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

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:
Grant/Contract Number:
AC02-06CH11357
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
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; free fatty acid receptor-2; gut microbiome; islets
OSTI Identifier:
1339456