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2011 Fiscal Year Final Research Report

Molecular mechanism of visceral obesity controlled by endothelial cell-related growth factors and the search for a new strategy of adipogenecity control

Research Project

  • PDF
Project/Area Number 21591153
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKawasaki Medical School

Principal Investigator

KAKU Kohei  川崎医科大学, 医学部, 教授 (10116709)

Co-Investigator(Kenkyū-buntansha) MATSUKI Michihiro  川崎医科大学, 医学部, 准教授 (00165797)
HASHIRAMOTO Mitsuru  川崎医科大学, 医学部, 講師 (40346680)
KANDA Yukiko  川崎医科大学, 医学部, 講師 (40351895)
TAWARAMOTO Kazuhito  川崎医科大学, 医学部, 助教 (70368629)
Project Period (FY) 2009 – 2011
Keywordsメタボリックシンドローム
Research Abstract

Metabolic syndrome is known to induce various metabolic disorders such as diabetes mellitus and atherosclerotic diseases based on visceral obesity. In order to control the adiposity, we aimed at the relationship between angiogenesis and adipogenesity. The PI3K signaling pathway in vascular endothelial cells is important for systemic angiogenesis and glucose metabolism. To evaluate the systemic pathway of angiogenesis under PI3K signal, we generated endothelial cell specific PDK1 knock out mice using Cre-loxP system and investigated the degree of impaired angiogenesis of skeletal muscles under the normo-and hyperglycemia status. In normoglycemic status, VEPDK1KO mice manifested enhanced glucose tolerance and whole-body insulin sensitivity with a reduced volume of epididymal adipose tissues. These results provide the in vivo evidence that lowered angiogenesis through the deletion of PDK1 signaling not only interferes with thegrowth of adipose tissue but also induces increased energy expe … More nditure due to amelioration of the adipocytokine profile.
The diabetic VEPDK1KO mice generated by genetic cross with db gene, however, demonstrated a significant impairment of glucose metabolism and systemic insulin sensitivity was diminished by approximately 39% in 12-week-old db-KO mice during the insulin tolerance test(3U/kg) despite of a reduced adiposity. Plasma high molecular weight adiponectin was elevated and mRNA expression of PECAM-1 and VEGF in epigonadal adipose tissue was decreased in db-KO compared with the control mice by 32% and 47%, respectively. Protein expressions of the β subunit of the insulin receptors and mRNA expressions of PECAM-1 in the skeletal muscle were decreased by approximately 47% and 23%, respectively, in db-KO. Nevertheless, those in the liver were comparable in both groups. We concluded that a complete lack of endothelial PDK1 induces the defects of angiogenesis in adipose tissues and skeletal muscle, which lead to deterioration of systemic insulin sensitivity in mice with genetic susceptibility to diabetes.
Furthermore, protein expression of VCAM1, located in PI3K signal and regulated by PDK1, was significantly up-regulated by 2.4 times higher in Gastro of STZ-KO than in that of the control KO mice, but no significant difference was observed between two groups in the liver. VEGF, VEGF receptor, and HIF1 gene expressions in both Gastro and liver were not different between STZ-KO and the control-KO. These results indicated that ablation of PDK1 in vascular endothelial cells in diabetic state induces the lower vascularization and VCAM1-upregulation in skeletal muscle but not in the liver, and the underlying mechanism may be totally different from the reported angiogenic factors, including VEGF and HIF.
Our results clearly indicate that PI3K signaling pathway in vascular endothelial cells plays an important role on adiposity and angiogenesis, and adipose tissue-specific ablation of PDK1 in endothelial cells may reduce visceral fat and contribute on an amelioration of dismetabolism induced by metabolic syndrome. Less

  • Research Products

    (13 results)

All 2012 2011 2010 2009

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (8 results)

  • [Journal Article] Ablation of 3-Phosphoinositide-Dependent Protein Kinase 1(PDK1) in Vascular Endothelial Cells Enhances Insulin Sensitivity by Reducing Visceral Fat and Suppressing Angiogenesis2012

    • Author(s)
      Tawaramoto K, Kotani K, Hashiramoto M, Kanda Y, Nagare T, Sakaue H, Ogawa W, Emoto N, Yanagisawa M, Noda T, Kasuga M, Kaku K
    • Journal Title

      Mol Endocrinol

      Volume: 26(1) Pages: 95-109

    • DOI

      DOI:10.1210/me.2010-0412

    • Peer Reviewed
  • [Journal Article] Self-inducible secretion ofglucagon-like peptide-1(GLP-1) that allows MIN6 cells to maintain insulin secretion and insure cell survival2012

    • Author(s)
      Nakashima K, Shimoda M, Hamamoto S, Tatsumi F, Hirukawa H, Tawaramoto K, Kanda Y, Kaku K
    • Journal Title

      Mol Cell Endocrinol

      Volume: 349(2) Pages: 281-288

    • DOI

      DOI:10.1016/j.mce.2011.008

    • Peer Reviewed
  • [Journal Article] The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes2011

    • Author(s)
      Shimoda M, Kanda Y, Hamamoto S, Tawaramoto K, Hashiramoto M, Matsuki M, Kaku K
    • Journal Title

      Diabetologia

      Volume: 54(5) Pages: 1098-1108

    • DOI

      DOI:10.1007/s00125-011-2069-9

    • Peer Reviewed
  • [Journal Article] Molecular mechanism by which pioglitazone preserves pancreatic β cells in obese diabetic mice : Evidence for acute and chronic actions as a PPARγ agonist2010

    • Author(s)
      Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K
    • Journal Title

      Am J Physiol Endocrinol Metab

      Volume: 298(2) Pages: 278-286

    • DOI

      DOI:10.1152/ajpendo.00388.2009.

    • Peer Reviewed
  • [Journal Article] Molecular Analysis of db Gene-related Pancreatic beta Cell Dysfunction ; Evidence for a Compensatory Mechanism Inhibiting Development of Diabetes in the db Gene Heterozygote2009

    • Author(s)
      Kanda Y, Shimoda M, Tawaramoto K, Hamamoto S, Tatsumi F, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K
    • Journal Title

      Endocr J

      Volume: 56(8) Pages: 997-1008

    • URL

      https://www.jstage.jst.go.jp/article/endocrj/56/8/56_K09E-028/_pdf

    • Peer Reviewed
  • [Presentation] Ablation of PDK1 in vascular endothelial cells in diabetic condition deteriorates vascularity only in skeletal muscles but not in liver2012

    • Author(s)
      Tawaramoto K, Hashiramoto M, Kimura T, Hirukawa H, Shimoda M, Ogawa W, Kasuga M, Kaku K
    • Organizer
      72^<nd> American Diabetes Association Scientific Session
    • Place of Presentation
      Philadelphia
    • Year and Date
      2012-06-11
  • [Presentation] 血管内皮特異的PDK1欠損における肝、骨格筋内血管面積の解析ー高血糖による影響2012

    • Author(s)
      俵本和仁、柱本満、木村友彦、蛭川英典、辰巳文則、濱本純子、下田将司、小川渉、春日雅人、加来浩平
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2012-05-17
  • [Presentation] Ablation of PDK1 in vascular endothelial cells deteriorates systemic insulin sensitivity and angiogenesis of skeletal muscles in STZ-induced hyperglycemic mice2011

    • Author(s)
      Tawaramoto K, Hashiramoto M, Kotani K, Ogawa W, Hirukawa H, Tatsumi F, Hamamoto S, Shimoda M, Kanda Y, Kasuga M, Kaku K
    • Organizer
      71^<st> American Diabetes Association Scientific Session
    • Place of Presentation
      San Diego
    • Year and Date
      2011-06-25
  • [Presentation] 高血糖状態での血管内皮細胞PDK1欠損は骨格筋内血管数減少と全身インスリン感受性悪化を惹起する2011

    • Author(s)
      俵本和仁、柱本満、蛭川英典、辰巳文則、濱本純子、下田将司、菅田有紀子、小谷光、小川渉、春日雅人、加来浩平
    • Organizer
      第54回日本糖尿病学会年次学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2011-05-19
  • [Presentation] Ablation of vascular endothelial phosphoinositide-dependent protein kinase 1 deteriorates the volume of blood flow in skeletal muscle2010

    • Author(s)
      Tawaramoto K, Hashiramoto M, Kotani K, Ogawa W, Tatsumi F, Hamamoto S, Shimoda M, Kanda Y, Kasuga M, Kaku K
    • Organizer
      46th European Association for the Study of Diabetes Annual Meeting
    • Place of Presentation
      Stockholm
    • Year and Date
      2010-09-22
  • [Presentation] 肥満2型糖尿病モデルでの血管内皮細胞PDK1欠損は筋肉内血管新生を低下させ、全身インスリン抵抗性を増悪させる2009

    • Author(s)
      俵本和仁、柱本満、小谷光、小川渉、辰巳文則、濱本純子、下田将司、菅田有紀子、春日雅人、加来浩平
    • Organizer
      第30回日本肥満学会
    • Place of Presentation
      浜松
    • Year and Date
      2009-10-09
  • [Presentation] Ablation of Vascular Endothelial PDK1 in Diabetic db/db Mice Further Deteriorates Insulin Sensitivity through Defects of Angiogenesis in Skeletal Muscle and Adipose Tissue2009

    • Author(s)
      Tawaramoto K, Hashiramoto M, Kotani K, Ogawa W, Tatsumi F, Hamamoto S, Shimoda M, Kanda Y, Kasuga M, Kaku K
    • Organizer
      69^<th> American Diabetes Association Scientific Session
    • Place of Presentation
      New Orleans
    • Year and Date
      2009-06-08
  • [Presentation] 肥満2型糖尿病での血管内皮細胞PDK1欠損は筋肉内血管新生を低下させ、全身インスリン抵抗性を増悪させる2009

    • Author(s)
      俵本和仁、柱本満、小谷光、小川渉、辰巳文則、濱本純子、下田将司、菅田有紀子、春日雅人、加来浩平
    • Organizer
      第52回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2009-05-22

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Published: 2013-07-31  

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