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Abstract
Estrogen sulfotransferase (EST/SULT1E1) is known to catalyze the sulfoconjugation and deactivation of estrogens. The goal of this study is to determine whether and how EST plays a role in human adipogenesis. By using human primary adipose-derived stem cells (ASCs) and whole-fat tissues from the abdominal subcutaneous fat of obese and nonobese subjects, we showed that the expression of EST was low in preadipocytes but increased upon differentiation. Overexpression and knockdown of EST in ASCs promoted and inhibited differentiation, respectively. The proadipogenic activity of EST in humans was opposite to the antiadipogenic effect of the same enzyme in rodents. Mechanistically, EST promoted adipogenesis by deactivating estrogens. The proadipogenic effect of EST can be recapitulated by using an estrogen receptor (ER) antagonist or ERα knockdown. In contrast, activation of ER in ASCs inhibited adipogenesis by decreasing the recruitment of the adipogenic peroxisome proliferator-activated receptor γ (PPARγ) onto its target gene promoters, whereas ER antagonism increased the recruitment of PPARγ to its target gene promoters. Linear regression analysis revealed a positive correlation between the expression of EST and body mass index (BMI), as well as a negative correlation between ERα expression and BMI. We conclude that EST is a proadipogenic factor which may serve as a druggable target to inhibit the turnover and accumulation of adipocytes in obese patients.
ACKNOWLEDGMENTS
We thank Donald DeFranco (University of Pittsburgh) for his insightful comments on this study and Jiang Li (University of Pittsburgh) for some of the data analysis.
This work was supported in part by NIH grants DK083953 and HD073070 (to W.X.), and CA114246 (to J.P.R.). C.A.I was supported by the NIH Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31-DK-095589). W.X. is the Joseph Koslow Endowed Chair in Pharmaceutical Sciences at the University of Pittsburgh School of Pharmacy.