Evidence for a common mechanism of action for fatty acids and thiazolidinedione antidiabetic agents on gene expression in preadipose cells
ABSTRACT In diabetic rodents, thiazolidinediones are able to improve insulin sensitivity of target tissues and to reverse, at least partially, the diabetic state. The effects of these drugs on phenotypic expression in various tissues, including adipose tissue, have been reported. We report here that a new thiazolidinedione compound, BRL 49653, exerts, in preadipose cells, potent effects on the expression of genes encoding proteins involved in fatty acid metabolism. These effects of BRL 49653 in Ob 1771 preadipose cells are similar, in terms of kinetics, reversibility, specificity of genes affected, and requirement for protein synthesis, to those already described for natural or nonmetabolizable fatty acids. Moreover, when used at submaximally effective concentrations, BRL49653 and 2-bromopalmitate act in an additive manner to induce gene expression in preadipose cells, but this additivity of effects is lost when one of the compounds is used at a maximally effective concentration. These observations, suggesting similar mechanisms of action for thiazolidinediones and fatty acids, are strongly supported by the demonstration that (i) both molecules activate, in a heterogolous trans-activation assay, the same nuclear receptor of the steroid/thyroid hormone nuclear receptor superfamily and (ii) transfection of 3T3-C2 fibroblasts with an expression vector for this nuclear receptor confers thiazolidinedione inducibility of adipocyte lipid-binding protein gene expression.
- SourceAvailable from: Ricardo Uauy
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- "While antagonistic ligands include n-3 and n-6 PUFA-CoA (Hertz et al. 1998). The net effects of PPAR on cellular processes and metabolism include enhanced peroxisomal proliferation, increased fatty acid oxidation, lower plasma triacylglycerol levels and improved glucose tolerance (Ibrahimi et al. 1994; Tontonoz et al. 1994; Hertz et al. 1998). More recently, PPAR-α-induced macrophage activation of oxidized LDL uptake has been demonstrated, this process was mediated by a scavenger CD36 protein. "
ABSTRACT: Essential fatty acids (EFA) are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFA). These fatty acids serve as specific precursors for eicosanoids that regulate numerous cell and organ functions. Results from animal and recent human studies support the essential nature of n-3 EFA in addition to the well-established role of n-6 EFA for human subjects, particularly in early life. The most significant effects relate to neural development and maturation of sensory systems. Recent studies using stable-isotope-labelled tracers demonstrate that even preterm infants are able to form arachidonic acid (AA) and docosahexaenoic acid (DHA), but that synthesis is extremely low. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation, and retinal and nervous system development. Regulation of gene expression by LCPUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the steroid hormone receptor family. Two types of polyunsaturated fatty acid responsive transcription factors have been characterized, the peroxisome proliferator-activated receptor (PPAR) and the hepatic nuclear factor 4alpha. DHA also has significant effects on photoreceptor membranes involved in the signal transduction process, rhodopsin activation, and rod and cone development. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oils, sources of LCPUFA, results in increased blood levels of DHA and AA, as well as an associated improvement in visual function in formula-fed premature infants to match that of human milk-fed infant. Recent clinical trials convincingly support LCPUFA supplementation of preterm infant formulations and possibly term formula to mimic human milk composition.Proceedings of The Nutrition Society 03/2000; 59(1):3-15. DOI:10.1017/S0029665100000021 · 4.94 Impact Factor
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- "These data suggest that inhibition of PEPCK gene transcription can occur through at least two di¡erent signaling mechanisms, one being a wortmannin-sensitive insulin-dependent pathway  and another which is insulin-independ- ent. It is now documented that thiazolidinediones, like troglitazone, can lead to changes in gene expression by speci¢cally binding to and activating PPARQ   . While we have no evidence as to whether troglitazone inhibits PEPCK gene expression via a direct mechanism, the fact that the PEPCK promoter has two PPAR response elements  makes this a reasonable hypothesis. "
ABSTRACT: Troglitazone is an oral insulin-sensitizing drug used to treat patients with type 2 diabetes. A major feature of this hyperglycemic state is the presence of increased rates of hepatic gluconeogenesis, which troglitazone is able to ameliorate. In this study, we examined the molecular basis for this property of troglitazone by exploring the effects of this compound on the expression of the two genes encoding the major regulatory enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary cultures of rat hepatocytes. Insulin is able to inhibit expression of both of these genes, which was verified in our model system. Troglitazone significantly reduced mRNA levels of PEPCK and G6Pase in rat hepatocytes isolated from normal and Zucker-diabetic rats, but to a lesser extent than that observed with insulin. Interestingly, troglitazone was unable to reduce cAMP-induced levels of PEPCK mRNA, suggesting that the molecular mechanism whereby troglitazone exerted its effects on gene expression differed from that of insulin. This was further supported by the observation that troglitazone was able to reduce PEPCK mRNA levels in the presence of the insulin signaling pathway inhibitors wortmannin, rapamycin, and PD98059. These results indicate that troglitazone can regulate the expression of specific genes in an insulin-independent manner, and that genes encoding gluconeogenic enzymes are targets for the inhibitory effects of this drug.Biochimica et Biophysica Acta 09/1999; 1451(1):122-31. DOI:10.1016/S0167-4889(99)00080-4 · 4.66 Impact Factor
Proceedings of The Nutrition Society 04/1996; 55(1B):19-37. DOI:10.1079/PNS19960009 · 4.94 Impact Factor
- "Interestingly, PPAR are activated also by physiological concentrations of LCFA (Gottlincher et al. 1992; Schmidt et al. 1992; Dreyer et al. 1993). In adipocytes, LCFA lead to transcriptional induction of various LBP including ALBP (Amri et al. 1991) and Ma1 1 (Ibrahimi et al. 1994), the two isoforms of FABP, expressed in the adipose tissue and FAT (Amri et al. 1995) through the activation of a new member of the PPAR family, termed fatty acid-activated receptor (FAAR; Amri et al. 1995). Since PPARa and FAAR are found in the small intestine (Beck et al. 1992; Amri et al. 199.5) and L-FABP, is transcriptionally up-regulated by dietary fats (Mallordy et al. 199.5; "