Hypothyroidism is associated with development of obesity and dysplidemia. Emerging evidence suggests that thyroid receptor associated proteins (TRAP) are key regulatory components of chromatin remodeling complexes. Our prior studies demonstrate that a high fat (HF) maternal diet induces fetal non-alcoholic steatohepatitis (NASH), while epigenetically altering chromatin structure of reprogrammed fetal genes. We hypothesized that a HF maternal diet influences the fetal thyroid and TRAP expression, thereby setting the stage for obesity via alterations in chromatin remodeling complexes.
Pregnant macaques were fed control (n12) or HF (n14) diet up to yr4, with a subset reverted to control diet in yr5 (n7). On e130 serum/tissue of delivered maternal-offspring pairs in successive gestations were obtained to assay thyroid hormones (TH: fT4,fT3,T3RU,TBG), lipids/FFA, cortisol, and leptin. Correlation of fetal TH to lipid levels was performed with Fishers z transformation in regression models stratified by maternal diet and controlling for maternal TH and leptin/bw ratio.
Consistent with marked disruption of fetal thyroxine regulation, maternal and fetal fT4 became inversely correlated with HF diet (r+.43,−.57 p<.01), and adjusted fetal fT4 was significantly less (1.97vs1.34, p<.0001). Moreover, while under control diet adjusted fetal TH to lipids trended in an inverse correlation (r−.09, −.6), HF diet reversed this correlation (r+.01,+.57) with a modest restoration following gestational diet reversal (r−.02,+.4). In Affymetrix (HG-U133 40K human genes) microarrays of fetal hepatic tissue, TRAP3 alone bore significant differential expression (>4.0-fold) among thyroid-related genes.
These data demonstrate that an obese in utero environment alters both fetal thyroid levels and correlative dyslipidemia in a reversible fashion, as well as hepatic TRAP3. We speculate this serves as a potential novel mechanistic link relating development of obesity with fetal hypothyroidism, NASH, chromatin remodeling complexes, and gene-specific regulation.
© 2007 Mosby, Inc. Published by Elsevier Inc. All rights reserved.