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FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ - Nature (2014)

Bottom Line: Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach.Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities.Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA.

ABSTRACT
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

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FXR contributes to the maintenance of weight loss following VSGBoth WT and FXR KO mice A) weighed more than 30g and B) carried more than 30% of their weight as fat prior to the surgery. C) WT-VSG mice lose weight and maintain this weight loss, relative to WT-sham controls, whereas D) KO-VSG mice recover the initial weight loss within 5 weeks after surgery, relative to KO-sham controls. E) 11-weeks following surgery, WT-VSG mice carry half the body fat of WT-sham mice whereas the body fat of KO-VSG and KO-sham mice is equivalent. F) 11-weeks following surgery, WT-VSG mice have lost 41% of their pre-surgical body fat, whereas KO-VSG mice exhibit no significant fat loss. Data are shown as mean ± SE. *= p< 0.05, ** = p< 0.01, *** = p< 0.001. For panels A-D, n= 12 WT-sham, 8 WT-VSG, 9 KO-sham, 8 KO-VSG. For panels E-F, n= 12 WT-sham, 9 WT-VSG, 9 KO-sham, 10 KO-VSG.
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Figure 2: FXR contributes to the maintenance of weight loss following VSGBoth WT and FXR KO mice A) weighed more than 30g and B) carried more than 30% of their weight as fat prior to the surgery. C) WT-VSG mice lose weight and maintain this weight loss, relative to WT-sham controls, whereas D) KO-VSG mice recover the initial weight loss within 5 weeks after surgery, relative to KO-sham controls. E) 11-weeks following surgery, WT-VSG mice carry half the body fat of WT-sham mice whereas the body fat of KO-VSG and KO-sham mice is equivalent. F) 11-weeks following surgery, WT-VSG mice have lost 41% of their pre-surgical body fat, whereas KO-VSG mice exhibit no significant fat loss. Data are shown as mean ± SE. *= p< 0.05, ** = p< 0.01, *** = p< 0.001. For panels A-D, n= 12 WT-sham, 8 WT-VSG, 9 KO-sham, 8 KO-VSG. For panels E-F, n= 12 WT-sham, 9 WT-VSG, 9 KO-sham, 10 KO-VSG.

Mentions: Because we and others have consistently observed increased circulating total bile acids9,10,15,16 and increased FXR signaling9,17 following various bariatric procedures including VSG, and because FXR was one of the regulated genes identified in our pathway analysis, we hypothesized that FXR-signaling contributes to the metabolic benefits of VSG. To test this, we first generated whole-body FXR knockout mice (KO), and their wild-type littermate controls (WT) from founders purchased from Jackson Labs (Bar Harbor ME). Because KO mice are somewhat resistant to diet-induced obesity18 we maintained these mice on a 60% high-fat diet (HFD) for 10 weeks prior to surgery, such that both WT and KO mice became obese. Both genotypes carried more than 30% of their body weight as fat prior to surgery (Fig 2 A-B); our previous data indicate this level of adiposity provides more-than-sufficient opportunity for VSG-induced body weight and fat loss3,19.


FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ - Nature (2014)

FXR contributes to the maintenance of weight loss following VSGBoth WT and FXR KO mice A) weighed more than 30g and B) carried more than 30% of their weight as fat prior to the surgery. C) WT-VSG mice lose weight and maintain this weight loss, relative to WT-sham controls, whereas D) KO-VSG mice recover the initial weight loss within 5 weeks after surgery, relative to KO-sham controls. E) 11-weeks following surgery, WT-VSG mice carry half the body fat of WT-sham mice whereas the body fat of KO-VSG and KO-sham mice is equivalent. F) 11-weeks following surgery, WT-VSG mice have lost 41% of their pre-surgical body fat, whereas KO-VSG mice exhibit no significant fat loss. Data are shown as mean ± SE. *= p< 0.05, ** = p< 0.01, *** = p< 0.001. For panels A-D, n= 12 WT-sham, 8 WT-VSG, 9 KO-sham, 8 KO-VSG. For panels E-F, n= 12 WT-sham, 9 WT-VSG, 9 KO-sham, 10 KO-VSG.
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Figure 2: FXR contributes to the maintenance of weight loss following VSGBoth WT and FXR KO mice A) weighed more than 30g and B) carried more than 30% of their weight as fat prior to the surgery. C) WT-VSG mice lose weight and maintain this weight loss, relative to WT-sham controls, whereas D) KO-VSG mice recover the initial weight loss within 5 weeks after surgery, relative to KO-sham controls. E) 11-weeks following surgery, WT-VSG mice carry half the body fat of WT-sham mice whereas the body fat of KO-VSG and KO-sham mice is equivalent. F) 11-weeks following surgery, WT-VSG mice have lost 41% of their pre-surgical body fat, whereas KO-VSG mice exhibit no significant fat loss. Data are shown as mean ± SE. *= p< 0.05, ** = p< 0.01, *** = p< 0.001. For panels A-D, n= 12 WT-sham, 8 WT-VSG, 9 KO-sham, 8 KO-VSG. For panels E-F, n= 12 WT-sham, 9 WT-VSG, 9 KO-sham, 10 KO-VSG.
Mentions: Because we and others have consistently observed increased circulating total bile acids9,10,15,16 and increased FXR signaling9,17 following various bariatric procedures including VSG, and because FXR was one of the regulated genes identified in our pathway analysis, we hypothesized that FXR-signaling contributes to the metabolic benefits of VSG. To test this, we first generated whole-body FXR knockout mice (KO), and their wild-type littermate controls (WT) from founders purchased from Jackson Labs (Bar Harbor ME). Because KO mice are somewhat resistant to diet-induced obesity18 we maintained these mice on a 60% high-fat diet (HFD) for 10 weeks prior to surgery, such that both WT and KO mice became obese. Both genotypes carried more than 30% of their body weight as fat prior to surgery (Fig 2 A-B); our previous data indicate this level of adiposity provides more-than-sufficient opportunity for VSG-induced body weight and fat loss3,19.

Bottom Line: Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach.Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities.Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA.

ABSTRACT
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Show MeSH
Related in: MedlinePlus