Limits...
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.

Show MeSH

Related in: MedlinePlus

Unbiased pathway analysis in VSG ileumBased on a pathway analysis of genes differentially regulated (fold change >=1.5) in the terminal ileum of VSG mice relative to sham-operated, pair-fed (SPF) controls, the following top 5 pathways were significantly enriched: Glutathione mediated detoxification (p=6.00E-8), Nicotine degredation (p=5.64E-4), Metapathway biotransformation (p=4.81E-5), Nuclear receptors in lipid metabolism and toxicity (p=7.18E-5), and Type II interferon signaling (p=1.25E-4). n= 5 per group.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4016120&req=5

Figure 1: Unbiased pathway analysis in VSG ileumBased on a pathway analysis of genes differentially regulated (fold change >=1.5) in the terminal ileum of VSG mice relative to sham-operated, pair-fed (SPF) controls, the following top 5 pathways were significantly enriched: Glutathione mediated detoxification (p=6.00E-8), Nicotine degredation (p=5.64E-4), Metapathway biotransformation (p=4.81E-5), Nuclear receptors in lipid metabolism and toxicity (p=7.18E-5), and Type II interferon signaling (p=1.25E-4). n= 5 per group.

Mentions: We used mRNA-seq, together with subsequent unbiased pathway analysis, to identify key biological pathways that were altered in the distal small intestine following VSG (Fig 1). Consistent with our recent report that VSG significantly alters the expression of hepatic genes involved in lipid and bile acid metabolism9, the pathway ‘Nuclear receptors in lipid metabolism and toxicity’ emerged as one of the top pathways enriched in genes differentially regulated (fold change >= 1.5) in VSG (p=7.18E-5). Intriguingly, among the other top pathways, several point towards an altered gut microbiota. Specifically, the glutathione pathway (p=6.00E-8), which plays important roles in nutrient metabolism and antioxidant defense, is known to be significantly altered by the presence/absence of a microbiota—and this is associated with changes in bile acid composition11,12. Likewise, many of the biotransformations (p=4.81E-5) that are increased likely reflect an altered microbiota, induced for detoxification of metabolites such as secondary bile acids. Finally, changes in gut microbial communities have been extensively linked to altered host immune response including interferon-signaling13,14 (p=1.25E-4).


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)

Unbiased pathway analysis in VSG ileumBased on a pathway analysis of genes differentially regulated (fold change >=1.5) in the terminal ileum of VSG mice relative to sham-operated, pair-fed (SPF) controls, the following top 5 pathways were significantly enriched: Glutathione mediated detoxification (p=6.00E-8), Nicotine degredation (p=5.64E-4), Metapathway biotransformation (p=4.81E-5), Nuclear receptors in lipid metabolism and toxicity (p=7.18E-5), and Type II interferon signaling (p=1.25E-4). n= 5 per group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Unbiased pathway analysis in VSG ileumBased on a pathway analysis of genes differentially regulated (fold change >=1.5) in the terminal ileum of VSG mice relative to sham-operated, pair-fed (SPF) controls, the following top 5 pathways were significantly enriched: Glutathione mediated detoxification (p=6.00E-8), Nicotine degredation (p=5.64E-4), Metapathway biotransformation (p=4.81E-5), Nuclear receptors in lipid metabolism and toxicity (p=7.18E-5), and Type II interferon signaling (p=1.25E-4). n= 5 per group.
Mentions: We used mRNA-seq, together with subsequent unbiased pathway analysis, to identify key biological pathways that were altered in the distal small intestine following VSG (Fig 1). Consistent with our recent report that VSG significantly alters the expression of hepatic genes involved in lipid and bile acid metabolism9, the pathway ‘Nuclear receptors in lipid metabolism and toxicity’ emerged as one of the top pathways enriched in genes differentially regulated (fold change >= 1.5) in VSG (p=7.18E-5). Intriguingly, among the other top pathways, several point towards an altered gut microbiota. Specifically, the glutathione pathway (p=6.00E-8), which plays important roles in nutrient metabolism and antioxidant defense, is known to be significantly altered by the presence/absence of a microbiota—and this is associated with changes in bile acid composition11,12. Likewise, many of the biotransformations (p=4.81E-5) that are increased likely reflect an altered microbiota, induced for detoxification of metabolites such as secondary bile acids. Finally, changes in gut microbial communities have been extensively linked to altered host immune response including interferon-signaling13,14 (p=1.25E-4).

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