Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid (RA), a bioactive metabolite of vitamin A, is a critical mediator of cell differentiation. RA blocks adipogenesis, but mechanisms remain to be established. ZFP423 is a key transcription factor maintaining white adipose identity. We found that RA inhibits Zfp423 expression and adipogenesis via blocking DNA demethylation in the promoter of Zfp423, a process mediated by growth arrest and DNA-damage-inducible protein alpha (GADD45A). RA induces the partnering between retinoic acid receptor (RAR) and tumor suppressor inhibitor of growth protein 1 (ING1), which prevents the formation of GADD45A and ING1 complex necessary for locus-specific Zfp423 DNA demethylation. In vivo, vitamin A supplementation prevents obesity, downregulates Gadd45a expression, and reduces GADD45A binding and DNA demethylation in the Zfp423 promoter. Inhibition of Zfp423 expression due to RA contributes to the enhanced brown adipogenesis. In summary, RA inhibits white adipogenesis by inducing RAR and ING1 interaction and inhibiting Gadd45a expression, which prevents GADD45A-mediated DNA demethylation.
 ...
PMID:Retinoic acid inhibits white adipogenesis by disrupting GADD45A-mediated Zfp423 DNA demethylation. 2899 91

White adipocytes represent the principle site for energy storage whereas brown/beige adipocytes emerge from seemingly distinct cellular lineages and burn chemical energy to produce heat. Thermogenic adipocytes utilize cell-type selective master regulatory transcription factors to drive the expression of their adipocyte thermogenic gene program. White adipocytes harbor transcriptional mechanisms to suppress the thermogenic gene program and maintain an energy-storing function. Here, we summarize some of the key developmental and transcriptional mechanisms leading to the postnatal recruitment of thermogenic adipocytes under physiological conditions, with a particular emphasis on the transcriptional "brakes" on the thermogenic gene program. We highlight a number of recent studies, including our own work on the transcription factor, ZFP423, that illustrate the potential to engineer the subcutaneous and visceral white fat lineages to adopt a thermogenic fat cell fate by releasing the inhibition of the adipocyte thermogenic gene program. These transcriptional brakes on adipocyte thermogenesis may represent potential targets of therapeutic interventions designed to combat obesity and associated metabolic disorders.
 ...
PMID:Transcriptional brakes on the road to adipocyte thermogenesis. 2980 Jul 20