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

Abstract

Insufficient expression of hepatic fibroblast growth factor 21 (FGF21) and stromal cell-derived factor 2 like 1 (Sdf2l1) reportedly leads to insulin resistance and hepatosteatosis in obesity and type 2 diabetes. On the other hand, increased expression of hepatic serotonin receptor 2a (htr2a) in diet-induced obesity contributes to hepatosteatosis. Here we show that increases in circulating FGF21 levels and expression of hepatic FGF21 preceded weight gain, hyperinsulinemia, and hyperglycemia in C57BLJ6 mice fed a high-fat diet. Expression of hepatic htr2a and Sdf2l1 increased in insulin-resistant mice fed a high-fat diet. Intake of whey protein isolate decreased plasma FGF21 levels and expression of hepatic FGF21 in mice fed either a high-fat diet or a chow diet, whereas it only suppressed the overexpression of hepatic Sdf2 and htr2a in insulin-resistant mice fed a high-fat diet. Moreover, intake of whey protein isolate decreased plasma serotonin levels in mice fed either a high-fat diet or a chow diet. Genetic inhibition of tryptophan hydroxylase 1 decreased hepatic FGF21 expression and plasma FGF21 levels in mice. These findings suggest that increased hepatic FGF21 production precedes diet-induced weight gain, hyperinsulinemia, and hyperglycemia, and that intake of whey protein isolate could inhibit hepatic FGF21 production by suppressing peripheral serotonin synthesis.

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

“…Whole blood was mixed with EDTA-2Na (2 mg/ml) and aprotinin (500 kIU/ml) to determine the plasma levels of FGF21. 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-011T, Shibayagi, Gunma, Japan, respectively) as described previously [ 16 ]. Blood glucose levels were measured using glucose strips (blood glucose monitoring system; Accu-Check, Roche Diagnostics, Tokyo, Japan).…”

“…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, which received saline as described previously [ 16 , 20 , 21 ].…”

“…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 ]. Thus, peripheral 5-HT is essential to maintain plasma FGF21 levels and hepatic FGF21 expression [ 16 ].…”

“…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 ]. Thus, peripheral 5-HT is essential to maintain plasma FGF21 levels and hepatic FGF21 expression [ 16 ].…”

“…On the other hand, our recent studies demonstrated that expression of hepatic FGF21 and Sdf2l1 is increased in insulin-resistant C57BL6J mice fed a high-fat diet for 13 days, and that the suppression of hepatic FGF21 and Sdf2l1 expression induced by whey protein insolate decreases insulin resistance and hyperglycemia in C57BL6J mice fed a high-fat diet [ 16 ]. Alterations of hepatic htr2a and htr2b expression in obese and diabetic mice and role of htr2b in the regulation of hepatic htr2a, FGF21 and Sdf2l1 expression and glucose metabolism, however, have not been evaluated.…”