Role of lipid phosphatase in brain insulin resistance related to neuroprotection and memory function

• Project/Area Number: 20591053
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Toyama
• Principal Investigator: SASAOKA Toshiyasu University of Toyama, 大学院・医学薬学研究部(薬学), 教授 (00272906)
• Co-Investigator(Kenkyū-buntansha): TSUNEKI Hiroshi 富山大学, 大学院・医学薬学研究部, 准教授 (20332661)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: エネルギー・糖代謝異常 / インスリン作用 / 認知機能 / ホスファターゼ / 認知障害 / ボスファターゼ / SHIP2 / PI3-キナーゼ / PTEN / 神経変性

Research Abstract

Although brain insulin resistance is a cause of cognitive impairment associated with type 2 diabetes and Alzheimer's disease, the precise underlying mechanism is largely unknown. In the present study, we found that lipid phosphatase SHIP2, a negative regulator of insulin signaling, is increased in the brain of type 2 diabetic db/db and aged mice. Mice overexpressing SHIP2 exhibited impaired memory performance with disrupted insulin signaling and increased apoptosis in the brain. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that inhibition of SHIP2 is a novel therapeutic approach in brain dysfunction related to insulin resistance with type 2 diabetes.

Research Products

• [Journal Article] Both type I and II IFN induces insulin resistance by inducing different isoform of SOCS expression in 3T3-L1 adipocytes. (2011)
  • Author(s): Wada T, Hoshino M, Kimura Y, Ojima M, Nakano T, Koya D, Tsuneki H, Sasaoka T.
  • Journal Title: American Journal of Physiol-Endocrinology & Metabolism 300
  • Peer Reviewed
• [Journal Article] The inositol phosphatase SHIP2 negatively regulates insulin/IGF-1actions implicated in neuroprotection and memory function in mouse brain. (2010)
  • Author(s): Soeda Y, Tsuneki H, Muranaka H, Mori N, Hosoh S, Ichihara Y, Kagawa S, Wang X, Toyooka N, Uwano T, Nishijo H, Wada T,Sasaoka T.
  • Journal Title: Molecular Endocrinology 24 Pages: 1965-1977
  • Peer Reviewed
• [Journal Article] Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. (2010)
  • Author(s): Wada T, Kenmochi H, Miyashita Y, Sasaki M, Ojima M, Sasahara M, Koya D, Tsuneki H, Sasaoka T.
  • Journal Title: Endocrinology 151 Pages: 2040-2049
  • Peer Reviewed
• [Journal Article] Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes. (2010)
  • Author(s): Wada T, Hori S, Sugiyama M, Fujisawa E, Nakano T, Tsuneki H, Nagira K, Saito S, Sasaoka T.
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism 298
  • Peer Reviewed
• [Journal Article] The inositol phosphatase SHIP2 negatively regulates insulin/IGF-1 actions implicated in neuroprotection and memory function in mouse brain. (2010)
  • Author(s): Soeda Y.,…, Sasaoka T.
  • Journal Title: Molecular Endocrinology Volume: 24 Pages: 1965-1977
  • Peer Reviewed
• [Journal Article] Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. (2010)
  • Author(s): Wada T.,…, Sasaoka T.
  • Journal Title: Endocrinology Volume: 151 Pages: 2040-2049
  • Peer Reviewed
• [Journal Article] Role of orexin in the regulation of glucose homeostasis. (2010)
  • Author(s): Tsuneki T., Wada T., Sasaoka T.
  • Journal Title: Acta Physiologica 198 Pages: 335-348
  • Peer Reviewed
• [Journal Article] Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes. (2010)
  • Author(s): Wada T., …, Sasaoka T.
  • Journal Title: Am J Physiol Endocrinol Metab 298(4)
  • Peer Reviewed
• [Journal Article] Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3T3-L1 adipocytes. (2009)
  • Author(s): Wada T, Ohshima S, Fujisawa E, Koya D, Tsuneki H, Sasaoka T.
  • Journal Title: Endocrinology 150 Pages: 1662-1669
  • Peer Reviewed
• [Journal Article] Impact of lipid phosphatases SHIP2 and PTEN on the time- and Akt-isoformspecific amelioration of TNF?-induced insulin resistance in 3T3-L1 adipocytes. (2009)
  • Author(s): Ikubo M, Wada T, Fukui K, Ishiki M, Ishihara H, Asano T, Tsuneki H, Sasaoka T.
  • Journal Title: American Journal of Physiology-Endocrinology & Metabolism 296
  • Peer Reviewed
• [Journal Article] Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3T3-L1 adipocytes. (2009)
  • Author(s): Wada T., …, Sasaoka T.
  • Journal Title: Endocrinology 150 Pages: 1662-1669
  • Peer Reviewed
• [Journal Article] Impact of lipid phosphatase SHIP2 and PTEN on the time-and Akt-isoform-specific amelioration of TNFα-induced insulin resistance in 3T3L1 adipocytes. (2009)
  • Author(s): Ikubo M., ・・・Sasaoka T.
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism 296(1)
  • Peer Reviewed
• [Journal Article] Age-related insulin resistance in hypothalamus and peripheral tissue of orexin knockout mice. (2008)
  • Author(s): Tsuneki H., ・・・Sasaoka T.
  • Journal Title: Diabetologia 51(4) Pages: 657-667
  • Peer Reviewed
• [Presentation] 視床下部ニューロンでのSHIP2の発現が,摂食シグナルとインスリン感受性,エネルギー代謝に与える影響の解明 (2011)
  • Author(s): 市原克則, 和田努, 添田義行, 石井陽子,笹原正清, 恒枝宏史, 笹岡利安
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌
• [Presentation] 2型糖尿病モデルマウスの認知機能障害に対するリピッドホスファターゼSHIP2阻害剤の改善効果 (2011)
  • Author(s): 村中勇人, 恒枝宏史, 添田義行, 森規彦, 岡本健太郎, 細尾脩史, 市原克則, 和田努, 笹岡利安
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌
• [Presentation] 加齢に伴うインスリン抵抗性の分子機構 (2011)
  • Author(s): 笹岡利安
  • Organizer: 第45回糖尿病学の進歩
  • Place of Presentation: 福岡
• [Presentation] Overexpression of SHIP2 causes hypothalamic insulin but not leptin resistance in the regulation of glucose homeostasis in mice. (2011)
  • Author(s): 笹岡利安, 市原克則, 添田義行, 恒枝宏史, 和田努
  • Organizer: Keystone symposia.
  • Place of Presentation: Keystone, U.S.A.
• [Presentation] Impact of the elevation of lipid phosphatase SHIP2 on brain insulin action for the cognitive function in mice. (2010)
  • Author(s): 笹岡利安, 添田義行, 村中勇人, 森規彦, 和田努, 恒枝宏史
  • Organizer: XI International Symposium on Insulin Receptors and Insulin Action.
  • Place of Presentation: Naples, Italy.
• [Presentation] ホスファターゼと肥満 (2010)
  • Author(s): 笹岡利安, 和田努, 恒枝宏史
  • Organizer: 第31回日本肥満学会(シンポジウム)
  • Place of Presentation: 前橋
• [Presentation] Impact of hypothalamic insulin resistance caused by overexpression of SHIP2 on glucose and energy homeostasis in mice. (2010)
  • Author(s): 笹岡利安, 市原克則, 添田義行, 恒枝宏史, 和田努
  • Organizer: American Diabetes Association (ADA) 70th Scientific Sessions
  • Place of Presentation: Orlando, U.S.A.
• [Presentation] SHIP2 過剰発現による視床下部インスリン抵抗性がマウス個体のエネルギー代謝に与える影響 (2010)
  • Author(s): 市原克則, 和田努, 添田義行, 恒枝宏史, 笹岡利安
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] マウス脳におけるリピッドホスファターゼSHIP2 の異常増加が認知機能に及ぼす影響の解析 (2010)
  • Author(s): 村中勇人, 恒枝宏史, 添田義行, 森規彦, 和田努, 笹岡利安
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
• [Presentation] Impact of hypothalamic insulin resistance caused by overexpression of SHIP2 on glucose and energy homeostasis in mice. (2010)
  • Author(s): Sasaoka T., Ichihara Y., Soeda Y., Tsuneki H., Wada H.
  • Organizer: American Diabetes Association (ADA) 70^<th> Scientific Sessions
  • Place of Presentation: Orlando, U.S.A.
• [Presentation] Impairment of central insulin action in neuronal cell survival and spatial memory in mice overexpressing SH2-containing inositol 5'-phosphatase 2. (2009)
  • Author(s): 笹岡利安, 添田義行, 村中勇人, 森規彦, 和田努, 恒枝宏史
  • Organizer: American Diabetes Association (ADA) 69th Scientific Sessions
  • Place of Presentation: New Orleans, U.S.A.
• [Presentation] 糖尿病によるマウス脳でのリピッドホスファターゼSHIP2発現の異常増加:神経細胞死および記憶・学習能力に及ぼすインパクト (2009)
  • Author(s): 添田義行, 恒枝宏史, 村中勇人, 森規彦, 和田努, 笹岡利安
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] 高脂肪食負荷に伴う視床下部SHIP2発現増加が視床下部インスリン感受性に与える影響の解析 (2009)
  • Author(s): 市原克則, 和田努, 添田義行, 恒枝宏史, 笹岡利安
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] マウス脳において糖尿病および加齢によるリピッドホスファターゼSHIP2の増加は神経保護機能および記憶・学習機能を破綻させる (2009)
  • Author(s): 添田義行, 恒枝宏史, 村中勇人, 森規彦, 和田努, 笹岡利安
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Impairment of central insulin action in neuronal cell survival and spatial memory in mice overexpressing SH2-containing inositol 5'-phosphatase 2. (2009)
  • Author(s): Sasaoka T., Soeda Y., Muranaka H., Mori N., Wada T., Tsuneki H.
  • Organizer: American Diabetes Association (ADA) 69^<th> Scientific Sessions
  • Place of Presentation: New Orleans, U.S.A.
• [Presentation] Overexpression of SHIP2 causes insulin resistance in peripheral tissues and brain of mice. (2008)
  • Author(s): Soeda Y., Tsuneki H., Kagawa S., Wada T., Sasaoka T
  • Organizer: American Diabetes Association (ADA) 68th Scientific Sessions
  • Place of Presentation: San Francisco, U. S. A.
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