PPARs in the Control of Uncoupling Proteins Gene Expression

Abstract

Uncoupling proteins (UCPs) are mitochondrial membrane transporters involved in the control of energy conversion in mitochondria. Experimental and genetic evidence relate dysfunctions of UCPs with metabolic syndrome and obesity. The PPAR subtypes mediate to a large extent the transcriptional regulation of the UCP genes, with a distinct relevance depending on the UCP gene and the tissue in which it is expressed. UCP1 gene is under the dual control of PPARgamma and PPARalpha in relation to brown adipocyte differentiation and lipid oxidation, respectively. UCP3 gene is regulated by PPARalpha and PPARdelta in the muscle, heart, and adipose tissues. UCP2 gene is also under the control of PPARs even in tissues in which it is the predominantly expressed UCP (eg, the pancreas and liver). This review summarizes the current understanding of the role of PPARs in UCPs gene expression in normal conditions and also in the context of type-2 diabetes or obesity.

Figure 1

Schematic representation of the regulation of UCP1 gene expression by ligand-dependent activation of PPARα and PPARγ, and coactivation by PGC-1α. The diagram shows the PPAR response element in the rat UCP1 gene enhancer (24). Major features of the transcriptional regulation of the mouse and human UCP1 genes appear to be similar (16, 23). During brown adipocyte differentiation, adipogenic signals activate transcription of the UCP1 gene through PPARγ and coactivation by PGC-1α, in concert with overall induction of adipocyte differentiation towards the brown fat lineage. In response to thermogenic simuli on mature brown adipocytes, activation of PPARα by lipolysis-derived fatty acids contributes to the coordination of UCP1 gene transcription (thermogenesis) with the lipid oxidation pathways providing metabolic fuel for oxidation.

Figure 2

Schematic representation of the regulation of UCP3 gene transcription by PPARs. The proximal region responsive to PPARα and PPARδ activation via PPAR/RXR heterodimers is shown. The −55 C to T polymorphism is adjacent to this region. MyoD and TFs indicate the binding of MyoD and of basal transcription factors, respectively, close to the site of transcription initiation. P300, the main coactivator linking ligand-dependent activation of PPARs with transcriptional activation is shown. AC indicates the acetylation sites involved in transcriptional activation.