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

Research output: Contribution to journalArticle

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

Original languageEnglish
Pages (from-to)E399-E410
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume317
Issue number2
Early online date6 Aug 2019
DOIs
Publication statusPublished - Aug 2019

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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 non-pregnant 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 non-pregnant 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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