Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes

Isidor, Marie S.; Winther, Sally; Markussen, Lasse K.; Basse, Astrid L.; Quistorff, Bjørn; Nedergaard, Jan; Emanuelli, Brice; Hansen, Jacob B.

doi:10.1002/1873-3468.13716

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…Substantial evidence indicates that PKM2 is important for cell differentiation [17] and metabolism [18]. PKM2 is expressed in MSCs and adipocytes [19], and the regulation of PKM2 expression or kinase activity can affect cell differentiation. Jiang et al found that PKM2 could regulate adipocyte differentiation via the PI3K-AKT pathway [20].…”

Section: Introductionmentioning

confidence: 99%

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

Cen

Cai

et al. 2020

EBioMedicine

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Background: Mesenchymal stem cells (MSCs) selectively differentiate into adipocytes or osteoblasts, and several molecules control the fate determination of MSCs. Understanding these key checkpoints greatly contributes to the ability to induce specific MSC differentiation for clinical applications. In this study, we aimed to explore whether TNF receptor-associated factor 4 (TRAF4) affects MSC adipogenic differentiation, which we previously reported that could positively regulated the osteogenic differentiation. Methods: Western blotting and Real-time Polymerase Chain Reaction were used to detected the expression pattern of TRAF4 during adipogenic differentiation. Lentivirus was constructed to regulate TRAF4 expression, and oil red O staining and Western blotting were used to assess its role in adipogenesis, which was confirmed in vivo by implanting an MSC-matrigel mixture into nude mice. Western blotting was used to detect the activated signaling pathways, and a specific inhibitor and agonist were used to clear the roles of the key signaling pathways. Additionaly, Co-Immunoprecipitation was conducted to find that Pyruvate kinase isozyme type M2 (PKM2) interacts with TRAF4, and to further explore their binding and functional domains. Finally, an RNA-binding protein immunoprecipitation assay and Western blotting were used to detect whether N6methyladenosine mediates the decreased TRAF4 expression during adipogenic differentiation. Findings: The results demonstrated that TRAF4 negatively regulates MSC adipogenesis in vitro and in vivo. Mechanistically, we revealed that TRAF4 binds to PKM2 to activate the kinase activity of PKM2, which subsequently activates b-catenin signaling and then inhibits adipogenesis. Furthermore, TRAF4 downregulation during adipogenesis is regulated by ALKBH5-mediated N6-methyladenosine RNA demethylation. Interpretation: TRAF4 negatively regulates the adipogenesis of MSCs by activating PKM2 kinase activity, which may act as a checkpoint to fine-tune the balance of adipo-osteogenic differentiation, and suggests that TRAF4 may be a novel target of MSCs in clinical use and may also illuminate the underlying mechanisms of bone metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

Cen

Cai

et al. 2020

EBioMedicine

View full text Add to dashboard Cite

show abstract

“…It has also been reported that lipid biosynthesis is required for the thermogenic response of BAT because it modulates the expression of mitochondrial electron transport chain components ( Tan et al., 2015 ). Accumulating evidence suggests a critical role of glycolysis in regulating adipose tissue function ( Hankir and Klingenspor, 2018 ; Isidor et al., 2020 ; Jung et al., 2021 ; Nguyen et al., 2020 ), but it remains unclear how glycolytic enzymes differently act on various adipose tissues. Therefore, we investigated whether BAT and WAT were regulated by the glycolytic enzyme phosphoglycerate mutase (PGAM), which catalyzes conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), by generating mice with adipose tissue-specific PGAM deficiency.…”

Section: Introductionmentioning

confidence: 99%