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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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Effect of genotype and VSG on the relative abundance of Lactobacillus, Lactococcus, and Escherichia/ ShigellaVSG was associated with a significant increase in the relative abundance of Lactobacillus (A), Lactococcus (B), and Escherichia/ Shigella that did not vary according to genotype. Data are presented as Tukey boxplots. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
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Figure 10: Effect of genotype and VSG on the relative abundance of Lactobacillus, Lactococcus, and Escherichia/ ShigellaVSG was associated with a significant increase in the relative abundance of Lactobacillus (A), Lactococcus (B), and Escherichia/ Shigella that did not vary according to genotype. Data are presented as Tukey boxplots. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.

Mentions: In addition we observed genotype-independent changes in the relative abundance of the genera Lactobacillus and Lactococcus and of Enterobacteriaceae (Extended Data Fig5). Consistent with this, an increase in E. coli and other enterobacteria has likewise been reported after RYGB23,24,26. Such changes may indeed contribute to the benefits of VSG and other bariatric procedures, but the present data suggest they are not sufficient to elicit improvements in energy balance and glucose homeostasis.


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)

Effect of genotype and VSG on the relative abundance of Lactobacillus, Lactococcus, and Escherichia/ ShigellaVSG was associated with a significant increase in the relative abundance of Lactobacillus (A), Lactococcus (B), and Escherichia/ Shigella that did not vary according to genotype. Data are presented as Tukey boxplots. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016120&req=5

Figure 10: Effect of genotype and VSG on the relative abundance of Lactobacillus, Lactococcus, and Escherichia/ ShigellaVSG was associated with a significant increase in the relative abundance of Lactobacillus (A), Lactococcus (B), and Escherichia/ Shigella that did not vary according to genotype. Data are presented as Tukey boxplots. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
Mentions: In addition we observed genotype-independent changes in the relative abundance of the genera Lactobacillus and Lactococcus and of Enterobacteriaceae (Extended Data Fig5). Consistent with this, an increase in E. coli and other enterobacteria has likewise been reported after RYGB23,24,26. Such changes may indeed contribute to the benefits of VSG and other bariatric procedures, but the present data suggest they are not sufficient to elicit improvements in energy balance and glucose homeostasis.

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