Abstract
Transcriptional coactivator PPAR γ coactivator (PGC)-1α and its splice variant N-terminal (NT)-PGC-1α mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. PGC-1α is dispensable for cold-induced BAT thermogenesis as long as NT-PGC-1α is present. However, the functional significance of NT-PGC-1α in BAT has not been determined. In the present study, we generated NT-PGC-1α-/- mice to investigate the effect of NT-PGC-1α deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1α-/- mice exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets concomitant with marked downregulation of FA oxidation (FAO)-related genes. Consistent with transcriptional changes, mitochondrial FAO was significantly diminished in NT-PGC-1α-/- BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1α-/- BAT mitochondria. In line with this, NT-PGC-1α-/- mice had higher reliance on carbohydrates. In response to cold or β3-adrenergic receptor agonist, NT-PGC-1α-/- mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1α is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1α and NT-PGC-1α to temperature-regulated BAT remodeling.
Highlights
Transcriptional coactivator PPAR coactivator (PGC)-1 and its splice variant N-terminal (NT)-PGC-1 mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature
The NADH and FADH2 are used by the electron transport system to AR, adrenergic receptor; BAT, brown adipose tissue; EE, energy expenditure; ETC, electron transport chain; FAO, FA oxidation; inguinal WAT (IWAT), inguinal white adipose tissue; Krebs– Henseleit buffer (KHB), Krebs-Henseleit buffer; NT-PGC1, N-terminal PPAR coactivator 1- ; PDH, pyruvate dehydrogenase; qPCR, quantitative real-time PCR; RER, respiratory exchange ratio; TAG, triacylglycerol; UCP1, uncoupling protein 1; VWAT, visceral white adipose tissue; WAT, white adipose tissue
Generation of NT-PGC-1 / mice We previously reported that alternative 3′ splicing of the PPARGC1A gene produces an additional transcript encoding a shorter isoform of PGC-1 named NT-PGC-1 [19] and that NT-PGC-1 is sufficient to maintain normal BAT function and activate cold-induced thermogenesis in mice selectively deficient in full-length PGC-1 [21,22,23]
Summary
Transcriptional coactivator PPAR coactivator (PGC)-1 and its splice variant N-terminal (NT)-PGC-1 mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. Brown adipose tissue (BAT) is specialized in dissipating energy in the form of heat This process, known as nonshivering thermogenesis, requires an abundant fuel supply, a high number of mitochondria, and high levels of uncoupling protein 1 (UCP1), a BAT-specific transport protein located in the inner mitochondrial membrane (IMM) [1]. The NADH and FADH2 are used by the electron transport system to AR, adrenergic receptor; BAT, brown adipose tissue; EE, energy expenditure; ETC, electron transport chain; FAO, FA oxidation; IWAT, inguinal white adipose tissue; KHB, Krebs-Henseleit buffer; NT-PGC1 , N-terminal PPAR coactivator 1- ; PDH, pyruvate dehydrogenase; qPCR, quantitative real-time PCR; RER, respiratory exchange ratio; TAG, triacylglycerol; UCP1, uncoupling protein 1; VWAT, visceral white adipose tissue; WAT, white adipose tissue
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