Sexually Dimorphic Effects of Maternal Nutrient Reduction on Expression of Genes Regulating Cortisol Metabolism in Fetal Baboon Adipose and Liver Tissues

Abstract

Maternal nutrient reduction (MNR) during fetal development may predispose offspring to chronic disease later in life. Increased regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in metabolic tissues is fundamental to the developmental programming of metabolic syndrome, but underlying mechanisms are unknown. Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH, the cofactor for 11β-HSD1 reductase activity. CCAAT/enhancer binding proteins (C/EBPs) and the glucocorticoid receptor (GR) regulate 11β-HSD1 expression. We hypothesize that MNR increases expression of fetal C/EBPs, GR, and H6PD, thereby increasing expression of 11β-HSD1 and reductase activity in fetal liver and adipose tissues. Pregnant MNR baboons ate 70% of what controls ate from 0.16 to 0.9 gestation (term, 184 days). Cortisol levels in maternal and fetal circulations increased in MNR pregnancies at 0.9 gestation. MNR increased expression of 11β-HSD1; H6PD; C/EBPα, -β, -γ; and GR in female but not male perirenal adipose tissue and in male but not female liver at 0.9 gestation. Local cortisol level and its targets PEPCK1 and PPARγ increased correspondingly in adipose and liver tissues. C/EBPα and GR were found to be bound to the 11β-HSD1 promoter. In conclusion, sex- and tissue-specific increases of 11β-HSD1, H6PD, GR, and C/EBPs may contribute to sexual dimorphism in the programming of exaggerated cortisol regeneration in liver and adipose tissues and offsprings’ susceptibility to metabolic syndrome.

Aging, glucocorticoids and developmental programming

“…Importantly, life-span effects are influenced by developmental programming by challenges such as altered F 1 nutrition during their development. The mechanisms are likely multiple and include both programmed changes within the hypothalamo-pituitary adrenal axis (Braun et al 2013;Zambrano et al 2014) and altered peripheral production of glucocorticoids in adipose tissue that are influenced by maternal nutrition (Guo et al 2013). The influence of developmental programming is clearly shown by the difference in the corticosterone concentrations in the F 1 from control and obese mothers.…”

Depot- and sex-specific effects of maternal obesity in offspring’s adipose tissue

“…type 2 (11β-HSD2) contents) and fat expansion has been observed in offspring from malnourished dams (Gnanalingham et al 2005, Lukaszewski et al 2011, Guo et al 2013. Third, increased expression of GR and 11β-HSD1 in visceral adipose tissue has been associated with the development of obesity in rats overfed during lactation (Boullu-Ciocca et al 2008).…”

Nutritional manipulations in the perinatal period program adipose tissue in offspring

“…Nutritional manipulations in the perinatal period can predispose to obesity and imprint adipogenesis in offspring in a Review E1202 PERINATAL NUTRITION AND ADIPOSE TISSUE PROGRAMMING sex-dependent manner (7,42,43,50,61,100). The reasons for these sex-specific programming effects remain unknown but could reflect direct interactions between nutritional signals and sex hormones in tissues of the developing fetus (1).…”