PGC-1α: A Multifunctional Transcriptional Coactivator Involved in Human Metabolic Disorders

Nuclear hormone receptor function is controlled by a number of ancillary factors termed coregulators. Such coactivators and corepressors afford considerable flexibility in the coordinate expression of gene networks in numerous physiological, developmental and metabolic processes. PGC-1α, originally described as transcriptional coactivator of PPARγ, has since been shown to act in a much broader context. PGC-1α coordinates the transcriptional programs of several key cellular pathways including mitochondrial biogenesis, thermogenesis, hepatic gluconeogenesis and β- oxidation of fatty acids via interactions with a growing number of transcription factors. A central issue to understand the diverse functions of PGC-1α is to gain insight into the mechanisms that confer specificity to its interactions with transfactors in response to intra- and extracellular signals. This review focuses on the different modes of regulation of PGC-1α function and the implications for tissue and context-specific transcriptional responses. Moreover, the role of sequence substitutions at the PGC-1α gene locus and their haplotype structure is discussed in relation to human disease phenotypes.