ACTIVATORS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA HAVE DEPOT-SPECIFIC EFFECTS ON HUMAN PREADIPOCYTE DIFFERENTIATION

Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differ entiation of murine preadipocyte cell lines. Recently, thiazolidinedio nes (TZDs), a novel class of insulin-sensitizing compounds effective i n the treatment of non-insulin-dependent diabetes mellitus (NIDDM) hav e been shown to bind to PPAR gamma with high affinity. We have examine d the effects of these compounds on the differentiation of human pread ipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, a nd mRNA levels, subcultured preadipocytes isolated from either SC or O m depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxy Delta(12,14)prostagland in J(2) (a natural PPAR gamma ligand) enhanced markedly the differenti ation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPAR gamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPAR gamma was expressed at similar level s in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDD M, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo i nsulin sensitivity.