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NT-PGC-1? deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo.

ABSTRACT: 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. PGC-1? is dispensable for cold-induced BAT thermogenesis as long as NT-PGC-1? is present. However, the functional significance of NT-PGC-1? in BAT has not been determined. In the present study, we generated NT-PGC-1?-/- mice to investigate the effect of NT-PGC-1? deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1?-/- 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-1?-/- BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1?-/- BAT mitochondria. In line with this, NT-PGC-1?-/- mice had higher reliance on carbohydrates. In response to cold or ?3-adrenergic receptor agonist, NT-PGC-1?-/- mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1? is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1? and NT-PGC-1? to temperature-regulated BAT remodeling.

SUBMITTER: Kim J

PROVIDER: S-EPMC6121938 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo.

Kim Jihyun J Park Min Sung MS Ha Kyoungsoo K Park Chulhong C Lee Jisu J Mynatt Randall L RL Chang Ji Suk JS

Journal of lipid research 20180719 9

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<sup>-/-</sup> mice to investigate the effect of NT-PGC- ...[more]

PMID: 30026188

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Project description:The β3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

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NT-PGC-1? deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo.

Publications

NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo.

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