Intestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice

Nadejda Bozadjieva-Kramer,Ruth Gutierrez-Aguilar,Samuel Chiang,Ormond A Macdougald,Randy J Seeley,Ziru Li,Yikai Shao,Sara G Vargo,Darleen A Sandoval,Jae Hoon Shin,Kristy M Heppner,Katrina Granger

doi:10.1038/s41467-021-24914-y

Abstract

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.

Highlights

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes
We and others have hypothesized that changes in the enterohepatic metabolism play important role in the potent metabolic effects of vertical sleeve gastrectomy (VSG) and Roux-Y Gastric Bypass (RYGB)[10,11]
We reported that bile acids are increased after VSG and that farnesoid X receptor (FXR) is essential for the positive effects of bariatric surgery on weight loss and glycemic control[6,12]

Summary

Introduction

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. Unlike wild-type mice, FXR−/− mice do not maintain body weight loss and do not have improved glucose tolerance after VSG or after bile diversion to the ileum[12,13] These studies highlighted the importance of enterohepatic circulation in the metabolic effects following bariatric surgery. Most importantly, fasting and postprandial plasma FGF19 levels in humans[22,32,33,38,39,40] and ileal FGF15 expression in mice (as shown in the present studies) increase after VSG These data point to FGF15/19 as a potential target to mediate VSG’s effects to produce sustained weight loss and improved glucose tolerance. These findings point to an important role for FGF15 in the regulation of multiple metabolic parameters following VSG

Methods

Results

Conclusion