A Novel Regulatory Pathway of Brown Fat Thermogenesis

Abstract

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.

Phytanic acid, but not pristanic acid, mediates the positive effects of phytol derivatives on brown adipocyte differentiation

“…10 Wg RNA was used for Northern blot analysis, as reported [9]. For detection of PhyH mRNA, a probe was obtained after coupled reverse transcription and PCR ampli¢cation of mouse liver RNA using the primers 5P-GCAGTTTCGTCTGCTG-GCC-3P and 5P-GTACCTCACTCTTGAAGGGC-3P, which correspond to positions 14^29 and 1080^1061 in the PhyH cDNA sequence (GenBank AF023463).…”

Nuclear receptor corepressor RIP140 regulates fat accumulation

“…Transcriptional regulation of genes encoding enzymes such as SCD1, ACC1, and FAS is complex, and the direct targets for RIP140 action have yet to be elucidated. In BAT, transcription from the UCP1 gene may be regulated by PPARs, retinoids, and thyroid hormone, as well as through the activation of ␤-adrenergic receptor intracellular signaling pathways (19,(48)(49)(50)(51). Expression of UCP1 has been shown to be induced in WAT in transgenic mice by introduction of an activated form of PPAR␦ (20) and also in human white adipocytes in culture as a result of expression of PGC-1␣ and activation by ligands for PPAR␥ (52).…”

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…The genomic organization of the mouse, rat and human UCP1 genes has been analysed in several laboratories [7,8,[130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145]. The structure of the UCP1 gene is highly conserved in these three species.…”

“…The response elements for these factors were functionally identified in the enhancer [132,[136][137][138][139][140][141]159]. Response elements for retinoids seem to be particularly important for the control of UCP1 gene transcription.…”