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2007 Fiscal Year Final Research Report Summary

Molecular medicine of adipocyte differentiation

Research Project

Project/Area Number 15081203
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Medical and Dental University

Principal Investigator

OGAWA Yoshihiro  Tokyo Medical and Dental University, Medical Research Institute, Professer (70291424)

Project Period (FY) 2003 – 2007
Keywordstype 1 angiotensin receptor / adipose tissue remodeling / adipocytes / macrophages / fatty acids / TNFα / MKP-1 / inflammation
Research Abstract

1. Pathophysiologic role of type 1 angiotensin receptor
The renin-angiotensin system (RAS) plays an important role in the regulation of body fluid homeostasis and blood pressure control. Angiotensinogen (Agt), the precursor of All, is produced primarily by the liver. It also occurs in the adipose tissue, where it is up-regulated during the development of obesity. To understand the functional role of Agtrl in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtrla (Agtrla^<-/-> mice) during a high-fat diet. We have found the attenuation of diet-induced body weight gain and adiposity, and insulin resistance in Agtrla^<-/-> mice relative to wild-type littermates, suggesting the role of Agtrl in the metabolic syndrome. These observations suggest the pathophysiologic role of Agtrl in the development of obesity.
2. Molecular mechanism of adipose tissue remodeling
Obese adipose tissue is characterized by adipocyte hypertrophy, followed by increas … More es in angiogenesis, macrophage infiltration, and pro-inflammatory adipocytokine production, suggesting the previously unrecognized dynamic changes in function and morphology, which may be referred to as "adipose tissue remodeling". Using an in vitro co-culture composed of adipocytes and macrophages, we have provided evidence that a paracrine loop involving saturated fatty acids and TNFα derived from adipocytes and macrophages, respectively, establishes a vicious cycle that aggravates inflammatory changes in obese adipose tissue. Interestingly, saturated fatty acids, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in obese adipose tissue.
MCP-1, an important chemokine whose expression is increased during the course of obesity, plays a role in macrophage infiltration into obese adipose tissue. We have recently found that MCP-1 production is induced, which is followed by ERK activation and MKP-1 down-regulation in obese adipose tissue prior to macrophage infiltration. In vitro studies with 3T3-Ll adipocytes have demonstrated that ERK activation through MKP-1 down-regulation is involved in increased production of MCP-1 during the course of adipocyte hypertrophy, suggesting that MKP-1 down-regulation is critical for the inflammatory changes in hypertrophied adipocytes at the early stage of obesity. Our data help elucidate the molecular mechanism underlying "adipose tissue remodeling" and identify a novel therapeutic target that may reduce obesity-induced adipose tissue inflammation. Less

  • Research Products

    (17 results)

All 2007 2006 2005 Other

All Journal Article (11 results) (of which Peer Reviewed: 7 results) Presentation (4 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages2007

    • Author(s)
      T. Suganami, et al.
    • Journal Title

      Arterioscler. Thromb. Vase. Biol. 27

      Pages: 84-91

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Role of mitogen-activated protein kinase phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy2007

    • Author(s)
      A. Ito, et al.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 25445-25452

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects2007

    • Author(s)
      M. Itoh, et al.
    • Journal Title

      Arterioscler. Thromb. Vasc. Biol. 27

      Pages: 1918-1925

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Role of the Toll-like receptor 4/NF-кB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages2007

    • Author(s)
      T. Suganami, et al.
    • Journal Title

      Arterioscler. Thromb. Vasc. Biol. 27

      Pages: 84-91

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects2007

    • Author(s)
      M. Itoh, et al.
    • Journal Title

      Arteriosler. Thromb. Vase. Biol. 27

      Pages: 1918-1925

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signal2006

    • Author(s)
      J. Park, et al.
    • Journal Title

      Diabetes 55

      Pages: 2939-2949

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Role of premature leptin surge in obesity resulting from intrauterine undernutrition2005

    • Author(s)
      S. Yura, et al.
    • Journal Title

      Cell Metabolism 1

      Pages: 371-378

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type la receptor2005

    • Author(s)
      R. Kouyama, et al.
    • Journal Title

      Endocrinology 146

      Pages: 3481-3489

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] A paracrine loop between adipocytes and macrophages aggravates inflammatory changes : role of free fatty acids and tumnor necrosis factor α2005

    • Author(s)
      T. Suganami, et al.
    • Journal Title

      Arterioscler. Thromb. Vasc. Biol. 25

      Pages: 2062-2068

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Role of premature leptin surge in obesity resulting from intrauterine undermutrition2005

    • Author(s)
      S. Yura, et al.
    • Journal Title

      Cell Metabolism 1

      Pages: 371-378

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A paracrine loop between adipocytes and macrophages aggravatesi nflammatory changes : role of free fatty acids and tumor necrosis factor α2005

    • Author(s)
      T. Suganami, et al.
    • Journal Title

      Arterioscler. Thromb. Vase. Biol. 25

      Pages: 2062-2068

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Mechanism of adipose tissue remodeling2007

    • Author(s)
      Y. Ogawa
    • Organizer
      The 6th National Obesity Symposium
    • Place of Presentation
      Denpasar-Bali
    • Year and Date
      20070728-20070729
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A paracrine interaction between adipocytes and macrophages in obese adipose tissue2007

    • Author(s)
      Y. Ogawa
    • Organizer
      The 4th Asia-Oceania Conference on Obesity
    • Place of Presentation
      Seoul
    • Year and Date
      20070209-20070211
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A Paracrine Loop Involving FFAs and TNFα between Adipocytes and Macrophages2006

    • Author(s)
      Y. Ogawa
    • Organizer
      5th Congress of Asian Pacific Society of Atherosclerosis and Vascular Diseases
    • Place of Presentation
      Jeju
    • Year and Date
      20060412-20060415
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Leptin and the metabolic syndrome2005

    • Author(s)
      Y. Ogawa
    • Organizer
      3^<rd> AOASO Conference on Obesity
    • Place of Presentation
      Taipei
    • Year and Date
      20050225-20050226
    • Description
      「研究成果報告書概要(和文)」より
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.tmd.ac.jp/mri/prm/index.html

  • [Patent(Industrial Property Rights)] 脂肪細胞の炎症性変化を抑制する物質のスクリーニング系及びそれを用いたスクリーニング方法2007

    • Inventor(s)
      小川佳宏, 菅波孝祥
    • Industrial Property Rights Holder
      国立大学法人東京医科歯科大学
    • Industrial Property Number
      特願2007-528129
    • Filing Date
      2007-09-28
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2010-06-09  

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