Transcriptional Activity of PGC-1α and NT-PGC-1α Is Differentially Regulated by Twist-1 in Brown Fat Metabolism

Brown fat expresses two PGC-1 alpha isoforms (PGC-1 alpha and NT-PGC-1 alpha) and both play a central role in the regulation of cellular energy metabolism and adaptive thermogenesis by interacting with a wide range of transcription factors including PPAR gamma, PPAR alpha, ERR alpha, and NRF1. PGC-1 alpha consists of 797 amino acids, whereas alternative splicing of the PGC-1 alpha gene produces a shorter protein called NT-PGC-1 alpha (aa 1-270). We report in this paper that transcriptional activity of PGC-1 alpha and NT-PGC-1 alpha is differently affected by the transcriptional regulator, Twist-1. Twist-1 suppresses PGC-1 alpha but not NT-PGC-1 alpha. The inhibition of PGC-1 alpha activity by Twist-1 is mediated by direct interaction through the C-terminal region of PGC-1a (aa 353-797). Thus, the absence of the corresponding C-terminal domain in NT-PGC-1 alpha allows NT-PGC-1 alpha to be free from Twist-1-mediated inhibition. Overexpression of Twist-1 in brown adipocytes suppresses transcription of a subset of PGC-1 alpha-target genes involved in mitochondrial fatty acid oxidation and uncoupling (CPT1 beta, UCP1, and ERR alpha). In contrast, NT-PGC-1 alpha-mediated induction of these genes is unaffected by Twist-1. These findings show that differences in inhibitory protein-protein interactions of PGC-1 alpha and NT-PGC-1 alpha with Twist-1 lead to differential regulation of their function by Twist-1.