Genotype, diet and environment or life style factors are known to be associated with the development of obesity and metabolic syndrome in adults. However, recent evidence suggests that prenatal factors could contribute to obesity as well. One of the prenatal factors implicated in the development of metabolic syndrome in the offspring is stress, which is known to increase circulating glucocorticoids during pregnancy. Prolonged exposure of the developing fetus to excess glucocorticoid levels results in long lasting neuroendocrine changes which predispose the offspring to obesity and other cardiovascular disorders. Considering the fact that 30% of today's maternal population is obese, it is also important to address the impact of prenatal stress in the background of maternal obesity. Hence, we used diet-induced obese (DIO) and dietary resistant (DR) rat model to explore the mechanisms underlying prenatal stress mediated fetal programming of obesity in DIO and DR rats. Prenatal stress was associated with catch up growth and hyperinsulinemia in the DIO offspring. Although, prenatal stress reduced birth weight in the DR offspring, it did not result in any other adverse metabolic outcomes. Next, we investigated the role of stress axis hyperactivation in prenatal stress-induced metabolic programming in the DIO offspring. In the DIO rats, prenatal stress resulted in hyperactivation of stress axis marked by increased norepinephrine (NE) levels in the paraventricular nucleus in the hypothalamus and increased corticotrophin releasing hormone levels in the median eminence. However, the serum corticosterone (CORT) levels were not altered in the prenatally stressed DIO and DR offspring. Despite, no change in circulating CORT levels, glucocorticoids might play a role in metabolic syndrome through increasing 11β-hydroxysteroid dehydrogenase enzyme (11βHSD1) in the target tissues. 11βHSD1 is highly expressed in metabolically active tissues like liver and adipose tissue and is involved in the intracellular generation of CORT by converting inactive 11-dehydroCORT to active CORT. Hence, we investigated the role of 11βHSD1 in the liver and adipose tissue in prenatal stress mediated metabolic programming. Prenatal stress significantly increased 11βHSD1 mRNA and protein expression in the visceral adipose tissue accompanied with hypertrophied adipocytes in the DIO offspring. There were no differences in 11βHSD1 expression in the liver suggesting prenatal stress results in tissue-specific programming of 11βHSD1 expression. Taken together, the results suggest that prenatal stress produces differential metabolic effects in DIO and DR rats. Further, 11βHSD1 could mediate the metabolic effects observed in the prenatally stressed offspring and thus may be a potential mechanism for fetal origins of obesity.
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