title: Inhibitory effect of p53 on mitochondrial content and function during adipogenesis.
abstract: The p53 protein is known as a guardian of the genome and is involved in energy metabolism. Since the metabolic system is uniquely regulated in each tissue, we have anticipated that p53 also would play differential roles in each tissue. In this study, we focused on the functions of p53 in white adipose tissue (adipocytes) and skeletal muscle (myotubes), which are important peripheral tissues involved in energy metabolism. We found that in 3T3-L1 preadipocytes, but not in C2C12 myoblasts, p53 stabilization or overexpression downregulates the expression of Ppargc1a, a master regulator of mitochondrial biogenesis. Next, by using p53-knockdown C2C12 myotubes or 3T3-L1 preadipocytes, we further examined the relationship between p53 and mitochondrial regulation. In C2C12 myoblasts, p53 knockdown did not significantly affect Ppargc1a expression and mtDNA, but did suppress differentiation to myotubes, as previously reported. However, in 3T3-L1 preadipocytes and mouse embryonic fibroblasts, p53 downregulation enhanced both differentiation into adipocytes and mitochondrial DNA content. Furthermore, p53-depleted 3T3-L1 cells showed increase in mitochondrial proteins and enhancement of both Citrate Synthase and Complex IV activities during adipogenesis. These results show that p53 differentially regulates cell differentiation and mitochondrial biogenesis between adipocytes and myotubes, and provide evidence that p53 is an inhibitory factor of mitochondrial regulation in adipocyte lineage.
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan; Department of Internal Medicine Research, Sasaki Institute, Sasaki Foundation, 2-2 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: okita@po.kyoundo.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Okita
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ishikawa
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Mizunoe
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Oku
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nagai
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mikami
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okado
authors.affiliation: Department of Internal Medicine Research, Sasaki Institute, Sasaki Foundation, 2-2 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Division of Translational and Molecular Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-8567, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-0022, Japan. Electronic address: higami@rs.noda.tus.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: Adipogenesis; Mitochondrial biogenesis; Ppargc1a; p53