JP5339664B2 - AMPK activator - Google Patents
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- JP5339664B2 JP5339664B2 JP2004035974A JP2004035974A JP5339664B2 JP 5339664 B2 JP5339664 B2 JP 5339664B2 JP 2004035974 A JP2004035974 A JP 2004035974A JP 2004035974 A JP2004035974 A JP 2004035974A JP 5339664 B2 JP5339664 B2 JP 5339664B2
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Description
本発明は、レプチン及びアディポネクチン代替物質として有用なAMPK(AMP-activated protein kinase)活性化剤に関する。 The present invention relates to an AMPK (AMP-activated protein kinase) activator useful as a substitute for leptin and adiponectin.
AMPKは運動のような細胞内ATPレベルが低下するような状況下において活性が上昇し、その結果代謝を促進してATP合成を促す“metabolic sensor”として機能している。 AMPK functions as a “metabolic sensor” that promotes metabolism and promotes ATP synthesis under the circumstances where intracellular ATP levels decrease such as exercise.
AMPKはアセチルCoAカルボキシラーゼ(ACC)への活性制御を通してミトコンドリアでの脂肪酸酸化に影響を及ぼす事が知られている。長鎖脂肪酸をミトコンドリア内に取り込むカルニチンパルミトイルトランスフェラーゼ(CPT-1)は、ミトコンドリアにおける脂肪酸酸化の律速酵素であるとともに、ACCの産生物であるマロニルCoAにより強い阻害を受ける。そのため、AMPKはACCをリン酸化(Ser79)することによってACCの活性を抑制し、マロニルCoA量を低下させる結果、CPT−1の活性が亢進して脂肪酸酸化を促進すると考えられている。このように、AMPKは細胞内のエネルギー不足下において活性化するだけでなく、生体のエネルギー代謝あるいは栄養代謝に重要な作用を営んでいると考えられる。 AMPK is known to affect mitochondrial fatty acid oxidation through regulation of acetyl CoA carboxylase (ACC) activity. Carnitine palmitoyltransferase (CPT-1), which takes in long-chain fatty acids into mitochondria, is a rate-limiting enzyme for fatty acid oxidation in mitochondria and is strongly inhibited by malonyl-CoA, the product of ACC. Therefore, it is considered that AMPK phosphorylates ACC (Ser79) to suppress the activity of ACC and reduce the amount of malonyl CoA, thereby increasing the activity of CPT-1 and promoting fatty acid oxidation. As described above, AMPK is not only activated in the presence of intracellular energy, but is thought to have an important effect on the energy metabolism or nutrient metabolism of the living body.
最近の研究によって、AMPKはレプチン(非特許文献1)やアディポネクチンのような脂肪細胞由来ホルモン(非特許文献2)によっても活性化されることが報告され、医学的にはこれらの蛋白質を投与することにより、種々の疾患の治療が試みられている。
しかしながら、レプチンやアディポネクチンを一般市民が用いることは不可能である。このような状況を鑑みれば、もし、AMPK活性化作用を有する化合物を見出すことが出来れば、簡便にレプチンやアディポネクチンの作用を模倣する事が出来、それらの代替物質として有用であると考えられる。
従って本発明の目的は、安全性に優れ、レプチン及びアディポネクチン代替物質として有用なAMPK活性化剤を提供することにある。
更にまた、AMPKの活性化はエネルギー産生を亢進することから、運動時のようなエネルギーを必要とする状況、あるいは日常生活において、本発明のカテキン類を摂取すれば、エネルギーの産生を促進することにより、運動能力の向上や疲労の軽減も可能となる。
However, it is impossible for the general public to use leptin or adiponectin. In view of such a situation, if a compound having an AMPK activating action can be found, the action of leptin or adiponectin can be easily mimicked, and it is considered useful as a substitute for them.
Accordingly, an object of the present invention is to provide an AMPK activator that is excellent in safety and useful as a substitute for leptin and adiponectin.
Furthermore, activation of AMPK enhances energy production, so if the catechins of the present invention are ingested in situations that require energy, such as during exercise, or in daily life, the production of energy is promoted. Thus, it is possible to improve athletic ability and reduce fatigue.
そこで本発明者は、長期間摂取しても安全で、副作用の少ないAMPK活性化剤の探索を行い、長い食経験を有するカテキン類にAMPK活性化作用という全く新しい機能を発見し、レプチンやアディポネクチンの代替物質として有用であることを見出した。
すなわち、本発明は、カテキン類を有効成分とするAMPK活性化剤を提供するものである。
Therefore, the present inventor has searched for an AMPK activator that is safe even when ingested for a long time and has few side effects, discovered a completely new function of AMPK activation action for catechins having a long dietary experience, and has found leptin and adiponectin. It was found to be useful as an alternative substance.
That is, this invention provides the AMPK activator which uses catechin as an active ingredient.
本発明のAMPK活性化剤は、安全性が高く、長期間摂取可能であることから、レプチン及びアディポネクチン代替物質として有用である。 The AMPK activator of the present invention is useful as a substitute for leptin and adiponectin because it is highly safe and can be taken for a long time.
本発明でカテキン類とは、カテキン、ガロカテキン、カテキンガレート、ガロカテキンガレート、エピカテキン、エピガロカテキン、エピカテキンガレート、エピガロカテキンガレートの個々、又はそれらの混合物の総称である。カテキン類及びカテキン類を豊富に含む茶抽出物などが本発明に有効である。 In the present invention, catechins is a general term for catechin, gallocatechin, catechin gallate, gallocatechin gallate, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, or a mixture thereof. Catechins and tea extracts rich in catechins are effective in the present invention.
本発明に使用する成分であるカテキン類は、Camellia属、例えばC.sinensis、C.assamica及び、やぶきた種、又はそれらの雑種から得られる茶葉から製茶された茶葉から水や熱水、場合によってはこれに抽出助剤を添加したもので抽出することができる。当該製茶された茶葉には、(1)煎茶、番茶、玉露、てん茶、釜入り茶等の緑茶類;(2)総称して烏龍茶と呼ばれる鉄観音、色種、黄金桂、武夷岩茶などの半発酵茶;(3)紅茶と呼ばれるダージリン、ウバ、キーマン等の発酵茶が含まれる。茶を抽出する方法については、撹拌抽出など従来の方法により行うことができる。また抽出時の水に、あらかじめアスコルビン酸ナトリウムなどの有機酸又は有機酸塩類を添加してもよい。また煮沸脱気や窒素ガス等の不活性ガスを通気して溶存酸素を除去しつつ、いわゆる非酸化的雰囲気下で抽出する方法を併用してもよい。また、茶葉から直接抽出するかわりに、茶抽出物の濃縮物又は精製物を配合してもよい。 The catechins that are the components used in the present invention include tea leaves made from tea leaves obtained from the genus Camellia, for example, C. sinensis, C. assamica, and bamboo seeds, or hybrids thereof. Can be extracted with the addition of an extraction aid. The tea leaves produced include (1) green teas such as sencha, bancha, gyokuro, tencha, and kettle; (2) iron kannon, color species, golden katsura, wushuiwa tea, etc. (3) Fermented teas such as Darjeeling, Uba, and Keyman called black tea are included. About the method of extracting tea, it can carry out by conventional methods, such as stirring extraction. Moreover, you may add organic acids or organic acid salts, such as sodium ascorbate, to the water at the time of extraction beforehand. Moreover, you may use together the method of extracting in so-called non-oxidative atmosphere, ventilating inert gas, such as boiling deaeration and nitrogen gas, and removing dissolved oxygen. Further, instead of extracting directly from tea leaves, a concentrate or purified product of tea extract may be blended.
ここでいう茶抽出物の濃縮物とは、茶葉から熱水もしくは水溶性有機溶剤により抽出された抽出物を濃縮したものであり、茶抽出物の精製物とは溶剤やカラムを用いて精製したものである。例としては、特開昭59−219384号、特開平4−20589号、特開平5−260907号、特開平5−306279号等に詳細に例示されている方法で調製したものが挙げられる。市販品としては、東京フードテクノ(株)「ポリフェノン」、(株)伊藤園「テアフラン」、太陽化学(株)「サンフェノン」、サントリー(株)「サンウーロン」等が挙げられる。そのほか、カテキン類は他の原料起源、例えばブドウ、及びワイン、ジュース類等のブドウを原料とする加工品やカカオ豆、及びこれを原料とする加工品由来のもの、更には化学合成品でも使用できる。茶抽出物の濃縮物及び茶抽出物の精製物の形態としては、固体、水溶液、スラリー状等種々のものが挙げられる。茶抽出物の濃縮物又は茶抽出物の精製物を溶解、希釈する液は、水、炭酸水、一般に抽出された茶類抽出液等が挙げられる。 The concentrate of tea extract here is a concentrate obtained by concentrating an extract extracted from tea leaves with hot water or a water-soluble organic solvent. The purified tea extract is purified using a solvent or a column. Is. Examples thereof include those prepared by the methods exemplified in detail in JP-A-59-219384, JP-A-4-20589, JP-A-5-260907, JP-A-5-306279, and the like. Commercially available products include Tokyo Food Techno Co., Ltd. “Polyphenone”, ITO EN “Theafranc”, Taiyo Kagaku Co., Ltd. “Sunphenon”, Suntory Co., Ltd. “Sunwoolon”, and the like. In addition, catechins are also used in other raw materials such as grapes, processed products made from grapes such as wine and juice, cocoa beans, processed products made from these raw materials, and chemical synthetic products. it can. Examples of the form of the concentrate of tea extract and the purified product of tea extract include various forms such as solids, aqueous solutions, and slurries. Examples of the solution for dissolving and diluting the concentrate of tea extract or the purified product of tea extract include water, carbonated water, generally extracted tea extracts and the like.
カテキン類としては、一般的に茶抽出物の濃縮物又は茶抽出物の精製物を用いるが、特に緑茶抽出物の濃縮物又は緑茶抽出物の精製物を用いるのが好ましい。 As catechins, a concentrate of tea extract or a purified product of tea extract is generally used, but it is particularly preferable to use a concentrate of green tea extract or a purified product of green tea extract.
本発明のAMPK活性化剤は、医薬品としてヒト及び動物に投与できる。医薬品として使用する場合は、例えば、錠剤、顆粒剤等の経口用固形製剤や、内服液剤、シロップ剤等の経口用液体製剤とすることができる。また、本発明のAMPK活性化剤は、各種の医薬品や、飲食品、ペットフード等に配合することもできる。 The AMPK activator of the present invention can be administered to humans and animals as a pharmaceutical. When used as a pharmaceutical, for example, oral solid preparations such as tablets and granules, and oral liquid preparations such as oral liquids and syrups can be used. In addition, the AMPK activator of the present invention can be blended in various pharmaceuticals, foods and drinks, pet foods and the like.
尚、経口用固形製剤を調製する場合には、カテキン類に賦形剤、必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。また、経口用液体製剤を調製する場合は、矯味剤、緩衝剤、安定化剤、矯味剤等を加えて常法により内服液剤、シロップ剤、エリキシル剤等を製造することができる。 In addition, when preparing an oral solid preparation, an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a flavoring agent and the like are added to catechins, followed by a conventional method. Thus, tablets, coated tablets, granules, powders, capsules and the like can be produced. Moreover, when preparing a liquid preparation for oral use, a liquid preparation, a syrup, an elixir, etc. can be manufactured by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent and the like.
上記各製剤中のカテキン類の配合量は、その使用形態により異なるが、医薬品、例えば錠剤、顆粒剤、カプセル剤等の経口用固形製剤、内服液剤、シロップ剤等の経口用液体製剤等の場合は、通常0.01〜95重量%、更に5〜95重量%、特に10〜95重量%とするのが好ましい。飲食品やペットフード等に配合する場合には、0.01〜5重量%、更に0.05〜5重量%、特に0.1〜1重量%とするのが好ましい。 The amount of catechins in each of the above preparations varies depending on the form of use, but in the case of pharmaceuticals such as oral solid preparations such as tablets, granules and capsules, oral liquid preparations such as oral liquids and syrups, etc. Is usually 0.01 to 95% by weight, more preferably 5 to 95% by weight, and particularly preferably 10 to 95% by weight. When blended in foods and drinks, pet foods, etc., 0.01 to 5% by weight, more preferably 0.05 to 5% by weight, and particularly preferably 0.1 to 1% by weight.
本発明のAMPK活性化剤の投与量(有効摂取量)は、一日当り100〜3000mg/60kg体重とするのが好ましく、特に250〜2000mg/60kg体重、更に250〜1000mg/60kg体重とするのが好ましい。 The dose (effective intake) of the AMPK activator of the present invention is preferably 100 to 3000 mg / 60 kg body weight per day, particularly 250 to 2000 mg / 60 kg body weight, more preferably 250 to 1000 mg / 60 kg body weight. preferable.
試験例1(カテキン類によるAMPK活性化効果)
AMPKの活性化は、マウス肝細胞株(Hepa1-6)を用い、AMPK及びACC(acetyl-CoA carboxylase)のリン酸化を指標に評価した。
マウス肝細胞株(Hepa1-6)を25cm2フラスコにまき、DMEM(+10%FBS,+抗菌剤)中37℃で1−2日培養する。サブコンフルエントになった時点で培養液を除去し、PBS(−)で洗浄後、DMEM(−FBS)に置き換え更に1日培養する。培養液を除去後、所定濃度のカテキン類又は茶抽出物を含むDMEM(−FBS)を加え、60分間培養する。その後、培養液を除去、PBS(−)で洗浄後、細胞溶解液(10mM Tris (pH7.4), 50mM NaCl, 30mM sodium pyrophosphate, 0.5% Triton X-100, protease inhibitor cocktail (SIGMA P2714), phosphatase inhibitor cocktail-1 (SIGMA P2850), phosphatase inhibitor cocktail-2 (SIGMA P5726))を200μL添加、セルスクレイパーで細胞溶解液を回収した。回収した細胞溶解液は、23Gの針付シリンジを3回通すことにより良くホモジナイズし、その後30分間氷上に放置した。15000rpmで15分間、4℃で遠心し、その上清蛋白を以下の実験に用いた。
Test Example 1 (AMPK activation effect by catechins)
Activation of AMPK was evaluated using a mouse liver cell line (Hepa1-6) and phosphorylation of AMPK and ACC (acetyl-CoA carboxylase) as an index.
A mouse liver cell line (Hepa1-6) is seeded in a 25 cm 2 flask and cultured in DMEM (+ 10% FBS, + antibacterial agent) at 37 ° C. for 1-2 days. When subconfluent, the culture solution is removed, washed with PBS (−), replaced with DMEM (−FBS), and further cultured for 1 day. After removing the culture solution, DMEM (-FBS) containing a predetermined concentration of catechins or tea extract is added and cultured for 60 minutes. Thereafter, the culture solution was removed, washed with PBS (−), and then cell lysate (10 mM Tris (pH 7.4), 50 mM NaCl, 30 mM sodium pyrophosphate, 0.5% Triton X-100, protease inhibitor cocktail (SIGMA P2714) 200 μL of phosphatase inhibitor cocktail-1 (SIGMA P2850) and phosphatase inhibitor cocktail-2 (SIGMA P5726)) was added, and the cell lysate was recovered with a cell scraper. The collected cell lysate was well homogenized by passing a 23G syringe with a needle three times, and then left on ice for 30 minutes. After centrifugation at 15000 rpm for 15 minutes at 4 ° C., the supernatant protein was used in the following experiment.
上清蛋白質の濃度を測定後、サンプル間の蛋白濃度を一定に調整した。その4分の一量のSDSバッファー(250mM Tris, 12.5%SDS, 20% glycerol)を加えた後、更に2−メルカプトエタノール並びにブロモフェノールブルーを加え、95℃で熱変性、4℃で急冷し、電気泳動用のサンプルを調製した。 After measuring the concentration of the supernatant protein, the protein concentration between the samples was adjusted to be constant. Add one-fourth volume of SDS buffer (250 mM Tris, 12.5% SDS, 20% glycerol), then add 2-mercaptoethanol and bromophenol blue, heat denaturation at 95 ° C, and rapid cooling at 4 ° C. Samples for electrophoresis were prepared.
上記泳動用サンプルを、一定量(約20−40μg)をSDS−PAGE(4又は12%ゲル)に供し、膜へ転写後、anti-phospho-AMPKα(Thr72)抗体(Cell Signaling社製)、anti-phospho-AMPKβ(Ser108)抗体(Cell Signaling社製)又はanti-phospho-ACC(Ser79)抗体(Cell Signaling社製)を一次抗体、anti-rabbit-HRP抗体(アマシャム社製)を二次抗体、phototope-HRP Western Detection System (Cell Signaling社製)を検出試薬として用いて、phospho-AMPKα、phospho-AMPKβ及びphospho-ACCを検出した。AMPK活性化の度合いは、検出されたバンドの強度を画像解析(EDAS 290 画像解析システム:KODAK)により数値(ピクセル)化し、コントロール(カテキン類無添加群)を100とし、それに対する相対値として示した。尚、カテキン標品はSIGMA社又は和光純薬(株)製の物
を用いた。茶抽出物(茶カテキン)は伊藤園(株)製のテアフラン90Sを用いた。
A certain amount (about 20-40 μg) of the sample for electrophoresis is subjected to SDS-PAGE (4 or 12% gel), transferred to a membrane, anti-phospho-AMPKα (Thr72) antibody (manufactured by Cell Signaling), anti -phospho-AMPKβ (Ser108) antibody (Cell Signaling) or anti-phospho-ACC (Ser79) antibody (Cell Signaling) primary antibody, anti-rabbit-HRP antibody (Amersham) secondary antibody, phospho-AMPKα, phospho-AMPKβ and phospho-ACC were detected using phototope-HRP Western Detection System (manufactured by Cell Signaling) as a detection reagent. The degree of activation of AMPK is expressed as a relative value relative to the intensity of the detected band (pixels) by image analysis (EDAS 290 image analysis system: KODAK), with the control (catechin-free group) being 100. It was. In addition, the catechin preparation used the thing by SIGMA company or Wako Pure Chemical Industries Ltd. Tea extract 90% manufactured by ITO EN Co., Ltd. was used as the tea extract (tea catechin).
表1〜3の結果から、カテキン類は優れたAMPK活性化作用を有すること、特にガロカテキンガレート、エピガロカテキンガレート、ガロカテキン又はエピガロカテキンが優れたAMPK活性化効果を有する事が明らかとなった。また、カテキン類を含む茶抽出物も優れたAMPK活性化効果を発揮する事が明らかとなった。 From the results of Tables 1 to 3, it is clear that catechins have an excellent AMPK activating effect, in particular, gallocatechin gallate, epigallocatechin gallate, gallocatechin or epigallocatechin has an excellent AMPK activating effect. It was. Moreover, it became clear that the tea extract containing catechins also exhibits an excellent AMPK activation effect.
試験例2(カテキン類の運動能力向上作用、疲労緩和作用):
マウス(BALB/c系、雄、6週齢)を1週間予備飼育した後、限界遊泳時間を2回測定した。簡易プールで、マウスを流量7L/minで遊泳させ、流れに逆らって泳げなくなった時点を限界遊泳時間とし、その時間を記録した。限界遊泳時間に群間差のないように1群10匹とし、2群に分けた。表4に示す配合で調製した餌を用いて飼育した。10週間飼育しながら、各群の限界遊泳時間を週に1回測定した。試験開始10週時のマウス限界遊泳時間を表5に示す。
Test Example 2 (Catechins' ability to improve exercise ability and fatigue relief):
Mice (BALB / c strain, male, 6 weeks old) were preliminarily raised for 1 week, and then the limit swimming time was measured twice. The mouse was allowed to swim at a flow rate of 7 L / min in the simple pool, and the time when it became impossible to swim against the flow was defined as the limit swimming time, and that time was recorded. There were 10 animals per group so that there was no difference between the groups in the limit swimming time. They were raised using food prepared with the formulation shown in Table 4. While rearing for 10 weeks, the limit swimming time of each group was measured once a week. Table 5 shows the limit swimming time of mice at 10 weeks after the start of the test.
表5の結果から、エピガロカテキンガレート(EGCG)を摂取することにより、運動能力が向上し、疲労しにくくなっている事がわかる。 From the results in Table 5, it can be seen that by taking epigallocatechin gallate (EGCG), exercise ability is improved and fatigue is less likely.
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