Could Teenage Obesity Be Prompted By In Utero Conditions?

Jennifer Garcia

June 26, 2013

A new study suggests that maternal cholestasis during pregnancy may lead to future metabolic disease in children. The study results were published online June 24 in the Journal of Clinical Investigation.

To determine whether intrahepatic cholestasis of pregnancy (ICP) alters the metabolic profile of teenage offspring, researchers led by Georgia Papacleovoulou, PhD, from the Imperial College London and King's College London, United Kingdom, evaluated data from the Northern Finnish birth cohort 1985-1986. Data from mothers and 16-year-old children from 7808 control pregnancies (4034 male and 3774 female) and 45 ICP pregnancies (27 male and 18 female) were evaluated.

The authors found an increased body mass index and fasting insulin levels among males from ICP pregnancies when compared with the male offspring of normal pregnancies. Female offspring from ICP pregnancies were found to have increased hip and waist girth as well as lower fasting high-density lipoprotein cholesterol levels compared with females from normal pregnancies. There were no significant differences in the proportion of premature births, maternal body mass index, birth weight, or placental size between ICP and normal cases.

To further investigate the link between ICP and future metabolic disease of offspring, the researchers developed a murine model of ICP by feeding either a normal chow diet or a diet supplemented with 0.5% cholic acid before and during gestation. The researchers evaluated hepatic fatty acids, cholesterol biosynthesis, adipocytokines, and gene expression microarray analysis of the liver and adipose tissue from both mothers and offspring. Data from this model suggest "that maternal cholestasis affects lipid biosynthesis and transport in the fetoplacental unit."

The authors note that "maternal hypercholanemia in mice and humans has long-term implications for the health of their male and female offspring."

"Metabolic disease in the offspring can be programmed in utero through alterations in the structure or function of organs at the fetomaternal interface, e.g., the placenta," the researchers note.

"To our knowledge, this is the first direct evidence showing that cholestatic pregnancy can program metabolic disease in the offspring," they conclude.

Treatment Options

In an accompanying commentary, Susan K. Murphy, PhD, from Duke University Medical Center, Durham, North Carolina, notes that "Papacleovoulou et al. provide the first evidence that ICP is associated with long-term health consequences in the child."

Dr. Murphy poses the question of whether gestational conditions could set the stage for obesity later in life, noting that "[t]he results [of this study] suggest that in utero exposure to bile acids results in a reprogramming of metabolism that is fully realized under conditions of suboptimal nutritional intake, which may or may not occur later in life, depending on behavior."

Dr. Murphy notes that questions remain, such as whether treatment of pregnant mothers with ursodeoxycholic acid will prevent future metabolic problems in the child and, if so, at what point during pregnancy it should be administered.

The small sample size and lack of methylation analysis in the murine model are potential limitations of the study.

"Understanding the roots of metabolic dysfunction may provide inroads to improved treatment options involving the specific genes whose expression is altered by cholestatic programming," concludes Dr. Murphy.

Funding for this study was provided by the Genesis Research Trust, Imperial College London; the Biomedical Research Centre, Imperial College Healthcare NHS Trust; and the Wellcome Trust. The authors and commentator have disclosed no relevant financial relationships.

J Clin Invest. Published online June 24, 2013. Article full text, Commentary extract

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