Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2023; 29(21): 3280-3291
Published online Jun 7, 2023. doi: 10.3748/wjg.v29.i21.3280
Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy
Meng Wei, Wei-Bo Cao, Ru-Dong Zhao, Dan-Ping Sun, Yi-Ze Liang, Ya-Di Huang, Ze-Wei Cheng, Jun Ouyang, Wen-Shuo Yang, Wen-Bin Yu
Meng Wei, Wei-Bo Cao, Ru-Dong Zhao, Dan-Ping Sun, Yi-Ze Liang, Ya-Di Huang, Ze-Wei Cheng, Jun Ouyang, Wen-Shuo Yang, Wen-Bin Yu, Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Wei M and Yu WB contributed to conception and design of research; Wei M, Sun DP, Yang WS, Cao WB, and Zhao RD contributed to performed experiments; Wei M, Liang YZ, and Cheng ZW analyzed data; Wei M, Sun DP, Liang YZ, and Ouyang J prepared figures; Wei M, Huang YD, and Sun DP drafted manuscript; Wei M, Liang YZ, and Yu WB edited and revised manuscript; Wei M, Sun DP, Cao WB, Zhao RD, Liang YZ, Huang YD, Cheng ZW, Ouyang J, Yang WS, and Yu WB approved final version of manuscript.
Supported by the National Natural Science Foundation of China, No. 81600617.
Institutional review board statement: The study was reviewed and approved by the laboratory animal ethical and welfare committee of Shandong University Cheeloo College of Medicine Institutional Review Board (Approval No. 19200).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Wen-Bin Yu, MD, PhD, Chief Doctor, Professor, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan 250012, Shandong Province, China.
Received: March 6, 2023
Peer-review started: March 6, 2023
First decision: March 18, 2023
Revised: March 31, 2023
Accepted: May 8, 2023
Article in press: May 8, 2023
Published online: June 7, 2023

Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.


To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG).


By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected.


After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed.


Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Keywords: Sleeve gastrectomy, Fibroblast growth factor 15, Bile acids, Hepatic glucose metabolism, Type 2 diabetes mellitus

Core Tip: Sleeve gastrectomy (SG) improves hepatic glucose metabolism and alleviates type 2 diabetes mellitus through the intestine-liver crosstalk mediated by fibroblast growth factor 15 (FGF15). Following SG, bile acids are elevated, inducing the expression and secretion of FGF15 via the activation of farnesoid X receptor in the ileum. FGF15 then acts as an endocrine factor to promote glycogen synthesis and inhibit gluconeogenesis in the liver by specifically stimulating hepatic FGF receptor 4 and its corresponding signaling pathways.