Chemically distinct HDAC inhibitors prevent adipose conversion of subcutaneous human white preadipocytes at an early stage of the differentiation program

The present study investigated the effect of HDAC inhibitors on the differentiation of human subcutaneous white adipocytes. Results showed that trichostatin A, suberoylanilide hydroxamic acid, valproic acid and MS-275 inhibited triglyceride accumulation, GPDH activity and FABP4 protein expression in adipocytes, as well as leptin and VEGF release, while cells retained a fibroblist-like morphology. HDAC inhibitors exerted their antiadipogenic effect without inducing apoptosis or affecting cell viability and number, while 1-2 log unit higher concentrations were mostly required to exert an antiproliferative effect or to reduce LDH activity. A brief exposure to HDAC inhibitors at the beginning of the differentiation program was sufficient to observe the antiadipogenic effect while differentiation restarted after compound withdrawal and further exposure to inducers of differentiation demonstrating reversibility of the events. HDAC inhibitors hyperacetylated histone H4, but only hydroxamate-based Compounds produced a massive acetylation of alpha-tubulin, indicating that this latter event is not required to prevent adipose conversion. HDAC inhibitors induced a significant reduction of the expression of the transcription factorC/EBP alpha, an early marker of differentiation, and a diminution of fibronectin immunoreactivity was also observed. In conclusion, HDAC inhibitors from different chemical classes potently inhibited human adipose conversion at an early stage of the differentiation program. (C) 2009 Elsevier Inc. All rights reserved.