Compelling epidemiological evidence suggests that exposure to an adverse intrauterine environment, manifested by low-birth weight, is associated with cardiometabolic and behavioural disorders in adulthood. These observations have led to the concept of 'fetal programming'. The molecular mechanisms that underlie this relationship remain unclear, but are being extensively investigated using a number of experimental models. One major hypothesis for early life physiological programming implicates fetal overexposure to stress (glucocorticoid) hormones. Several animal studies have shown that prenatal glucocorticoid excess, either from endogenous overproduction with maternal stress or through exogenous administration to the mother or fetus, reduces birth weight and causes lifelong hypertension, hyperglycaemia and behavioural abnormality in the offspring. Intriguingly, these effects are transmitted across generations without further exposure to glucocorticoids, which suggests an epigenetic mechanism. These animal observations could have huge implications if extrapolated to humans, where glucocorticoids have extensive therapeutic use in obstetric and neonatal practice.

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OBJECTIVERecent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11β-HSD1 dysregulation are unknown. Here, we tested whether 11β-HSD1 expression, like the metabolic syndrome, is “programmed” by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.RESEARCH DESIGN AND METHODSWe used a “fetal programming” paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11β-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.RESULTSPrenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11β-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous—but not visceral—fat. The increase in 11β-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.CONCLUSIONSThese data suggest that long-term upregulation of 11β-HSD1 in metabolically active tissues may follow prenatal “stress” hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.

Hepatocyte nuclear factor 4-alpha (HNF4-alpha) regulates expression of a number of genes in several metabolic organs. The HNF4-alpha gene has two promoters and encodes at least nine isoforms through differential splicing. In mouse liver, transcription initiates at promoter 2 (P2) during fetal life, but switches to P1 at birth. Developmental and tissue-specific expression of HNF4-alpha in other organs is largely unknown. Here, we examined expression of P1- and P2-derived transcripts in a number of mouse and rat tissues. Both P1 and P2 were active in mouse fetal liver, but P2-derived isoforms were detected 50% more abundantly than P1 transcripts. Conversely, the adult mouse liver expressed significantly higher levels of P1- than P2-derived mRNA. In contrast, in the rat, P1 was used more predominantly in both fetal and adult liver. Exposure of fetal rats to the synthetic glucocorticoid dexamethasone caused suppression of P2 while enhancing hepatic expression of transcripts from P1. This was associated with increased expression of erythropoietin and phosphoenolpyruvate carboxykinase, which are key HNF4-alpha targets in the liver. Unlike liver, the kidney and stomach used promoters more selectively, so that only P1-derived isoforms were detected in fetal and adult kidneys in mice or rats, whereas the stomach in both species expressed P2-derived transcripts exclusively. No significant HNF4-alpha mRNA was detected in the spleen. These data reveal striking developmental and tissue-specific variation in expression of HNF4-alpha, and indicate that this can be influenced by environmental factors (such as exposure to glucocorticoid excess), with potential pathophysiological consequences.

The blood pressure phenotype of DEX-programmed rats may in part be explained by a life-long reduction in renal 11β-HSD2 activity. Salt-sensitive hypertension could be programmed by prenatal stress.

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