NT-PGC-1α Protein Is Sufficient to Link β3-Adrenergic Receptor Activation to Transcriptional and Physiological Components of Adaptive Thermogenesis

PGC-1 alpha is an inducible transcriptional coactivator that regulates cellular energy metabolism and adaptation to environmental and nutritional stimuli. In tissues expressing PGC-1 alpha, alternative splicing produces a truncated protein (NT-PGC-1 alpha) corresponding to the first 267 amino acids of PGC-1 alpha. Brown adipose tissue also expresses two novel exon 1b-derived isoforms of PGC-1 alpha and NT-PGC-1 alpha, which are 4 and 13 amino acids shorter in the N termini than canonical PGC-1 alpha and NT-PGC-1 alpha, respectively. To evaluate the ability of NT-PGC-1 alpha to substitute for PGC-1 alpha and assess the isoform-specific role of NT-PGC-1 alpha, adaptive thermogenic responses of adipose tissue were evaluated in mice lacking full-length PGC-1 alpha (FL-PGC-1(-/-)) but expressing slightly shorter but functionally equivalent forms of NT-PGC-1 alpha (NT-PGC-1 alpha(254)). At room temperature, NT-PGC-1 alpha and NT-PGC-1 alpha(254) were produced from conventional exon 1a-derived transcripts in brown adipose tissue of wild type and FL-PGC-1 alpha(-/-) mice, respectively. However, cold exposure shifted transcription to exon 1b, increasing exon 1b-derived mRNA levels. The resulting transcriptional responses produced comparable increases in energy expenditure and maintenance of core body temperature in WT and FL-PGC-1 alpha(-/-) mice. Moreover, treatment of the two genotypes with a selective beta(3)-adrenergic receptor agonist produced similar increases in energy expenditure, mitochondrial DNA, and reductions in adiposity. Collectively, these findings illustrate that the transcriptional and physiological responses to sympathetic input are unabridged in FL-PGC-1 alpha(-/-) mice, and that NT-PGC-1 alpha is sufficient to link beta(3)-androgenic receptor activation to adaptive thermogenesis in adipose tissue. Furthermore, the transcriptional shift from exon 1a to 1b supports isoform-specific roles for NT-PGC-1 alpha in basal and adaptive thermogenesis.