A Tryptophan Hydroxylase Inhibitor Increases Hepatic FGF21 Production and Decreases Hepatic Gluconeogenesis Independently of Insulin in db/db Mice

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


The aim of our study is to determine circulating fibroblast growth factor (FGF21) levels in obese and diabetic db/db mice, and role of serotonin (5-HT) in the regulation of hepatic FGF21 expression and circulating FGF21 levels in relation to hepatic gluconeogenesis in obese and diabetic db/db mice.

Methods and Results

Plasma FGF21 levels and expression of hepatic FGF21 were significantly decreased in obese and diabetic db/db mice compared with age-matched C57BL6J mice. Treatment with p-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, for 3 days significantly increased plasma FGF21 levels, and decreased body weight and hyperglycemia in db/db mice while having no significant effect on plasma insulin levels. In addition, treatment with PCPA significantly increased expression of hepatic FGF21 and decreased expression of hepatic nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in db/db mice, while having no significant effects on expression of hepatic peroxisome proliferator-activated receptor (PPAR) α, PPAR γ, and activating transcription factor 4. Moreover, treatment with PCPA significantly decreased phosphoenolpyruvate carboxykinase, glucose 6-phosphatase, fructose 1,6-bisphosphate1, Nur77, forkhead box protein O1 and peroxisome proliferatoractivated receptor γ coactivator-1α, which are involved in hepatic gluconeogenesis, in db/db mice.


These findings suggest that hepatic FGF21 production is decreased in db/db mice, and that a tryptophan hydroxylase inhibitor increases expression of hepatic FGF21 production and decreases hepatic gluconeogenesis and hyperglycemia independently of insulin in db/db mice.

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