Ingestion of whey protein and bconglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice


The Farnesoid X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5) are two important receptors found in the intestine that play a role in regulating various aspects of gut physiology. One of their key functions is the regulation of gut-derived hormones, including fibroblast growth factor 15/19 (FGF15/19) and serotonin (5-hydrooxytryptamine, 5-HT). Both FXR and TGR5 are involved in complex regulatory networks within the intestine, coordinating bile acid homeostasis, gut hormone secretion, energy metabolism, and inflammation. They serve as key mediators of the cross-talk between the intestine, liver, and other metabolic organs,

In a recent study conducted on C57BL6J mice, Professor Katsunori Nonogaki and Dr. Takao Kaji from Tohoku University investigated the effects of whey protein isolate, a type of milk protein, on the expression of certain proteins and genes involved in bile acid (BA) metabolism and hormone regulation. The authors found that ingestion of whey protein isolate had significant effects on the expression of various molecules in the intestine and liver. The research work is now published in the peer-reviewed Journal, Frontiers in Endocrinology.

Consumption of whey protein, which is a high-quality protein derived from milk is a popular dietary supplement commonly used by athletes, fitness enthusiasts, and individuals looking to increase their protein intake while β-conglycinin is a significant protein component of soybeans, providing nutritional value and contributing to the functional properties of soy products. The authors reported that firstly, whey protein isolate ingestion led to a decrease in the expression of the heteromeric organic solute transporter Ostα and Ostβ in the enterocytes. These transporters are responsible for transporting BAs from the enterocytes into the bloodstream. Additionally, whey protein isolate increased the expression of FXR and FGF15 in the mouse ileum, as well as the levels of FGF15 in the plasma. FXR is a nuclear receptor that plays a key role in regulating BA synthesis and transport, while FGF15 is a hormone involved in BA metabolism.

Furthermore, the researcher found that whey protein isolate ingestion suppressed the expression of hepatic cholesterol-7α hydroxylase (CYP7A1), an enzyme responsible for initiating the synthesis of primary BAs in the liver. It also downregulated the expression of the bile salt export pump (BSEP) and sodium-taurocholate cotransporting polypeptide (NTCP), which are key transporters involved in BA excretion and uptake in the liver. In addition, genes related to gluconeogenesis, a process involved in glucose production, were downregulated. These effects ultimately led to a decrease in the levels of primary BAs, such as cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid, in the liver compared to the control group.

Moreover, whey protein isolate ingestion had an impact on other molecules in the small intestine. It decreased the expression of TGR5, which is another BA receptor, as well as glucagon-like peptide 1 (GLP-1) and tryptophan hydroxylase 1 (Tph1). GLP-1 is a hormone involved in glucose regulation, while Tph1 is an enzyme responsible for serotonin synthesis. Consequently, these changes led to a decrease in plasma levels of serotonin (5-HT) and insulin. On the contrary, the ingestion of soy protein β-conglycinin had opposite effects compared to whey protein isolate. β-conglycinin increased the expression of Ostα and Ostβ in the ileum and decreased the expression of FGF15, leading to increased levels of FGF15 in the plasma. This, in turn, resulted in an increase in the expression of hepatic CYP7A1, BSEP, NTCP, and genes involved in gluconeogenesis, ultimately leading to an increase in primary BA levels in the liver. Furthermore, β-conglycinin ingestion increased the expression of intestinal TGR5, GLP-1, and Tph1, resulting in increased plasma levels of serotonin and insulin.

In a nutshell, Professor Katsunori Nonogaki and Dr. Takao Kaji demonstrated that whey protein isolate and β-conglycinin have opposing effects on the regulation of intestinal FGF15 and 5-HT secretion in mice. Whey protein isolate decreases the expression of BA transporters in the intestine, increases FGF15 levels, and reduces BA synthesis, while β-conglycinin has the opposite effects. These effects on BA metabolism and hormone regulation highlight the potential influence of dietary protein sources on gut physiology and overall metabolic health.

About the author

Katsunori Nonogaki, MD, PhD
Division of Diabetes and Nutrition
CYRIC, Tohoku University

Dr. Nonogaki is a specialist of Diabetes care and Internal medicine. He has worked as a Postdoc Research Fellow at the University of California, San Francisco and the Scripps Research Institute, La Jolla. He has studied role of serotonin network in the regulation of appetite and energy homeostasis. Lorcaserin (Belviq), a selective 5-HT2C receptor agonist, which was used for the treatment of obesity, is based on the original research works by Dr. Nonogaki et al. Current studies are to determine role of the gut-liver axis in the regulation of obesity and type 2 diabetes.


Nonogaki K, Kaji T. Ingestion of whey protein and β-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice. Front Endocrinol (Lausanne). 2023 Jan 27;14:1080790. doi: 10.3389/fendo.2023.1080790.

Go To Front Endocrinol (Lausanne).