Search

Differentiation of adipogenic precursor cells into mature adipocytes is a complex process. Adipocyte differentiation is characterized by the expression of several adipocyte-specific genes, which occurs in an ordered fashion, and is orchestrated by a set of interacting transcription factors. The most prominent transcription factors involved in this process are the γ form of peroxisome proliferator activated receptors (PPAR) and the various members of the CAAT enhancer binding proteins (α β, and γ). In addition to PPARγ and the C/EBPs, several other transcription factors, including ADD-1 (SRE-BP), HMGI-C, are involved in regulating the differentiation process. Altered activity and/or expression of these transcription factors, will change the expression of target genes in the differentiating cells, ultimately resulting in the differentiated adipocyte phenotype. Modulation of these transcription factors by either pharmacological or dietary manipulations might influence adipocyte differentiation and prove beneficial in the prevention and treatment of obesity

Differentiation of adipogenic precursor cells into mature adipocytes is a complex phenomenon, characterized by an ordered expression of adipocyte-specific genes, triggered by a set of interacting transcription factors. The most important transcription factors involved in this process are the gamma form of peroxisome proliferator activated receptors (PPAR gamma) and the various members of the CCAAT enhancer binding proteins (alpha, beta, and delta). In addition to PPAR gamma and these enhancer binding proteins, several other transcription factors, including ADD-1 (SRE-BP), HMGI-C, are involved in regulating this process. Altered activity and/or expression of these transcription factors, will induce the expression of target genes in the differentiating cells, ultimately resulting in the phenotypical characteristics of the adipocytes. It is speculated that modulation of these transcription factors by either pharmacological or dietary manipulations might influence adipocyte differentiation and prove beneficial in the prevention and treatment of obesity.

Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPARalpha. To determine whether PPARalpha activators also improve insulin sensitivity, we measured the capacity of three PPARalpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPARalpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPARalpha activation in vivo was demonstrated by marked alterations in the expression of PPARalpha target genes, whereas PPARgamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARalpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR., info:eu-repo/semantics/published