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Cell Death Dis. 2015 Aug 27;6:e1868. doi: 10.1038/cddis.2015.238.

Transglutaminase 2--a novel inhibitor of adipogenesis.

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Faculty of Dentistry, McGill University, Montreal, QC, Canada.
Department Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.


Differentiation of preadipocytes to lipid storing adipocytes involves extracellular signaling pathways, matrix remodeling and cytoskeletal changes. A number of factors have been implicated in maintaining the preadipocyte state and preventing their differentiation to adipocytes. We have previously reported that a multifunctional and protein crosslinking enzyme, transglutaminase 2 (TG2) is present in white adipose tissue. In this study, we have investigated TG2 function during adipocyte differentiation. We show that TG2 deficient mouse embryonic fibroblasts (Tgm2-/- MEFs) display increased and accelerated lipid accumulation due to increased expression of major adipogenic transcription factors, PPARγ and C/EBPα. Examination of Pref-1/Dlk1, an early negative regulator of adipogenesis, showed that the Pref-1/Dlk1 protein was completely absent in Tgm2-/- MEFs during early differentiation. Similarly, Tgm2-/- MEFs displayed defective canonical Wnt/β-catenin signaling with reduced β-catenin nuclear translocation. TG2 deficiency also resulted in reduced ROCK kinase activity, actin stress fiber formation and increased Akt phosphorylation in MEFs, but did not alter fibronectin matrix levels or solubility. TG2 protein levels were unaltered during adipogenic differentiation, and was found predominantly in the extracellular compartment of MEFs and mouse WAT. Addition of exogenous TG2 to Tgm2+/+ and Tgm2-/- MEFs significantly inhibited lipid accumulation, reduced expression of PPARγ and C/EBPα, promoted the nuclear accumulation of β-catenin, and recovered Pref-1/Dlk1 protein levels. Our study identifies TG2 as a novel negative regulator of adipogenesis.

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