title: Transglutaminase 2--a novel inhibitor of adipogenesis.
abstract: 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.
authors: Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors: V D
authors: VD
authors: Myneni
authors: Department Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors: G
authors: G
authors: Melino
authors: Faculty of Dentistry, McGill University, Montreal, QC, Canada.|Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.
authors: M T
authors: MT
authors: Kaartinen
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D051176:beta Catenin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D019204:GTP-Binding Proteins