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The study of modulation of brain-immune function and searching for new functional molecule regulated by leptin receptor

Research Project

Project/Area Number 14572047
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

OKUMA Yasunobu  Hokkaido Univ., Grad.School of Pharmac., Sci.Assoc.Prof., 大学院・薬学研究科, 助教授 (20127939)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordsleptin / cytokine / interleukin-1β / vagus nerve / neuro-immune-endocrine interaction / inflammation / STAT3 / hypothalamus-pituitary-adrenal axis / STST3
Research Abstract

Leptin is known to be an important circulating signal for regulation of food intake and body weight. These effects were suggested to be mediated through the hypothalamic center via the Ob-Rb receptor. We found that peripherally applied leptin increased Interleukin (IL)-1b transcripts in many regions of the brain. Although leptin did not induce STAT3 activation or suppressor of cytokine signaling3 (SOCS3) expression in the hypothalamus of the db/db mice, which lack a functional Ob-Rb receptor, leptin increased the IL-1b levels to similar extents as normal mice. Therefore, a novel function of leptin is suggested as the induction of IL-1b expression in many regions of the brain via STAT3-independent mechanisms.
Although leptin receptors exist in many regions of the brain, there have been few in vivo functional studies of leptin's target site other than the hypothalamus. We demonstrated that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in … More the brainstem as assessed by Western blotting and. Immunohistochemistry. These findings represent physiologically functional leptin Ob-Rb receptor in the brainstem as well as in the hypothalamus.
Glucocorticoids were suggested to play a physiological role in the feedback inhibition of immune/inflammatory responses Pretreatment with dexamethasone dose dependently inhibited leptin-induced IL-1b expression in the hypothalamus. Moreover, dexamethasone inhibited leptin-induced IL-1b expression in the primary cultured glial cells. In contrast, pretreatment with dexamethasone did not inhibit leptin-induced STAT3 phosphorylation in the hypothalamus. Therefore, it is suggested that glucocorticoid negatively regulates leptin-induced IL-1b expression in the brain.
We investigated role of double-stranded RNA-activated protein kinase (PKR) as a possible signaling pathway of leptin. 2-aminopurine, an inhibitor of PKR inhibited leptin-induced intracellular signaling. However, we observed that leptin did not activate PK, and found the site of action of 2-aminopurine to inhibit leptin signaling was Janus kinase. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Hosoi T. et al.: "Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1β expression in the hypothalamus."American Journal of Physiology. 282(2). R627-R631 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyazaki H. et al.: "Expression of Ret receptor tyrosine kinase after transient forebrain ischemia is modulated by glial cell line-derived neurotrophic factor in rat hippocampus."Neuroscience Letters. 318(1). 1-4 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Leptin induces IL-1 receptor antagonist expression in the brain."Biochem Biophys Res Commun. 294(2). 215-219 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Brainstem is a Direct Target for Leptin's Action in the CNS."Endocrinology. 143(9). 3498-3504 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Leptin regulates interleukin-1β expression in the brain via the STAT3-independent mechanisms."Brain Research. 949(1-2). 139-146 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Inhibition of leptin-induced IL-1β expression by glucocorticoids in the brain."Brain Research. 969(1-2). 95-101 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyazaki H. et al.: "Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain."J pharmacol Sci. 92(1). 28-34 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhan L.et al.: "Cholecystokinin inhibits food intake independent of interleukin-1b expression in the brain"Biol Pharm Bull. 26(8). 1181-1183 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horie T. et al.: "Contraction of isolated guinea-pig ileum by urotensin II via activation of ganglionic cholinergic neurons and acetylcholine release."Neuropharmacology. 45(7). 1019-1027 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimma N. et al.: "Possible role of interleukin-6 in PC12 cell death induced by MPP+ and tetrahydroisoquinoline."J pharmacol Sci. 93(4). 471-477 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1β expression in the hypothalamus."Am J Physiol. 282(2). R627-R631 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyazaki H. et al.: "Expression of Ret receptor tyrosine kinase after transient forebrain ischemia is modulated by glial cell line-derived neurotrophic factor in rat hioppocampus."Neuroscience Letters. 318(1). 1-4 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Leptin induces IL-1 receptor antagonist expression in the brain."Biochem Biophys Res Communy. 294(2). 215-219 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Brainstem is a Direct Target for Leptin's Action in the CNS."Endocrinology. 143(9). 3498-3504 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Leptin regulates interleukin-1β expression in the brain via the STAT3-independent mechanisms."Brain Research. 949(1-2). 139-146 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T. et al.: "Inhibition of leptin-induced IL-1β expression by glucocorticoids in the brain."Brain Research. 969(1-2). 95-101 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyazaki H. et al.: "Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain."J pharmacol Sci. 92(1). 28-34 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhan L.et al.: "Cholecystokinin inhibits food intake independent of interleukin-1β expression in the brain."Biol Pharm Bull. 26(8). 1181-1183 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horie T. et al.: "Contraction of isolated guinea-pig ileum by urotensin II via activation of ganglionic cholinergic neurons and acetylcholine release."Neuropharmacology. 45(7). 1019-1027 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimma N. et al.: "Possible role of interleukin-6 in PC12 cell death induced by MPP+ and tetrahydroisoquinoline."J pharmacol Sci. 93(4). 471-477 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hosoi T.et al.: "Inhibition of leptin-induced IL-1b expression by glucocorticoids in the brain"Brain Research. 969(1-2). 95-101 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyazaki H.et al.: "Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain"J pharmacol Sci. 92(1). 28-34 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Zhan L.et al.: "Cholecystokinin inhibits food intake independent of interleukin-1b expression in the brain"Biol Pharm Bull. 26(8). 1181-1183 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Horie T.et al.: "Contraction of isolated guinea-pig ileum by urotensin II via activation of ganglionic cholinergic neurons and acetylcholine release"Neuropharmacology. 45(7). 1019-1027 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimma N.et al.: "Possible role of interleukin-6 in PC12 cell death induced by MPP+ and tetrahydroisoquinoline"J pharmacol Sci. 93(4). 471-477 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hosoi T. et al.: "Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1β expression in the hypothalamus"American Journal of Physiology. 282(2). R627-R631 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyazaki H. et al.: "Expression of Ret receptor tyrosine kinase after transient forebrain ischemia is modulated by glial cell line-derived neurotrophic factor in rat hioppocampus"Neuroscience Letters. 318(1). 1-4 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hosoi T. et al.: "Leptin induces IL-1 receptor antagonist expression in the brain"Biochem Biophys Res Commun. 294(2). 215-219 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hosoi T. et al.: "Brainstem is a Direct Target for Leptin's Action in the CNS"Endocrinology. 143(9). 3498-3504 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hosoi T. et al.: "Leptin regulates interleukin-1β expression in the brain via the STAT3-independent mechanisms"Brain Research. 949(1-2). 139-146 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hosoi T. et al.: "Inhibition of leptin-induced IL-1β expression by glucocorticoids in the brain"Brain Research. (in press).

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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