@AikoHIRAKI:4629_tf2 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/@AikoHIRAKI/sourceid/4629_tf2","sourcedb":"@AikoHIRAKI","sourceid":"4629_tf2","text":"〈タイトル〉PPARγのアゴニストはPRDM16の安定化を介して白色脂肪細胞の褐色脂肪細胞への分化を誘導する\r\n\r\n〈タイトル〉大野晴也・篠田幸作・梶村真吾\r\n〈著者所属〉米国California大学San Francisco校UCSF Diabetes Center\r\n〈著者email〉haruya.ono@ucsf.edu（大野晴也），kshinoda@diabetes.ucsf.edu（篠田幸作），skajimura@diabetes.ucsf.edu（梶村真吾）\r\n\r\n〈対象論文〉\r\nPPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein.\r\nHaruya Ohno, Kosaku Shinoda, Bruce M. Spiegelman, Shingo Kajimura\r\nCell Metabolism, 15, 395-404 (2012)\r\n\r\n〈要 約〉\r\n　褐色脂肪組織はエネルギーを消費して熱を産生することで体温の恒常性に寄与しており，近年では，抗肥満効果をもつ組織としても大きな注目をあつめている．PPARγのある種のリガンドは白色脂肪細胞を褐色化，つまり，誘導型の褐色脂肪細胞への分化を誘導することがよく知られていたが，その分子機構は不明であった．今回，筆者らは，PPARγのリガンドのなかでも完全アゴニスト活性をもつものが，とくに皮下脂肪組織において白色脂肪細胞を褐色脂肪細胞へと分化誘導することを明らかにした．また，この効果は褐色脂肪細胞の分化を制御する主要なタンパク質であるPRDM16を必要としていた．in vivoでの検討において，PRDM16とPPARγリガンドは協調して褐色脂肪細胞に特異的な遺伝子の発現を上昇させた．この作用はPRDM16の増加と密接に関係しており，PPARγリガンドによりPRDM16の半減期が延長することが明らかになった．今回の研究から，PRDM16を安定化させるような化合物を同定することにより，肥満や糖尿病に対する新たな側面からの治療が可能になるものと期待される．\r\n\r\nはじめに\r\n　ヒトを含めた哺乳類の脂肪組織はその機能と組織学的な特性により，白色脂肪組織と褐色脂肪組織の2つに大きく分類される．白色脂肪細胞は余剰のエネルギーを単胞性の巨大な脂肪滴に中性脂肪として蓄積する機能をもつ．一方，褐色脂肪細胞は小さな複数の脂肪滴を含み，ミトコンドリア内膜に存在するUCP-1（uncoupling protein-1）を介した発熱によりエネルギーを消費し熱を産生する．マウスなどの小動物やヒト胎児は体温を失いやすく，褐色脂肪組織による熱の産生が体温の調節において非常に重要な役割を担っている．褐色脂肪細胞は非常に活発なエネルギー消費能をもつことから，褐色脂肪細胞と肥満との関連性が示唆されている．たとえば，高カロリー食をあたえても肥満になりにくい系統のマウスは，筋肉組織もしくは白色脂肪組織に多くの褐色脂肪細胞を含むことが知られている．従来，褐色脂肪組織はヒト成人には存在しないとされていたが，PET（positron emission tomography，陽電子放射断層法）を用いた近年の研究から，成人にもこれまで考えられていた以上に多くの褐色脂肪細胞が存在することが明らかになった．よって，褐色脂肪細胞の分化機構の解明が，エネルギー消費の亢進に着目した肥満および糖尿病の新しい治療法へと発展することが期待されている．\r\n　褐色脂肪細胞には発生の過程の異なる2つの種類の細胞が存在することが知られている．筋前駆細胞に特異的なmyf5遺伝子を発現するmyf5陽性細胞を追跡した実験結果によると，マウスにおいて肩甲骨の付近の褐色脂肪細胞は，骨格筋細胞と共通するmyf5陽性を示す筋前駆細胞に由来し，白色脂肪細胞とは細胞系譜が異なることが示唆された．興味深いことに，マウスの肩甲骨の付近から採取した褐色脂肪細胞において褐色脂肪細胞の分化における分子スイッチであるPRDM16（PRD1-BF-1-RIZ1 homologous domain containing protein 16）をノックダウンすると，細胞が融合した骨格筋様の細胞が出現する．さらに，脂肪細胞を分化誘導する培地条件において筋前駆細胞にPRDM16を導入すると褐色脂肪細胞が出現することが明らかになった．これらの結果から，胚発生の過程においてmyf5陽性を示す筋前駆細胞の一部の細胞がPRDM16の作用により褐色脂肪細胞へと分化していることが示唆された1)．PRDM16はミトコンドリアの産生に重要な役割をはたす転写共役因子PGC-1αやPGC-1βと直接に結合するほか，PPARγ（peroxisome proliferator-activated receptor-γ，ペルオキシソーム増殖因子活性化受容体γ）やC/EBPsをはじめとするさまざまな転写因子と結合しこれらの転写活性を制御する転写共役因子として機能する2)．さらに，PRDM16は転写抑制因子として知られるCtBP-1/2と結合し，細胞がもともともつ遺伝子プログラムを抑制することにより標的遺伝子の活性化と抑制の両方の機能を備える分子スイッチとして機能する3)．\r\n　以前より，長期にわたる寒冷刺激などさまざまな環境要因により白色脂肪組織において散在的に出現する\"誘導型\"の褐色脂肪細胞の存在が知られていた．これら誘導型の褐色脂肪細胞はmyf5遺伝子を発現していないことから，肩甲骨のあいだに存在する古典的な褐色脂肪細胞とは異なる起源をもつと考えられる．この褐色脂肪細胞は，肩甲骨のあいだに存在する褐色脂肪細胞と同様に，熱産生の機能に重要なucp-1遺伝子を発現しているものの異なる遺伝子発現プロファイルを示すことから，この2種類の褐色脂肪細胞は前駆細胞の起源のみならず，機能的にも異なる特性をもつものと推察される4)．\r\n　抗糖尿病薬であるチアゾリジン誘導体のターゲットとして知られるPPARγは，脂肪細胞の前駆細胞から脂肪細胞への分化にかかわる\"マスター制御タンパク質\"としてさまざまな遺伝子の発現を制御している5)．PPARγのリガンドを投与すると白色脂肪組織において誘導型の褐色脂肪細胞が認められることは以前より報告があり，この効果はPPARγによる褐色脂肪細胞における遺伝子の特異的な転写制御の面から説明されていた．しかし，この分子機構の説明は以下の2点から十分とはいえなかった．第1に，PPARγは白色脂肪細胞と褐色脂肪細胞のどちらにおいても豊富に発現しており，白色脂肪細胞にPPARγそのものを過剰に発現させたとしても褐色脂肪細胞への分化誘導は起こらないという点，そして第2に，PPARγリガンドによる白色脂肪細胞の褐色脂肪細胞への分化誘導には少なくとも2〜3日間がかかるという点である．このような遅い発現は，転写因子が一般的に数時間でその標的遺伝子の発現を上昇させるキネティクスとは大きく異なっている．\r\n\r\n1．PPARγのリガンドは白色脂肪細胞において褐色脂肪細胞に特異的な遺伝子の発現を誘導する\r\n　PPARγの完全アゴニストであるロシグリタゾンやピオグリタゾンに比べ，部分アゴニスト活性をもつMRL24などはCDK5によるPPARγのSer273のリン酸化を阻害することにより二次的な効果をもつことが報告されている6)．そこで，マウスの鼠径部の脂肪組織より採取した前駆脂肪細胞に，通常の脂肪細胞を分化誘導する培地にくわえ，さまざまなPPARγリガンドを添加することで褐色脂肪細胞への分化誘導の活性を検討した．PPARγの完全アゴニストであるロシグリタゾンの添加により，褐色脂肪細胞に特異的な遺伝子であるucp-1遺伝子（721倍）やcidea遺伝子（128倍）の発現は上昇したが，部分アゴニストによるこれらの遺伝子の発現誘導は認められなかった．このような効果はPPARγの転写活性と強く相関することがルシフェラーゼアッセイなどから知られており，褐色脂肪細胞に特異的な遺伝子の発現には古典的な強力なアゴニスト活性が必要であることが明らかになった．また，ロシグリタゾンによる白色脂肪細胞の褐色脂肪細胞への分化誘導は精巣上体の脂肪組織から採取した前駆脂肪細胞においてはほとんど認められなかった．褐色脂肪細胞への分化スイッチの遺伝子であるprdm16遺伝子は鼠径部に由来する前駆脂肪細胞により多く発現しており，ロシグリタゾンの添加によりその発現のレベルはわずかに上昇する程度であった．\r\n\r\n2．PPARγのリガンドによる褐色脂肪細胞への分化誘導にはPRDM16を必要とする\r\n　PPARγリガンドによる白色脂肪細胞の褐色脂肪細胞への分化誘導におけるPRDM16の役割を検討するため，マウスの鼠径部に由来する前駆脂肪細胞においてshRNAを組み込んだアデノウイルスを用いてPRDM16のノックダウンを行った．興味深いことに，PRDM16のノックダウンにともない，Oil Red O染色により評価した脂肪細胞の分化そのものに変化はなかったが，PPARγの完全アゴニストであるロシグリタゾンの添加にともなうUCP-1の増加は抑制された．また，マイクロアレイを用いて遺伝子の発現パターンを解析すると，ロシグリタゾンの添加により発現が有意に変化した194遺伝子のうち，PRDM16のノックダウンにともない147遺伝子（75.8％）の発現に変化が認められ，そのなかには褐色脂肪細胞に特異的に発現する遺伝子であるucp-1遺伝子，cidea遺伝子，cox8b遺伝子などが含まれていた．酸素消費量の計測による機能面の評価においても，PRDM16のノックダウンによりロシグリタゾンの添加にともなう酸素消費量の増加は認められなくなった．以上の結果より，PPARγの完全アゴニストであるロシグリタゾンの投与にともなう白色脂肪組織における褐色脂肪細胞に特異的な遺伝子の発現上昇と熱産生機能の増加にはPRDM16が必要であることが明らかになった．\r\n\r\n3．PRDM16はPPARγのリガンドと協調して褐色脂肪細胞を分化誘導する\r\n　精巣上体の脂肪組織に代表される内臓脂肪は，鼠径部の脂肪組織などの皮下脂肪に比べPRDM16をほとんど発現していない．そこで，内臓脂肪組織において特異的に発現するfabp4遺伝子のプロモーターによりprdm16遺伝子を発現するトランスジェニックマウスを用いて7)，PRDM16の発現がPPARγリガンドに依存的な褐色脂肪細胞への分化誘導にあたえる影響について検討した．このPRDM16トランスジェニックマウスの精巣上体の脂肪組織では，野生型マウスの鼠径部の脂肪組織と同じ程度のPRDM16を発現していた．野生型マウスの精巣上体の脂肪組織より採取した前駆脂肪細胞にPPARγの完全アゴニストであるロシグリタゾンを添加しても褐色脂肪に特異的な遺伝子の発現上昇はわずかであったが，PRDM16トランスジェニックマウスの精巣上体の脂肪組織に由来する前駆脂肪細胞ではロシグリタゾンにより褐色脂肪細胞に特異的な遺伝子の大幅な発現上昇が認められた．さらに，in vivoにおけるPRDM16とPPARγリガンドの効果を検討するため，野生型マウスとPRDM16トランスジェニックマウスに対し生理食塩水もしくはロシグリタゾンを10日間にわたり腹腔内注入し鼠径部の脂肪組織を観察したところ，ロシグリタゾンを注入した野生型マウスと生理食塩水を注入したPRDM16トランスジェニックマウスにおいて，多泡性の脂肪滴をもつUCP-1陽性細胞が出現しており，この細胞はロシグリタゾンを注入したPRDM16トランスジェニックマウスにおいて顕著に増加していた．以上の結果より，PRDM16はPPARγリガンドと協調して白色脂肪細胞の褐色脂肪細胞への分化を誘導することが明らかになった．\r\n\r\n4．PPARγのリガンドによる褐色脂肪細胞への分化誘導にはPRDM16の安定化が関与している\r\n　PPARγリガンドはどのような機構でPRDM16を介し白色脂肪細胞を褐色脂肪細胞へと分化誘導しているのであろうか？　マウスの鼠径部に由来する前駆脂肪細胞に，通常の脂肪細胞を分化誘導する培地にくわえ，PPARγの完全アゴニストであるロシグリタゾンを添加して培養すると，ucp-1遺伝子の発現レベルは著明に上昇し，これはPRDM16タンパク質の発現レベルと強く相関していた．しかし，prdm16遺伝子のmRNAレベルはロシグリタゾンの添加によりほとんど変わらないかわずかな上昇を認めるのみであった．そこで，ロシグリタゾンがPRDM16の安定化にかかわっている可能性を考え，タンパク質合成阻害剤であるシクロヘキシミドの添加のうえPRDM16のタンパク質量の経時的な変化を検討した．通常の状態ではPRDM16の半減期は5.9時間だったが，驚いたことに，ロシグリタゾンの添加により半減期は17.8時間まで延長した．ここから計算すると，3日間で250倍ものPRDM16のタンパク質量の差がもたらされることになり，ロシグリタゾンの添加によるucp-1遺伝子の発現誘導には少なくとも2〜3日間を必要とするという時間経過パターンと一致していた．さらに詳細な機序を調べるためPRDM16のユビキチン化について検討した．ロシグリタゾンの添加によりPRDM16のユビキチン化は大きく抑制され，また，PRDM16の量とユビキチン化したPRDM16の量とは逆相関を示した．鼠径部の脂肪組織に由来する前駆脂肪細胞にロシグリタゾンをくわえ4日間にわたり培養したのちロシグリタゾンの添加を中止すると，その4日のちにはPRDM16の発現はほとんど認められなくなるが，プロテアソーム阻害剤であるMG132を添加することでこのPRDM16の分解は抑制された．以上の結果より，PPARγリガンドによる白色脂肪細胞の褐色脂肪細胞への分化誘導にはユビキチン-プロテアソーム系を介したPRDM16の分解の抑制が深く関与していると考えられた．\r\n\r\nおわりに\r\n　ピオグリタゾンに代表されるチアゾリジン誘導体は抗糖尿病薬として広く使用されている．しかし，ある種のチアゾリジン薬は心血管イベントを増加させる可能性があるなど，その使用を制限される動きもあり，より抗糖尿病作用に特化した薬剤の登場が望まれている．今回，筆者らが示したように，PRDM16を安定化させ白色脂肪細胞を効率よく褐色脂肪細胞へと誘導できるような薬剤が開発されれば，肥満や糖尿病の治療への新たな扉が開かれるものと期待される（図1）．\r\n\r\n〈文 献〉\r\n 1) Seale, P., Bjork, B., Yang, W. et al.: PRDM16 controls a brown fat/skeletal muscle switch. Nature, 454, 961-967 (2008)\r\n 2) Kajimura, S., Seale, P., Kubota, K. et al.: Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature, 460, 1154-1158 (2009)\r\n 3) Kajimura, S., Seale, P., Tomaru, T. et al.: Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev., 22, 1397-1409 (2008)\r\n 4) Kajimura, S., Seale, P. \u0026 Spiegelman, B. M.: Transcriptional control of brown fat development. Cell Metab., 11, 257-262 (2010)\r\n 5) Farmer, S. R.: Transcriptional control of adipocyte formation. Cell Metab., 4, 263-273 (2006)\r\n 6) Choi, J. H., Banks, A. S., Estall, J. L. et al.: Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by CDK5. Nature, 466, 451-456 (2010)\r\n 7) Seale, P., Conroe, H. M., Estall, J. et al.: Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest., 121, 96-105 (2011)\r\n\r\n〈著者プロフィール〉\r\n大野 晴也（Haruya Ohno）\r\n略歴：2011年 広島大学大学院医歯薬学総合研究科 修了，同年より米国California大学San Francisco校Postdoc Fellow．\r\n研究テーマ：褐色脂肪細胞の分化の分子機構．\r\n\r\n篠田 幸作（Kosaku Shinoda）\r\n米国California大学San Francisco校Junior Specialist．\r\n\r\n梶村 真吾（Shingo Kajimura）\r\n米国California大学San Francisco校Assistant Professor．\r\n\r\n〈図説明〉\r\n図1　白色脂肪組織においてPRDM16を安定化させるようなPPARγ合成リガンドにより誘導型の褐色脂肪細胞への分化を誘導する","tracks":[{"project":"FA_Top107-forWeb","denotations":[{"id":"T1","span":{"begin":6,"end":11},"obj":"PPAR gamma"},{"id":"T10","span":{"begin":2769,"end":2774},"obj":"PPAR gamma"},{"id":"T100","span":{"begin":2173,"end":2179},"obj":"CtBP1"},{"id":"T101","span":{"begin":2179,"end":2181},"obj":"CtBP2"},{"id":"T102","span":{"begin":3086,"end":3090},"obj":"CDK5"},{"id":"T103","span":{"begin":3298,"end":3303},"obj":"cidea"},{"id":"T104","span":{"begin":4037,"end":4042},"obj":"cidea"},{"id":"T11","span":{"begin":2814,"end":2819},"obj":"PPAR 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