Abstract
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-1 α gene produces a shorter protein called NT-PGC-1α (aa 1–270). 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 353–797). 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.
Highlights
The transcriptional coactivator Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was first identified as a coactivator of PPARγ in brown adipose tissue and is known to interact with a broad range of nuclear receptors and transcription factors to regulate mitochondrial biogenesis in most tissues and control adaptive thermogenesis, fatty acid/glucose metabolism, ROS metabolism, and muscle fiber type switching in a tissue-specific manner [1,2,3,4,5,6,7]
NT-PGC-1α is relatively stable since it is less effectively targeted to the proteosome due to lack of the C-terminal domain involved in proteosomal targeting [15]
Constitutive activation of target genes by NT-PGC-1α is effectively limited by a mechanism that sequesters NT-PGC-1α to the cytoplasm in a CRM1-dependent manner [16]
Summary
The transcriptional coactivator PGC-1α was first identified as a coactivator of PPARγ in brown adipose tissue and is known to interact with a broad range of nuclear receptors and transcription factors to regulate mitochondrial biogenesis in most tissues and control adaptive thermogenesis, fatty acid/glucose metabolism, ROS metabolism, and muscle fiber type switching in a tissue-specific manner [1,2,3,4,5,6,7]. The function of PGC-1α among tissues is regulated by signaling inputs that increase transcription of PGC-1α and modulate the transcribed protein through tissue-specific posttranslational modifications [8,9,10,11,12,13,14]. This allows PGC-1α to function as a key regulator to link nutritional and environmental stimuli to the tissue-specific transcriptional programs. Constitutive activation of target genes by NT-PGC-1α is effectively limited by a mechanism that sequesters NT-PGC-1α to the cytoplasm in a CRM1-dependent manner [16]. PKA-dependent phosphorylation of NTPGC-1α increases its nuclear retention and subsequent recruitment to the transcriptional complexes [16]
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