Nuclear receptors, gestational metabolism and maternal metabolic disorders.

Normal pregnancy is characterised by a gradual alteration in metabolism that results in elevated serum bile acids, dyslipidaemia and impaired glucose tolerance in the third trimester. Nuclear receptors play important roles in regulating metabolic pathways that influence alterations in these parameters. There is evidence for altered function of FXR and LXR in gestation; these nuclear receptors play an integral role in bile acid and lipid homeostasis. There is some evidence for influence of clock genes in late pregnancy metabolic changes, and this may be linked to alterations in placental gene expression and function, thereby influencing fetal growth. This article will review the current data from human studies and investigation of animal models to illustrate the role of nuclear receptors (namely LXR, FXR, PPARs and clock genes) in gestational alterations in metabolism and the ways this may influence susceptibility to metabolic disorders of pregnancy such as gestational diabetes mellitus and intrahepatic cholestasis of pregnancy.

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis.

Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic ß-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect ß-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.