Transcriptional Activity of PGC-1αand NT-PGC-1αIs Differentially Regulated by Twist-1 in Brown Fat Metabolism

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