Endocrine Abstracts

Mechanisms underlying the association of low birth weight with the metabolic syndrome in adults remain poorly understood. Epidemiological studies suggest that obesity is not programmed by early life events, but amplifies the risks of intra-uterine growth retardation. We have explored the effects of dietary obesity in rats in which features of the metabolic syndrome have been programmed by prenatal dexamethasone.

16 pregnant Wistar rats were treated with dexamethasone (Dex; 100 mcg/kg/day) or vehicle (Veh) subcutaneously (days 15-21 of pregnancy). At birth, litters were weighed and culled to 8. At 21 days, males were weighed and weaned on to high-fat (HF; 45% kcal from fat) or control (C; 10% fat) diets. At 6 months, animals underwent glucose tolerance tests (8-10 per group).

Birth weight was reduced in Dex animals (by 12%, p<0.05), but full catch-up growth occurred by weaning. HF induced weight gain and hyperinsulinaemia, and increased retroperitoneal fat pad weight and liver triglyceride content. At 6 months, the effects of HF were similar in Dex and Veh groups for body weight (854 plus/minus 25 vs. 812 plus/minus 23 cf 713 plus/minus 28 vs. 688 plus/minus 16 in control diet animals) and fat pad weight. However, in response to HF, Dex animals showed greater hyperinsulinaemia (at 30 minutes following glucose) and hepatic triglyceride content (150 plus/minus 22 vs. 101 plus/minus 13 micromol/g, p<0.05) than Veh animals.

Thus, antenatal dexamethasone exposure does not confer increased sensitivity to obesity induced by high-fat feeding, but does confer increased sensitivity to high-fat diet-induced hepatic lipid accumulation and insulin resistance. This is consistent with previous observations that prenatal dexamethasone induces permanently increased hepatic glucocorticoid receptor and PEPCK expression. The combination of two apparently independent predictors of cardiovascular risk, obesity and adverse antenatal environment, may therefore interact to have a potent effect in determining hepatic insulin sensitivity.