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

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.

Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia

“…Conversely, in the maternal terminal ileum, the upregulation of Shp and Fgf15 expression suggests an increase in FXR activity induced by OCA administration to NC-fed mice, but levels remained below those observed outside of pregnancy and so similarly indicate that OCA is unable to fully activate FXR in the terminal ileum. In support of this data, we also observed in a mouse model of gestational diabetes mellitus a diminished effect of OCA in pregnant mice compared with nonpregnant controls ( 30 ). This highlights the issue that limited efficacy of FXR agonists should be taken into account in treatment of pregnant women.…”

“…A similar decrease in serum HDL cholesterol was seen in non-pregnant females. This decrease is not unexpected, as OCA has previously been shown to reduce HDL cholesterol in healthy humans, PBC, and NASH patients (22,37,43), and we recently reported that OCA reduced serum cholesterol in a mouse model of gestational diabetes mellitus (30). Furthermore, hepatic cholesterol content was raised in all bile acid-supplemented mice, albeit to a lesser extent in nonpregnant females fed an OCA diet.…”

GDM progenies exhibit sex disparity in metabolism after respective therapies of insulin, glibenclamide and metformin in dams during pregnancy

“…water available ad libitum. The GDM model was established by being fed with high-fat diet (HFD; 60% kcal from fat) for 4 wk before pregnancy 12,13 . The pregnant mice were obtained by proesterous normal females being left for one night to copulate with the normal males (2:1).…”

ENDOCRINOLOGY IN PREGNANCY: Metabolic impact of bile acids in gestation

“…The FXR agonist obeticholic acid (OCA) has delivered promising results in clinical trials for liver-based metabolic diseases and T2DM in non-pregnant adults, including improving insulin sensitivity (136). However, in mouse models of GDM, OCA did not produce the full effects seen in other studies; whilst treatment reduced plasma cholesterol, glucose tolerance was not improved (137). Research into FXR-specific therapeutics for gestational disorders such as ICP or GDM is also currently lacking.…”