Abstract
Retinoic acid (RA) is known to maintain the preadipocyte phenotype and inhibit adipocyte differentiation and maturation. Although RA has been showed to induce epigenetic changes during embryonic stem cell differentiation, the effect of RA on epigenetic modifications of adipogenic genes are unknown. C3H10T1/2 mesenchymal progenitor cells were induced adipogenesis with/without 1mM all‐trans retinoic acid (ATRA), and epigenetic changes in the zfp423 promoter, a critical transcription factor initiating adipogenesis, were analyzed. We found that Growth arrest and DNA‐damage‐inducible protein GADD45 alpha (gadd45α) is involved in adipogenesis of C3H10T1/2 by inducing DNA demethylation in the zfp423 promoter. During adipogenesis, both gadd45α and zfp423 expression was upregulated. Gadd45α overexpression upregulated zfp423 expression and enhanced adipogenesis whereas gadd45α knock down had opposite effects. RA strongly inhibited the expression of zfp423 and down‐stream adipogenic genes in both control and gadd45α overexpressing cells and completely blocked lipid accumulation, which was associated with a reduction in gadd45α expression and binding to the zfp423 promoter. Consistently, in vivo, we found that 30 IU/mL vitamin A supplementation (through water) prevented high fat diet (60 kcal% fat) induced obesity, which was correlated with attenuated zfp423 and pparg expression in the adipose tissue of mice. After one month of high fat diet challenge, vitamin A supplemented mice had lower body weight gain, less white fat deposition, smaller adipocytes size and higher insulin sensitivity compared with control mice. These data demonstrate that GADD45α mediated zfp423 promoter demethylation is required for adipogenesis. RA inhibits adipogenesis by preventing DNA demethylation of the zfp423 promoter and lipid accumulation. Thus, RA is beneficial for the prevention of high fat diet induced obesity.Support or Funding InformationSupported by NIH R01HD067449 and USDA‐NIFA 2015‐67015‐23219
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