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

Takao Kaji,Katsunori Nonogaki

doi:10.1038/s41598-020-72975-8

Takao Kaji, Katsunori Nonogaki

Open Access

https://doi.org/10.1038/s41598-020-72975-8

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Journal: Scientific Reports	Publication Date: Sep 25, 2020
Citations: 10	License type: open-access

Affiliation: Tohoku University

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.

Highlights

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
Expression of hepatic FGF21 (Fig. 1a) and plasma FGF21 levels (Fig. 1b) significantly increased in mice fed a high-fat diet for 1 day compared with a chow diet and gradually increased further over 13 days
These findings suggest that increases in plasma FGF21 levels and expression of hepatic FGF21 precede hyperinsulinemia, hyperglycemia, and body weight gain in mice fed a high-fat diet, and that increased expression of hepatic htr2a and Sdf2l1 is associated with insulin resistance in mice fed a high-fat diet

Summary

Introduction

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. 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. 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 dietinduced weight gain, hyperinsulinemia, and hyperglycemia, and that intake of whey protein isolate could inhibit hepatic FGF21 production by suppressing peripheral serotonin synthesis. Serotonin (5-HT) is an endocrine hormone primarily produced by the gut and peripheral organs via tryptophan hydroxylase 1 (Tph1), and plasma 5-HT levels and expression of hepatic serotonin receptor 2a (htr2a) are increased in obese mice fed a high-fat diet[10]. Increased expression of hepatic htr2a in diet-induced obesity can contribute to hepatosteatosis

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