Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-gamma, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1alpha is a transcriptional coactivator of PPARgamma and other transcription factors. It is involved in the control of mitochondrial biogenesis, and its activity has been linked to insulin sensitization. Here we report that PGC-1alpha gene expression in brown and white adipocytes is a direct target of TZDs via PPARgamma activation. Activators of the retinoid X receptor also induce PGC-1alpha gene expression. This is due to the presence of a PPARgamma-responsive element in the distal region of the PGC-1alpha gene promoter that binds PPARgamma/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1alpha gene through coactivation of PPARgamma responsiveness to TZDs by PGC-1alpha itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1alpha up-regulation via enhanced transcription of the PGC-1alpha gene.

The mitochondrial uncoupling protein (UCP) is responsible for the thermogenic function of brown fat, and it is a molecular marker of the brown adipocyte cell type. Retinoic acid (RA) increased UCP mRNA levels severalfold in brown adipocytes differentiated in culture. This induction was independent of adrenergic pathways or protein synthesis. RA stimulated ucp gene expression regardless of the stage of brown adipocyte differentiation. In transient transfection experiments RA induced the expression of chloramphenicol acetyltransferase vectors driven by 4.5 kilobases of the 5'-noncoding region of the rat ucp gene, and co-transfection of expression vectors for RA receptors enhanced the action of RA. Retinoic acid receptor alpha was more effective than retinoid X receptor in promoting RA action, whereas a mixture of the two was the most effective. The RA-responsive region in the ucp gene was located at -2469/-2318 and contains three motifs (between -2357 and -2330) of the consensus half-sites characteristic of retinoic acid response elements. This 27-base pair sequence specifically binds purified retinoic acid receptor alpha as well as related proteins from brown fat nuclei. In conclusion, a novel potential regulatory pathway of brown fat development and thermogenic function has been recognized by identifying RA as a transcriptional activator of the ucp gene.

Oral treatment with oleoyl-estrone resulted in the specific dose-related loss of fat reserves with little change to other metabolic parameters. These results agree with the postulated role of oleoyl-estrone as a ponderostat signal.

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CCAAT/enhancer-binding protein (C/EBP) alpha mRNA and its protein products C/EBP alpha and 30 kDa C/EBP alpha are expressed in rat brown-adipose tissue. Results also demonstrate the expression of C/EBP beta mRNA and its protein products C/EBP beta and liver inhibitory protein (LIP) in the tissue. The abundance of C/EBP alpha and C/EBP beta proteins in adult brown fat is similar to that found in adult liver. However, the expression of C/EBP alpha and C/EBP beta is specifically regulated in brown fat during development. C/EBP alpha, 30 kDa C/EBP alpha, C/EBP beta and LIP content is several-fold higher in fetal brown fat than in the adult tissue, or liver at any stage of development. Peak values are attained in late fetal life, in concurrence with the onset of transcription of the uncoupling protein (UCP) gene, the molecular marker of terminal brown-adipocyte differentiation. When adult rats are exposed to a cold environment, which is a physiological stimulus of brown-adipose tissue hyperplasia and UCP gene expression, a specific rise in C/EBP beta expression with respect to C/EBP alpha, 30 kDa C/EBP alpha and LIP is observed. Present data suggest that the C/EBP family of transcription factors has an important role in the development and terminal differentiation of brown-adipose tissue.