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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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Glucose tolerance in FXR-VSG and WT-VSG miceWhen the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes. Data are shown as mean ± SE. *= p< 0.05. n= 10 per group.
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Figure 7: Glucose tolerance in FXR-VSG and WT-VSG miceWhen the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes. Data are shown as mean ± SE. *= p< 0.05. n= 10 per group.

Mentions: To investigate whether FXR-signaling contributes to improvements in glucose tolerance observed following VSG, we challenged fasted mice with an intraperitoneal (i.p.) injection of 1 g/kg·bw dextrose. VSG was associated with a 20% decrease in fasting blood glucose in WT mice, whereas it was associated with a 24% increase in fasting blood glucose in KO mice (Fig 4A, 2-way ANOVA with Tukey posthoc, p< 0.001). WT-VSG mice exhibited a substantial improvement in the ability to clear the i.p. injection of glucose, reflected as a 35% reduction in the AUC relative to sham-operated controls. In contrast, KO-VSG and sham-operated mice exhibited no differences in glucose tolerance (Fig. 4B-C, 2-way ANOVA with Tukey posthoc, p< 0.01; t-test, p< 0.001). While the present findings do not address whether the improvements observed in WT-VSG relative to WT-sham mice are independent of weight loss, we note that KO-VSG and WT-VSG mice were equivalent body weights at the time of this GTT. Despite this, when the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes (2-way RM ANOVA with Tukey posthoc, Extended Data Fig2).


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)

Glucose tolerance in FXR-VSG and WT-VSG miceWhen the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes. Data are shown as mean ± SE. *= p< 0.05. n= 10 per group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Glucose tolerance in FXR-VSG and WT-VSG miceWhen the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes. Data are shown as mean ± SE. *= p< 0.05. n= 10 per group.
Mentions: To investigate whether FXR-signaling contributes to improvements in glucose tolerance observed following VSG, we challenged fasted mice with an intraperitoneal (i.p.) injection of 1 g/kg·bw dextrose. VSG was associated with a 20% decrease in fasting blood glucose in WT mice, whereas it was associated with a 24% increase in fasting blood glucose in KO mice (Fig 4A, 2-way ANOVA with Tukey posthoc, p< 0.001). WT-VSG mice exhibited a substantial improvement in the ability to clear the i.p. injection of glucose, reflected as a 35% reduction in the AUC relative to sham-operated controls. In contrast, KO-VSG and sham-operated mice exhibited no differences in glucose tolerance (Fig. 4B-C, 2-way ANOVA with Tukey posthoc, p< 0.01; t-test, p< 0.001). While the present findings do not address whether the improvements observed in WT-VSG relative to WT-sham mice are independent of weight loss, we note that KO-VSG and WT-VSG mice were equivalent body weights at the time of this GTT. Despite this, when the glucose excursion of WT-VSG and KO-VSG mice are compared directly, KO-VSG mice exhibit significantly impaired glucose clearance at both 30 and 60 minutes (2-way RM ANOVA with Tukey posthoc, Extended Data Fig2).

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