NT-PGC-1α activation attenuates high-fat diet-induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism.

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and its splice variant N terminal (NT)-PGC-1α regulate adaptive thermogenesis by transcriptional induction of thermogenic and mitochondrial genes involved in energy metabolism. We previously reported that full-length PGC-1α (FL-PGC-1α) is dispensable for cold-induced nonshivering thermogenesis in FL-PGC-1α(-/-) mice, since a slightly shorter but functionally equivalent form of NT-PGC-1α (NT-PGC-1α(254)) fully compensates for the loss of FL-PGC-1α in brown and white adipose tissue. In the current study, we challenged FL-PGC-1α(-/-) mice with a high-fat diet (HFD) to investigate the effects of diet-induced thermogenesis on HFD-induced obesity. Despite a large decrease in locomotor activity, FL-PGC-1α(-/-) mice exhibited the surprising ability to attenuate HFD-induced obesity. Reduced fat mass in FL-PGC-1α(-/-) mice was closely associated with an increase in body temperature, energy expenditure, and whole-body fatty acid oxidation (FAO). Mechanistically, FL-PGC-1α(-/-) brown adipose tissue had an increased capacity to oxidize fatty acids and dissipate energy as heat, in accordance with upregulation of thermogenic genes UCP1 and DIO2. Furthermore, augmented expression of FAO and lipolytic genes in FL-PGC-1α(-/-) white adipose tissue was highly correlated with decreased fat storage in adipose tissue. Collectively, our data highlight a protective effect of NT-PGC-1α on diet-induced obesity by enhancing diet-induced thermogenesis and FAO.

Jun HJ ，Joshi Y ，Patil Y ，Noland RC ，Chang JS ... -  《-》

Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1α.

Kim J ，Fernand VE ，Henagan TM ，Shin J ，Huypens P ，Newman S ，Gettys TW ，Chang JS ... -  《PLoS One》

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

Kim J ，Park MS ，Ha K ，Park C ，Lee J ，Mynatt RL ，Chang JS ... -  《-》

NT-PGC-1α protein is sufficient to link β3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis.

Chang JS ，Fernand V ，Zhang Y ，Shin J ，Jun HJ ，Joshi Y ，Gettys TW ... -  《-》

NT-PGC-1α deficiency attenuates high-fat diet-induced obesity by modulating food intake, fecal fat excretion and intestinal fat absorption.

Kim J ，Moon J ，Park CH ，Lee J ，Cheng H ，Floyd ZE ，Chang JS ... -  《Scientific Reports》