JPWO2005084697A1 - アディポネクチン受容体発現制御剤 - Google Patents
アディポネクチン受容体発現制御剤 Download PDFInfo
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- JPWO2005084697A1 JPWO2005084697A1 JP2006510738A JP2006510738A JPWO2005084697A1 JP WO2005084697 A1 JPWO2005084697 A1 JP WO2005084697A1 JP 2006510738 A JP2006510738 A JP 2006510738A JP 2006510738 A JP2006510738 A JP 2006510738A JP WO2005084697 A1 JPWO2005084697 A1 JP WO2005084697A1
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Abstract
Description
(1)FoxoIタンパク質またはFoxoI遺伝子を含むアディポネクチン受容体発現促進剤、
(2)FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有するアディポネクチン抵抗性改善剤、
(3)FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有するインスリン抵抗性改善剤、
(4)FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する肥満症予防または改善剤、
(5)FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する糖尿病予防または治療薬、
(6)FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する動脈硬化症の予防または治療薬、
(7)PI3キナーゼ-Akt経路阻害剤を含む、アディポネクチン受容体発現促進剤、
(8)PI3キナーゼ-Akt経路阻害剤が、PI3(Phosphoinositide 3)キナーゼ阻害剤である、上記(7)記載のアディポネクチン受容体発現促進剤、
(9)PI3(Phosphoinositide 3)キナーゼ阻害剤がLY294002である、上記(8)記載のアディポネクチン受容体発現促進剤、
(10)上記(7)から上記(9)のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有するアディポネクチン抵抗性改善剤、
(11)上記(7)から上記(9)のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有するインスリン抵抗性改善剤。
(12)上記(7)から上記(9)のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する肥満症予防または改善剤、
(13)上記(7)から上記(9)のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する糖尿病予防または治療薬、
(14)上記(7)から上記(9)のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する動脈硬化症の予防または治療薬、
(15)インスリンまたはインスリン遺伝子を含む、アディポネクチン受容体発現抑制剤、
(16)被験物質をPI3キナーゼおよびPI3キナーゼ基質と接触させる工程を含む、アディポネクチン受容体発現促進剤、アディポネクチン抵抗性改善剤、インスリン抵抗性改善剤、肥満症改善剤、糖尿病治療薬、動脈硬化症治療薬のスクリーニング方法、
(17)被験物質をAktおよびFoxoIと接触させる工程を含む、アディポネクチン受容体発現促進剤、アディポネクチン抵抗性改善剤、インスリン抵抗性改善剤、肥満症改善剤、糖尿病治療薬、動脈硬化症治療薬のスクリーニング方法。
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
AdipoR1かつ/またはAdipoR2の発現が、生理学的かつ/または病態生理学的状態下で制御されるか否かを明らかにするため、無制限の給餌下、絶食下および再摂食下に置いたマウスを用い、インスリンおよびアディポネクチン標的臓器におけるAdipoR1およびAdipoR2の発現レベルを検討した。
mAdipoR1用
フォワードプライマー: acgttggagagtcatcccgtat (配列番号10)
リバースプライマー: ctctgtgtggatgcggaagat (配列番号11)
プローブ: cctgctacatggccacagaccacct (配列番号12)
mAdipoR2用
フォワードプライマー: tcccaggaagatgaagggtttat (配列番号13)
リバースプライマー: ttccattcgttcgatagcatga (配列番号14)
プローブ: atgtccccgctcctacaggccc (配列番号15)
上記実施例1で絶食および給餌に反応してAdipoR1/R2遺伝子発現が制御されることが確認されたが、上記制御に特定のホルモンまたは栄養素が関与している可能性がある。インスリンは栄養時の古典的ホルモンであることから、無制限摂食、絶食および再摂食状態においた上記マウスの血漿インスリンレベルを測定した。血漿インスリンはインスリンイムノアッセイ(シバヤギ、群馬、日本)で測定した。
AdipoR1/R2発現に対するインスリンの効果をさらに検討するため、streptozotocin (STZ)処理をマウスに施し、該マウスにおけるAdipoR1/R2発現を観察した。STZは、膵臓β細胞を破壊し、急性インスリン欠乏症を引き起こす。糖尿病を誘導するため、STZ(200mg/kg body weight)を含む50mMクエン酸ナトリウム溶液(pH4.5) 0.2-0.3mlをマウスに二重腹腔内投与した。対照マウスには、50mMクエン酸ナトリウム溶液(pH4.5)を注射した。注射後三日間にわたり、血漿グルコースレベルを測定し、糖尿病を確認した(グルコース値>250mg/dl)。ヒトレギュラーインスリン(1単位/kg;Eli Lilly, Indianapolis, IN)を生理食塩水0.2mlに溶解し、STZおよびインスリン処理群に投与した。STZおよび溶媒処理群のマウスおよび非STZ処理群には、0.2mlの生理食塩水を腹腔内投与した。インスリンまたは生理食塩水を投与してから動物を6時間絶食させた後、絶命させて後肢の骨格筋を採取した。
肝細胞でのAdipoR1/R2発現に対するインスリンの直接的効果を検討した。絶食中の8週齢雄C57BL/6マウスから、肝細胞をコラゲナーゼ灌流法により調製した(文献20)。0.8x106の一定量の細胞を、コラーゲンIでコートした12穴の皿上の、5%(v/v) ウシ胎児血清、10nMデキサメタゾン、1nMインスリン、100units/mlペニシリン、100μg/mlストレプトマイシンを添加したWilliams培地E中に置いた。5%CO2、37℃で5時間インキュベーションした後、細胞をPBSで2度洗浄し、1%ウシ血清アルブミンを添加したWilliams培地Eで6時間インキュベートした。細胞を1%ウシ血清アルブミンおよび100nMインスリンを添加したWilliams培地Eに移し、100nMインスリン存在下または非存在下で6時間培養した。肝細胞を回収し、トータルAdipoR1,R2 mRNA量を測定した。その結果、インスリンはAdipoR1/R2 mRNA全量を減少させた(図3A,3B)。
C2C12細胞を1%ウシ血清アルブミン添加DMEMHで12時間インキュベートし、インスリン添加30分前に細胞をインスリン伝達経路阻害剤(10μM LY294002または10μM PD98059)に曝した。インスリン添加6時間後に細胞を回収し、添加6時間後のC2C12筋細胞中AdipoR1/R2 mRNAレベルを測定した(図3C,3D)。PI3-キナーゼインヒビターのLY294002は、インスリンによるAdipoR1/R2 mRNAレベル減少効果を帳消しした。逆に、mitogen-activated proteinキナーゼ活性化のインヒビターであるPD98059からは、インスリンよる反応は本質的に影響を受けなかった。上記結果から、AdipoR1/R2遺伝子発現の誘導はインスリンシグナル伝達経路のPI3-キナーゼ分岐経路を通じて仲介されているらしいとの結論が導かれる。図3Cおよび3Dに示すインヒビター効果は、試験した全ての試薬に対する最大値を示した。また、ポイントは用量反応実験で検証した(データ示さず)。
PI3-キナーゼシグナル伝達経路は、インスリンによる幾つかの遺伝子の制御、とりわけinsulin-like growth-factor binding protein (IGF-BP1)遺伝子の制御に関与していると考えられている(文献29)。最近、PI3-キナーゼの下流エフェクターであるAktが、in vitroおよび無処置細胞において、Foxo1を含むフォークヘッドファミリーの幾つかの転写活性化因子をリン酸化することが示された。これら因子の特定残基がリン酸化されると、リン酸化された該因子は細胞質中に隔絶され、結果として標的遺伝子の転写を活性化する能力が阻害される(文献30-32)。そこで、IGF-BP1遺伝子がプロモーター中にFoxo1と結合可能なシス活性エレメントを有していることから、IGF-BP1遺伝子のインスリン依存抑制は、少なくとも部分的には、Akt仲介リン酸化およびこのフォークヘッド転写活性化因子不活性化によるものと考えられる。(文献29)。
インスリン耐性ob/obマウスおよびコントロールとしてC57BL/6マウスを用い、インスリン感受性組織におけるAdipoR1およびR2の発現を検討した。ob/obマウスは、レプチン遺伝子の欠損により肥満、脂肪 肝および高インスリン血症を呈する遺伝的肥満マウスである。インスリン感受性組織として、肝臓、骨格筋(ヒラメ筋、長指伸筋(EDL))、脂肪組織(白色脂肪細胞(WAT)、褐色脂肪細胞(BAT))について検討した。結果を図4Aおよび4Bに示す。コントロールのC57BL/6マウスでは、AdipoR1は骨格筋において最も豊富に発現していたのに対し、AdipoR2は肝臓において最も多く発現した。興味深いことに、AdipoR1およびR2共に、ヒラメ筋よりもEDLにおいてより多く発現した。また、WATとBATの両方の脂肪組織において、AdipoR1とR2の両方の発現が観察された。
(実施例8)ob/obマウスにおけるAdipoR1/R2発現レベル減少と“アディポネクチン感受性”との相関関係
Claims (17)
- FoxoIタンパク質またはFoxoI遺伝子を含むアディポネクチン受容体発現促進剤。
- FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有するアディポネクチン抵抗性改善剤。
- FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有するインスリン抵抗性改善剤。
- FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する肥満症予防または改善剤。
- FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する糖尿病予防または治療薬。
- FoxoIタンパク質またはFoxoI遺伝子を有効成分として含有する動脈硬化症の予防または治療薬。
- PI3キナーゼ-FoxoI経路阻害剤を含む、アディポネクチン受容体発現促進剤。
- PI3キナーゼ- FoxoI経路阻害剤が、PI3(Phosphoinositide 3)キナーゼ阻害剤である、請求項7記載のアディポネクチン受容体発現促進剤。
- PI3(Phosphoinositide 3)キナーゼ阻害剤がLY294002である、請求項8記載のアディポネクチン受容体発現促進剤。
- 請求項7から請求項9のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有するアディポネクチン抵抗性改善剤。
- 請求項7から請求項9のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有するインスリン抵抗性改善剤。
- 請求項7から請求項9のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する肥満症予防または改善剤。
- 請求項7から請求項9のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する糖尿病予防または治療薬。
- 請求項7から請求項9のいずれかに記載のアディポネクチン受容体発現促進剤を有効成分として含有する動脈硬化症の予防または治療薬。
- インスリンまたはインスリン遺伝子を含む、アディポネクチン受容体発現抑制剤。
- 被験物質をPI3キナーゼおよびPI3キナーゼ基質と接触させる工程を含む、アディポネクチン受容体発現促進剤、アディポネクチン抵抗性改善剤、インスリン抵抗性改善剤、肥満症改善剤、糖尿病治療薬、動脈硬化症治療薬のスクリーニング方法。
- 被験物質をAktおよびFoxoIと接触させる工程を含む、アディポネクチン受容体発現促進剤、アディポネクチン抵抗性改善剤、インスリン抵抗性改善剤、肥満症改善剤、糖尿病治療薬、動脈硬化症治療薬のスクリーニング方法。
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