Improved FGF21 Sensitivity and Restored FGF21 Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Rats After Duodenal-Jejunal Bypass and Sleeve Gastrectomy

Abstract

Objective: Bariatric surgery can profoundly improve glucose and lipid metabolism in diabetic rats. Fibroblast growth factor 21 (FGF21) is an important hormone with multiple metabolic beneficial effects. Alteration in serum FGF21 level after bariatric surgery has been reported with conflicting results. Here, we investigated the effect of bariatric surgeries on FGF21 expression and sensitivity. Methods: We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG) and sham surgery in diabetic rats induced by high fat diet and streptozotocin. Metabolic parameters, including body weight, food intake, glucose tolerance, and lipid profiles, were monitored. FGF21 levels in both serum and liver were measured after surgery. FGF21 signaling pathway including FGF receptor 1 (FGFR1), β-klotho (KLB), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) was detected in the liver and white adipose tissue (WAT). We also determined FGF21 sensitivity post-operatively by acute recombinant human FGF21 injection. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were conducted immediately after FGF21 injection. Serum triglyceride (TG) and non-esterified fatty acid (NEFA) were measured and the mRNA levels of early growth response 1 (Egr1) and c-Fos in the liver and WAT were detected after FGF21 injection. Results: Improvements in glucose tolerance, insulin sensitivity, and lipid profiles were observed after bariatric surgeries along with ameliorated lipid metabolism in the liver and WAT. Serum and hepatic FGF21 levels decreased in both DJB and SG groups. FGFR1 and phosphorylated ERK1/2 levels increased in both DJB and SG groups 8 weeks after surgery. The expression of KLB was downregulated only in the WAT after DJB and SG. Significant alteration of OGTT and ITT were observed after acute FGF21 administration in DJB and SG groups. Serum TG and NEFA in DJB and SG groups also decreased after FGF21 administration. And increased mRNA levels of Egr1 and c-Fos were detected in the liver and WAT after DJB and SG surgeries. Conclusions: DJB and SG surgeries can downregulate hepatic expression of FGF21, restore FGF21 signaling pathway and improve FGF21 sensitivity in high-fat diet/streptozotocin-induced diabetic rats.

Effects of Bariatric Surgeries on Fetuin-A, Selenoprotein P, Angiopoietin-Like Protein 6, and Fibroblast Growth Factor 21 Concentration

“…However, when the HFD diet was used before DJOS surgery, the hepatic FGF-21 gene expression was lower after the surgery [ 33 ]. Similar results were achieved by Liu et al who subjected rats with diet-induced diabetes to duodenal-jejunal bypass surgery (DJB) and sleeve gastrectomy (SG) [ 70 ]. When compared to SHAM-operated rats, both DJB- and SG-operated rats showed improved glucose homeostasis and insulin sensitivity expressed through a reduction in fasting blood glucose, alleviation of oral glucose tolerance test and insulin tolerance test profiles, and depletion of HOMA-IR value.…”

“…After bariatric surgeries, both plasma concentration of FGF-21 and its hepatic expression were significantly reduced in comparison to rats after control surgery. The authors noted that both DJB and SG decreased the level of circulating FGF-21 and it was lower than that found in animals fed with a control diet, but SG was more effective in this regard [ 70 ]. Another noteworthy study, by Morrison et al, investigated the influence of bariatrics on changes in metabolism in FGF-deficient (FGF-21-/-) and wild-type (WT) mice [ 71 ].…”

Effect of Sleeve Gastrectomy on Bone Metabolism and Serum 5-Hydroxytryptamine in Obese Rats

“…The specific mechanism involved requires further study and discussion. Other studies by our research group showed that after SG surgery, gastrointestinal tract structure and hormone levels were changed [40,41]. In addition, relevant studies have found that intestinal flora was associated with bone mass loss and osteoporosis, and researchers [42] have suggested that SCFAs, the major metabolite of intestinal flora, act directly on bone cells.…”

Ileal transposition helps to regulate plasma hepatokine levels in obese Zucker (Crl:ZUC(ORL)-Leprfa) rats

“…Liu et al . reported the effects of duodenal-jejunal bypass and sleeve gastrectomy and observed a significant decrease in FGF21 concentration in rats after both types of surgeries 16 . Pop et al .…”

“…FGF21 ameliorates hepatic gluconeogenesis and insulin resistance. It also enhances the lipolysis, while suppressing the liver lipogenesis, and promotes fatty acid oxidation 13 , 16 that is particularly intensified in patients with morbid obesity and T2DM 12 . Morbid obesity leads to generalized low-grade chronic inflammation, which is reflected by an increased level of C-reactive protein (CRP) 17 , 18 .…”