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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.

ppar research

Transcriptional Activity of PGC-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi mathvariant="bold-italic">α</mml:mi></mml:mrow></mml:math>and NT-PGC-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mrow><mml:mi mathvariant="bold-italic">α</mml:mi></mml:mrow></mml:math>Is Differentially Regulated by Twist-1 in Brown Fat Metabolism

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