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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 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.
Highlights
Gestational diabetes mellitus (GDM) is increasingly prevalent worldwide in association with the rising incidence of obesity in women of reproductive age [13, 17]
Nonpregnant mice that were treated with obeticholic acid (OCA) gained significantly less weight than mice fed high-fat diet (HFD) alone; no difference was observed in pregnant mice (Fig. 1A)
When expression of lipid homeostasis targets was assayed in maternal liver, the analysis showed that in normal chow (NC)-fed mice OCA significantly reduced the expression of targets, including Srebp2, a transcription factor regulating cholesterol synthesis; Abcg5/8, which effluxes sterols into bile; and the LDL and HDL receptors, Ldlr and Srb1
Summary
Gestational diabetes mellitus (GDM) is increasingly prevalent worldwide in association with the rising incidence of obesity in women of reproductive age [13, 17]. A recent study found that elevated total serum bile acids in the first trimester of pregnancy was associated with increased risk of developing GDM [25]. Another study reported a strong inverse correlation between taurine-conjugated bile acids and glycemic index that enabled discrimination between GDM and uncomplicated pregnancy [15]. These changes in bile acid metabolism suggest that FXR activity is altered in GDM. FXR activity is reduced in pregnancy [36], and women with gestational cholestasis have increased rates of GDM [34, 61].
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