Establishment of the therapeutic strategy for the cardiovascular complications in Metabolic syndrome by gene trap method
Project/Area Number |
18590828
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Circulatory organs internal medicine
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Research Institution | Kyoto University |
Principal Investigator |
ONO Koh Kyoto University, Department of Cardiovascular Medicine, Assistant Professor (00359275)
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Co-Investigator(Kenkyū-buntansha) |
HASEGAWA Koji Kyoto Medical Center, Division of Translational Research, Director (50283594)
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Project Period (FY) |
2006 – 2007
|
Project Status |
Completed (Fiscal Year 2007)
|
Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
Keywords | gene-trap / metabolic syndrome / adipocyte / serotonin / cardiomyocyte / GLUT4 / AMPK / TGIF |
Research Abstract |
The differentiation of preadipocytes into mature adipocytes is closely associated with the expression of adipocyte-specific gene products that are deeply involved in insulin resistance. Therefore, it is critical that we identify the genes required for differentiation into mature adipocytes. We used retrovirus insertion-mediated random mutagenesis to generate 3T3-L1 cell lines which lose their ability to differentiate into mature adipocytes. Using this approach, we discovered that tryptophan hydroxylase-1 (TPH1), a rate-limiting enzyme for the biosynthesis of serotonin, was required for adipocyte differentiation. While differentiation was clearly reduced in a mutant 3T3L-1 cell line that lacked expression of the normal TPH1 gene, reconstitution of the TPH1 gene in this cell line restored its differentiation potential. The administration of serotonin enhanced the differentiation in 3T3-L1 cells and in cells of stromal vascular fraction from adult mice. On the other hand, the serotonin sy
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nthesis inhibitor p-chlorophenylalanine and 5-hydroxy tryptophan receptor type 2A antagonists inhibited differentiation. Differentiation was significantly impaired in preadipocytes prepared from TPH-/- mice compared to those from wild-type mice. We observed no differences in the histology of adipose tissue between TPH-/- and wild-type mice at the basal state. However, after obesity was induced by a high-fat diet, increases in body weight and mesenteric fat weight were more prominent in TPH1-/- mice than in wild-type mice. Furthermore, glucose tolerance was more prominently impaired in TPH-/- mice than in wild-type mice. Interestingly, in obese groups, we observed extremely large (140μm〜) adipocytes in TPH-/- mice, in contrast to the usually hypertrophied (〜80μm) adipocytes in wild-type mice. We also observed PCNA-positive adipocytes in wild-type mice but not in TPH-/- mice, which suggests that adipocyte production is impaired in TPH-/- mice. Thus, serotonin in adipose tissue acts as an autocrine factor and is involved in adipocyte differentiation. The results also suggest that serotonin is required for the physiological hypertrophy of adipocytes in response to a high-fat diet, and for the preservation of normal glucose tolerance in adult mice. We also found TG-interacting factor and preproenkephalin-1 are required for the differentiation of preadiopcytes. We are now trying to establish therapeutic strategies against obesity and metabolic syndrome by targeting these molecules. In hypoxia and metabolic stress condition, cardiomyocytes adapt themselves by utilizing glycolytic pathway for their major energy source. In order to find the signal transduction mechanisms involved in such conditions, we have established a method to measure GLUT4 translocation by flow cytometry and found that both CMKKβ and LKB1 activate AMPK in cardiomyocytes. Less
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Report
(3 results)
Research Products
(62 results)
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[Journal Article] Identification of p300-targeted acetylated residues in GATA-4 during hypertrophic responses in cardiac myocytes2008
Author(s)
Takaya, T., Kawamura, T., Morimoto, T., Kita, T., Shimatsu, A., Hasegawa, K
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Journal Title
J Biol Chem 283(Epub ahead of print)
Pages: 9828-35
Description
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[Journal Article] Inhibition of CCN1 suppressed neointimal hyperplasia in a rat balloon injury model2008
Author(s)
Matsumae-H., Yoshida-Y., Ono-K., Togi-K., Inoue-K., Furukawa-Y., Nakashima-Y., Kojima-Y., Nobuyoshi-M., Kita-T., Tanaka-M
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Journal Title
Arterioscler Thromb Vasa Biol 28
Pages: 1077-83
Description
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[Journal Article] TG-interacting factor is required for the differentiation of preadipocytes2008
Author(s)
Horie-T., Ono-K., Kinoshita-M., Nishi-H., Nagao-K., Kawamura-T., Abe-Y., Wada-H., Shimatsu-A., Kita-T., Hasegawa-K
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Journal Title
J Lipid Res 49
Pages: 1224-34
Description
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[Journal Article] Leptin induces elongation of cardiac myocyte and causes eccentric left ventricular dilatation with compensation2007
Author(s)
Abe, Y., Ono, K., Kawamura, T., Wada, H., Kita, T., Shimatsu, A., Hasegawa, K
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Journal Title
Am J Physiol Heart Circ Physiol 292
Pages: 2387-96
Description
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[Journal Article] Serum adiponectin level as an independent predictor of mortality in patients with congestive heart failure2007
Author(s)
Tamura, T., Furukawa, Y., Taniguchi, R., Sato, Y., Ono, K., Horiuchi, H., Nakagawa, Y., Kita, T., Kimura, T
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[Journal Article] Trichostatin A induces myocardial differentiation of monkey ES cells2007
Author(s)
Hosseinkhani, M., Hasegawa, K., Ono, K., Kawamura, T., Takaya, T., Morimoto, T., Wada, H., Shimatsu, A., Prat, SG., Suemori, H., Nakatsuji, N., Kita, T
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Journal Title
Biochem Biophys Res Commun 356
Pages: 386-91
Description
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[Journal Article] CCN1 protects cardiac myocytes from oxidative stress via 61 integrin輸kt pathway2007
Author(s)
Yoshida, Y., Togi, K., Matsumae, H., Nakashima, Y., Kojima, Y., Yamamoto, Y., Ono, K., Nakamura, T., Kita, T., Tanaka, M
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Journal Title
Biochem Biophys Res Commun 355
Pages: 611-8
Description
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[Journal Article] Trichostatin A induces myocardial differentiation of monkey ES cells.2007
Author(s)
Hosseinkhani M, Hasegawa K, Ono K, Kawamura T, Takaya T, Morimoto T, Wada H, Shimatsu A, Prat SG, Suemori H, Nakatsuji N, Kita T.
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Journal Title
Biochem Biophys Res Commun. 356
Pages: 386-391
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[Journal Article] Three catheter-based strategies for cardiac delivery of therapeutic gelatin microspheres2006
Author(s)
Hoshino, K., Kimura, T., De, Grand, AM., Yoneyama, R., Kawase, Y., Houser, S., Ly, HQ., Kushibiki, T., Furukawa, Y., Ono, K., Tabata, Y., Frangioni, JV., Kita, T., Hajjar, RJ., Hayase, M
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Journal Title
Gene Ther 13(18)
Pages: 1320-7
Description
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[Journal Article] Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling following myocardial infarction in adult mice in vivo2006
Author(s)
Miyamoto, S., Kawamura, T., Morimoto, T., Ono, K., Wada, H., Kawase, Y., Matsumori, A., Nishio, R., Kita, T., Hasegawa, K
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Journal Title
Circulation 113
Pages: 679-90
Description
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[Journal Article] Three catheter-based strategies for cardiac delivery of therapeutic gelatin microspheres.2006
Author(s)
Hoshino K, Kimura T, De Grand AM, Yoneyama R, Kawase Y, Houser S, Ly HQ, Kushibiki T, Furukawa Y, Ono K, Tabata Y, Frangioni JV, Kita T, Hajjar RJ, Hayase M.
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Journal Title
Gene Ther. 13
Pages: 1320-1327
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[Presentation] Serotonin in adipose tissue acts as an autocrine factor required for adipocyte differentiation and Iipolysis2007
Author(s)
Ono, K., Horie, T., Abe, Y., Kawamura, T., Kinoshita, M., Nishi, H., Nagao, K., Satoh, N., Shimatsu, A., Kita, T., Hasegawa, K
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
Description
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[Presentation] Activation of smad transcriptional coreppressor TGIF by insulin is required for adipocyte differentiation2007
Author(s)
Horie, T., Ono, K., Abe, Y., Kawamura, T., Shimatsu, A., Kita, T., Hasegawa, K
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
Description
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[Presentation] MicroRNA-133 regulates the expression of CPT-lb and GLUT4 by targeting SRF and KLF15 and is involved in metabolic control in cardiac myocytes2007
Author(s)
Horie, T., Ono, K., Iwanaga, Y., Nishi, H., Nagao, K., Kinoshita, M., Mori, R., Hasegawa, K., Kita, T
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
Description
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[Presentation] Oxidative stress induces GLUT4 translocation by dual AMPK kinase activation in cardiac myocytes2007
Author(s)
Hone, T., Ono, K., Abe, Y., Kawamura, T., Wada, H., Kinoshita, M., Nagao, K., Nishi, H., Shimatsu, A., Kita, T., Hasegawa, K
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
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[Presentation] MicroRNA-206 controls cardiac myosin heavy chain gene expression by targeting RXR-α2007
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Nishi, H., Ono, K., Iwanaga, Y., Hone, T., Kinoshita, M., Nagao, K., Mon, R., Hasegawa, K., Kita, T
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
Description
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[Presentation] Roles of muscle-specific microRNAs during differentiation of mouse embryonic stem cells into cardiac myocytes2007
Author(s)
Takaya-T., Kawamura, T., Ono, K., Mori, R., Kaichi, S., Kita, T., Wada, H., Morimoto, T., Shimatsu, A., Hasegawa, K
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
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[Presentation] Mulberry leaf ameliorates the production of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice2007
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Sugimoto, M., Arai, H., Tamura, Y., Murayama, T., Ono, K., Ariyasu, H., Akamizu, T., Kita, T., Kamei, K., Yokode, M
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American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
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[Presentation] Cyclin-dependent kinase-9, as a novel component of p300/GATA4 complex, is involved in the differentiation of mouse ES cells into cardiac myocytes2007
Author(s)
Kaichi, S., Takaya, T., Morimoto, T., Sunagawa, Y., Kawamura, T., Ono, K., Rita, T., Hidaka, K., Morisaki, T., Baba, S., Heike, T., Nakahata, T., Hasegawa, K
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American Heart Association Annual Scientific Sessions
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Orlando, Florida
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[Presentation] Chronic administration of endogenous inotropic peptide, apelin, prevents left ventricular remodeling and improves survival in hypertensive rats with heart failure2007
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Tamaki, Y., Iwanaga, Y., Niizuma, S., Kawashita, T., Kato, T., Inuzuka, Y., Ono, K., Shioi, T., Kita, T
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American Heart Association Annual Scientific Sessions
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Orlando, Florida
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[Presentation] C-C chomokine receptor-2 inhibitor ameliorates insulin resistance and hepatic steatosis in db/db mice2007
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Tamura, Y., Arai, H., Sugimoto, M., Murayama, T., Ueda, Y., Kanamori, H., Ono, K., Ariyasu, H., Akamizu, T., Kita, T., Yokode, M
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Orlando, Florida
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[Presentation] Identification of signaling pathways that mediate the oxidative stress-induced translocation of myocardial GLUT4 using a novel lenti viral-mediated GLUT4 reporter gene2006
Author(s)
Takahiro, Horie, Koh, Ono, Yukiko, Abe, Teruhisa, Kawamura, Akira, Shimatsu, Koji, Hasegawa, Toru, Kita
Organizer
American Heart Association Annual Scientific Sessions
Place of Presentation
Chicago, Illinois Department of Cardiovascular Medicine, Kyoto University Division of Translational Research, Kyoto Medical Center, National Hospital Organization
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[Presentation] Soluble Flk-1 and Soluble Tie-2, Endogenous Inhibitors of Endothelial Cell-specific Angiogenic Singals, are Increased in Serum of Patients with Metabolic Syndrome2006
Author(s)
Hiromichi, Wada., Koh, Ono, Noriko, Satoh, Sachika, Kameda, Daisuke, Shinjo, Yukiko, Abe, Teruhisa, Kawamura, Tatsuya, Morimoto, Tameo Nakano, Akira, Shimatsu, Masatoshi, Fujita, Koji, Hasegawa
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American Heart Association Annual Scientific Sessions
Place of Presentation
Chicago, Illinois
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