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 gut microbiome,more » 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:

Fuller, Miles ^[1]; Priyadarshini, Medha ^[1]; Gibbons, Sean M. ^[2]; Angueira, Anthony R. ^[1]; Brodsky, Michael ^[1]; Hayes, M. Geoffrey ^[1]; Kovatcheva-Datchary, Petia ^[3]; Backhed, Fredrik ^[3]; Gilbert, Jack A. ^[4]; Lowe, Jr., William L. ^[1]; Layden, Brian T. ^[5]

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+ Show Author Affiliations

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:

Tue Sep 22 00:00:00 EDT 2015

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES)

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