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

Abstract

Background 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. Conclusions 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.

Whey protein isolate inhibits hepatic FGF21 production, which precedes weight gain, hyperinsulinemia and hyperglycemia in mice fed a high-fat diet

“…Whereas C57BL6J mice fed a high-fat diet for 13 days exhibit mild hyperglycemia and normal body weight, db/ db mice exhibit remarkable hyperglycemia and obesity. In addition, whereas C57BL6J mice fed a high-fat diet show increased hepatic FGF21 expression and plasma FGF21 levels, db/db mice show decreased hepatic FGF21 expression and plasma FGF21 levels 21 . On the basis of these findings, altered expression of hepatic FGF21 might be related to altered expression of hepatic Sdf2l1.…”

“…Whole blood was mixed with EDTA-2Na (2 mg/ml) and aprotinin (500 kIU/ml) to determine the plasma levels of FGF21 and insulin. Plasma levels of FGF21 and insulin were measured by enzyme-linked immunosorbent assay (rat/mouse FGF21 ELISA Kit, R&D Systems, Tokyo, Japan; and a mouse Insulin ELISA Kit [TMB], AKRIN-011 T, Shibayagi, Gunma, Japan, respectively) as described previously 21 , 26 , 27 . Plasma 5-HT levels were measured by enzyme-linked immunosorbent assay (mouse 5-HT; BA E-5900, Labor Diagnostika Nord, Nordhorn, Germany).…”

“…The relative amount of mRNA was calculated using β-actin mRNA as the invariant control. Data are shown as fold-change of the mean value of the control group as described previously 21,26,27 .…”

Pharmacologic inhibition of serotonin htr2b ameliorates hyperglycemia and the altered expression of hepatic FGF21, Sdf2l1, and htr2a in db/db mice and KKAy mice

“…Although FGF21 has several beneficial effects on insulin sensitivity and glucose and lipid metabolism [ 6 , 7 ], circulating FGF21 levels are paradoxically increased in hepatosteatosis, obesity, and type 2 diabetes in rodents and humans [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Our previous study demonstrated that plasma FGF21 levels and hepatic FGF21 expression are decreased in old obese and diabetic db/db mice with leptin receptor mutation compared with age-matched C57BL6J mice [ 14 ], although these are increased in obese C57BL6J mice fed a high-fat diet [ 15 ].…”

“…Treatment with a tryptophan hydroxylase inhibitor, which inhibits 5-HT synthesis, reversed the alterations of hepatic FGF21 production in obese mice fed a high-fat diet and old db/db mice, suggesting that 5-HT may contribute to the regulation of hepatic FGF21 production in obese and diabetic mice [ 14 , 15 ]. Moreover, our recent studies demonstrated that plasma FGF21 levels and hepatic FGF21 expression are decreased in tryptophan hydroxylase 1 (Tph1)-deficient mice, which display a remarkable low levels of plasma 5-HT [ 16 ].…”