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Title: The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis

Abstract

The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene ( Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gutmore » microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Altogether, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [3];  [3];  [4];  [1];  [5]
  1. Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States)
  2. Univ. of Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Univ. of Gothenburg, Gothenburg (Sweden)
  4. Univ. of Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); Marine Biological Lab., Woods Hole, MA (United States); Zhejiang Univ., Hangzhou (China)
  5. Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States); Jesse Brown Veterans Affairs Medical Center, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1339456
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
American Journal of Physiology. Endocrinology and Metabolism
Additional Journal Information:
Journal Volume: 309; Journal Issue: 10; Journal ID: ISSN 0193-1849
Publisher:
American Physiological Society
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; free fatty acid receptor-2; gut microbiome; islets

Citation Formats

Fuller, Miles, Priyadarshini, Medha, Gibbons, Sean M., Angueira, Anthony R., Brodsky, Michael, Hayes, M. Geoffrey, Kovatcheva-Datchary, Petia, Backhed, Fredrik, Gilbert, Jack A., Lowe, Jr., William L., and Layden, Brian T. The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. United States: N. p., 2015. Web. doi:10.1152/ajpendo.00171.2015.
Fuller, Miles, Priyadarshini, Medha, Gibbons, Sean M., Angueira, Anthony R., Brodsky, Michael, Hayes, M. Geoffrey, Kovatcheva-Datchary, Petia, Backhed, Fredrik, Gilbert, Jack A., Lowe, Jr., William L., & Layden, Brian T. The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. United States. doi:10.1152/ajpendo.00171.2015.
Fuller, Miles, Priyadarshini, Medha, Gibbons, Sean M., Angueira, Anthony R., Brodsky, Michael, Hayes, M. Geoffrey, Kovatcheva-Datchary, Petia, Backhed, Fredrik, Gilbert, Jack A., Lowe, Jr., William L., and Layden, Brian T. Tue . "The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis". United States. doi:10.1152/ajpendo.00171.2015. https://www.osti.gov/servlets/purl/1339456.
@article{osti_1339456,
title = {The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis},
author = {Fuller, Miles and Priyadarshini, Medha and Gibbons, Sean M. and Angueira, Anthony R. and Brodsky, Michael and Hayes, M. Geoffrey and Kovatcheva-Datchary, Petia and Backhed, Fredrik and Gilbert, Jack A. and Lowe, Jr., William L. and Layden, Brian T.},
abstractNote = {The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Altogether, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.},
doi = {10.1152/ajpendo.00171.2015},
journal = {American Journal of Physiology. Endocrinology and Metabolism},
number = 10,
volume = 309,
place = {United States},
year = {2015},
month = {9}
}

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