice fed a high-fat diet.

Methods and Results: Treatment with p-chlorophenylalanine (PCPA;500 mg/kg), a tryptophan hydroxylase inhibitor, for 3 days, which decreases brain-derived and peripheral serotonin (5-HT), significantly decreased food intake, body weight, and plasma insulin and FGF21 levels in mice fed a highfat diet for 9 weeks compared with controls, while having no statistically significant effect on blood glucose levels. PCPA treatment significantly decreased the expression of hepatic FGF21 and increased the expression of hepatic nuclear factor (erythroid-derived 2)-like2, while having no effects on the expression of hepatic peroxisome proliferator-activated receptor (PPAR)α, PPARγ, and transcriptional factor 4. Moreover, PCPA treatment significantly increased the expression of hypothalamic 5-HT2C receptors and pro-opiomelanocortin in mice fed a high-fat diet.

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