Transcriptional activity of PGC-1 α and NT-PGC-1 α is differentially regulated by twist-1 in brown fat metabolism

Brown fat expresses two pgc-1α isoforms (pgc-1α and nt-pgc-1α) 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 pparγ,pparα,errα,and nrf1. pgc-1α consists of 797 amino acids,whereas alternative splicing of the pgc-1α gene produces a shorter protein called nt-pgc-1α (aa 1270). we report in this paper that transcriptional activity of pgc-1α and nt-pgc-1α is differently affected by the transcriptional regulator,twist-1. twist-1 suppresses pgc-1α but not nt-pgc-1α. the inhibition of pgc-1α activity by twist-1 is mediated by direct interaction through the c-terminal region of pgc-1α (aa 353797). thus,the absence of the corresponding c-terminal domain in nt-pgc-1α allows nt-pgc-1α to be free from twist-1-mediated inhibition. overexpression of twist-1 in brown adipocytes suppresses transcription of a subset of pgc-1α-target genes involved in mitochondrial fatty acid oxidation and uncoupling (cpt1β,ucp1,and errα). in contrast,nt-pgc-1α-mediated induction of these genes is unaffected by twist-1. these findings show that differences in inhibitory protein-protein interactions of pgc-1α and nt-pgc-1α with twist-1 lead to differential regulation of their function by twist-1. © 2012 hee-jin jun et al.