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Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes.

Journal article
Authors Saraid McIlvride
Vanya Nikolova
Hei Man Fan
Julie A K McDonald
Annika Wahlström
Elena Bellafante
Eugene Jansen
Luciano Adorini
David Shapiro
Peter Jones
Julian R Marchesi
Hanns-Ulrich Marschall
Catherine Williamson
Published in American journal of physiology. Endocrinology and metabolism
Volume 317
Issue 2
Pages E399-E410
ISSN 1522-1555
Publication year 2019
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages E399-E410
Language en
Links dx.doi.org/10.1152/ajpendo.00407.20...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Gastroenterology and Hepatology

Abstract

Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.

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