Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy

Figure 1 The weight-loss and anti-diabetic effects of sleeve gastrectomy. A: Body weight; B: Food intake; C: Body weight gain after surgery; D: The oral glucose tolerance test (OGTT) curves; E: Area under the curve for OGTT curves of SHAM and sleeve gastrectomy (SG) group at week 12 postoperation. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001; SG vs SHAM group. SG: Sleeve gastrectomy.

Figure 2 Sleeve gastrectomy increased the bile acids levels and hepatic glycogen content. A: The concentration of total bile acid; B and C: The levels of chenodeoxycholic acid, DCA, lithocholic acid, and cholic acid in serum and portal vein, respectively; D: The glycogen content in liver at week 12 postoperation in SHAM and SG group. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001; SG vs SHAM group. BA: Bile acid; TBA: Total bile acid; SG: Sleeve gastrectomy; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; CA: Cholic acid.

Figure 3 Sleeve gastrectomy promoted fibroblast growth factor 15, fibroblast growth factor receptor 4 expression and hepatic glycogen synthesis. A and D: The result of immune-histochemistry staining for ileal fibroblast growth factor (FGF) 15; B and E: The result of Periodic Acid-Schiff staining for glycogen in hepatocytes; C and F: Immune-histochemistry staining of hepatic FGF receptor 4 in SHAM and sleeve gastrectomy group at week 12 postoperation. Scale bar: 100 μm. SG: Sleeve gastrectomy; FGF: Fibroblast growth factor; FGFR4: Fibroblast growth factor receptor 4.

Figure 4 Farnesoid X receptor- fibroblast growth factor 15-fibroblast growth factor receptor 4 were stimulated and hepatic gluconeogenesis were depressed after sleeve gastrectomy. The mRNA relative expression of ileal fibroblast growth factor (FGF) 15, farnesoid X receptor, and hepatic glucose-6-phosphatase, phosphoenolpyruvate carboxykinase and fibroblast growth factor receptor 4 in SHAM and sleeve gastrectomy (SG) group at week 12 postoperation. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, SG vs SHAM group. SG: Sleeve gastrectomy; FXR: Farnesoid X receptor; FGF: Fibroblast growth factor; FGFR4: Fibroblast growth factor receptor 4; Pepck: Phosphoenolpyruvate carboxykinase; G6Pase: Glucose-6-phosphatase.

Figure 5 Sleeve gastrectomy regulated activities of the corresponding pathways of fibroblast growth factor 15. Western blotting for expression of extracellular signal regulated kinase (ERK), p-ERK, cAMP regulatory element-binding protein (CREB), p-CREB, glycogen synthase (GS), p-GS, and proliferator-activated receptor 𝛾 coactivator-1α (PGC-1α) in the liver of both SHAM and sleeve gastrectomy group at week 12 postoperation. PGC-1α: Proliferator-activated receptor 𝛾 coactivator-1α; ERK: Extracellular signal regulated kinase; CREB: cAMP regulatory element-binding protein; GS: Glycogen synthase; SG: Sleeve gastrectomy.