ABSTRACT
OBJECTIVE/METHODS: DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals. RESULTS: We identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two independent cohorts. Further, we identified six adipose tissue depot-specific genes (HAND2, HOXC6, PPARG, SORBS2, CD36, and CLDN1). The effects were further supported in additional independent cohorts. Our top hits might play a role in adipogenesis and differentiation, obesity, lipid metabolism, and adipose tissue expandability. Finally, we show that in vitro methylation of SORBS2 directly represses gene expression. CONCLUSIONS: Taken together, our data show distinct tissue specific epigenetic alterations which associate with obesity.
Subject(s)
Adipose Tissue/metabolism , Obesity/genetics , Adipogenesis , Aged , CpG Islands/genetics , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Epigenomics , Female , Gene Expression , Gene Expression Profiling/methods , Genome-Wide Association Study , Humans , Intra-Abdominal Fat/metabolism , Male , Middle Aged , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , Subcutaneous Fat/metabolismABSTRACT
OBJECTIVE: To determine whether increased levels of maternal serum total activin A and inhibin A in preeclampsia are related to total blood volume, urinary clearance, or placental production. STUDY DESIGN: Activin A and inhibin A levels were measured in preeclamptic subjects and matched normotensive gravidas. In a subset of preeclamptic subjects (n = 21) and controls (n = 30), we performed blood volume studies. In an overlapping subset of preeclamptic subjects (n = 56), creatinine clearance results were available. Placental tissue was obtained from six preeclamptics and matched normotensive gravida for analysis of activin A and inhibin A mRNA expression. RESULTS: Maternal serum levels of inhibin A but not activin A were significantly negatively correlated with blood volume in preeclampsia (r(2) =.26, P =.017, and r(2) =.02, P =.44, respectively). Levels of both proteins were negatively correlated to creatinine clearance (r(2) =.29, P <.0001, and r(2) =.15, P =.003, respectively). Placental mRNA expression for both the alpha and betaA subunits was increased in preeclampsia (P =.038 and.049, respectively). CONCLUSION: Although placental mRNA expression of the subunits for both analytes is increased in preeclampsia, the increased levels of activin A appear to be more specifically a reflection of increased placental production than do the increased levels of inhibin A.
