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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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Relative abundance of Bacteroides, an uncharacterized genus in Porphyromonadaceae, and Roseburia correlated with metabolic parametersThe relative abundance of Bacteroides was significantly correlated with change in body weight (A), change in body fat (B), and the area under the curve (AUC) in the glucose tolerance test (D), but not with fasting blood glucose (C). The relative abundance of an uncharacterized genus in Porphyromonadaceae was significantly correlated with change in body weight (E), fasting blood glucose (G), and the area under the curve (AUC) in the glucose tolerance test (H), but not with change in body fat (F). The relative abundance of Roseburia was significantly correlated with change in body weight (I), change in body fat (J), fasting blood glucose (K), and the area under the curve (AUC) in the glucose tolerance test (L). n=36.
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Figure 9: Relative abundance of Bacteroides, an uncharacterized genus in Porphyromonadaceae, and Roseburia correlated with metabolic parametersThe relative abundance of Bacteroides was significantly correlated with change in body weight (A), change in body fat (B), and the area under the curve (AUC) in the glucose tolerance test (D), but not with fasting blood glucose (C). The relative abundance of an uncharacterized genus in Porphyromonadaceae was significantly correlated with change in body weight (E), fasting blood glucose (G), and the area under the curve (AUC) in the glucose tolerance test (H), but not with change in body fat (F). The relative abundance of Roseburia was significantly correlated with change in body weight (I), change in body fat (J), fasting blood glucose (K), and the area under the curve (AUC) in the glucose tolerance test (L). n=36.

Mentions: The relative abundance of several bacteria previously identified as important modulators of systemic metabolism, was altered differently by VSG according to genotype. Specifically, the relative abundance of Bacteroides was substantially reduced in WT-VSG mice relative to WT-sham controls, but did not vary with surgery among KO mice (Fig 5D, 2-way ANOVA with Tukey posthoc, p< 0.05). A recent study investigating the therapeutic potential of probiotic treatment in obese women found that decreasing prevalence of Bacteroides was associated with decreasing adiposity and improved glucose control34. Likewise, in the present study, decreasing abundance of Bacteroides was associated with decreased weight gain, fat gain (Extended Data Fig4), and decreased AUC in a glucose tolerance test— suggesting a functional association that depends on FXR.


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)

Relative abundance of Bacteroides, an uncharacterized genus in Porphyromonadaceae, and Roseburia correlated with metabolic parametersThe relative abundance of Bacteroides was significantly correlated with change in body weight (A), change in body fat (B), and the area under the curve (AUC) in the glucose tolerance test (D), but not with fasting blood glucose (C). The relative abundance of an uncharacterized genus in Porphyromonadaceae was significantly correlated with change in body weight (E), fasting blood glucose (G), and the area under the curve (AUC) in the glucose tolerance test (H), but not with change in body fat (F). The relative abundance of Roseburia was significantly correlated with change in body weight (I), change in body fat (J), fasting blood glucose (K), and the area under the curve (AUC) in the glucose tolerance test (L). n=36.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 9: Relative abundance of Bacteroides, an uncharacterized genus in Porphyromonadaceae, and Roseburia correlated with metabolic parametersThe relative abundance of Bacteroides was significantly correlated with change in body weight (A), change in body fat (B), and the area under the curve (AUC) in the glucose tolerance test (D), but not with fasting blood glucose (C). The relative abundance of an uncharacterized genus in Porphyromonadaceae was significantly correlated with change in body weight (E), fasting blood glucose (G), and the area under the curve (AUC) in the glucose tolerance test (H), but not with change in body fat (F). The relative abundance of Roseburia was significantly correlated with change in body weight (I), change in body fat (J), fasting blood glucose (K), and the area under the curve (AUC) in the glucose tolerance test (L). n=36.
Mentions: The relative abundance of several bacteria previously identified as important modulators of systemic metabolism, was altered differently by VSG according to genotype. Specifically, the relative abundance of Bacteroides was substantially reduced in WT-VSG mice relative to WT-sham controls, but did not vary with surgery among KO mice (Fig 5D, 2-way ANOVA with Tukey posthoc, p< 0.05). A recent study investigating the therapeutic potential of probiotic treatment in obese women found that decreasing prevalence of Bacteroides was associated with decreasing adiposity and improved glucose control34. Likewise, in the present study, decreasing abundance of Bacteroides was associated with decreased weight gain, fat gain (Extended Data Fig4), and decreased AUC in a glucose tolerance test— suggesting a functional association that depends on FXR.

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