JP2019189598A - Adiponectin receptor agonists and uses thereof, and food compositions for activating adiponectin receptor and uses thereof - Google Patents
Adiponectin receptor agonists and uses thereof, and food compositions for activating adiponectin receptor and uses thereof Download PDFInfo
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Images
Abstract
Description
本発明は、アディポネクチン受容体作動薬及びその使用に関する。具体的には、本発明は、トマト由来のカロテノイド、又はフィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイド、或いはトマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、アディポネクチン受容体作動薬、該アディポネクチン受容体作動薬を有効成分として含有する、アディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤に関する。また、本発明は、アディポネクチン受容体作動用食品組成物及びその使用に関する。具体的には、本発明は、トマト由来のカロテノイド、又はフィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイド、或いはトマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、アディポネクチン受容体作動用食品組成物、該アディポネクチン受容体作動用食品組成物を含有する、アディポネクチン分泌異常に起因する疾患の治療及び／又は予防用食品組成物に関する。 The present invention relates to adiponectin receptor agonists and uses thereof. Specifically, the present invention is a carotenoid derived from tomato, or at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin, or tomato. An adiponectin receptor agonist containing an extract extracted using a mixed solvent of methanol and methyl tert-butyl ether as an active ingredient, and adiponectin secretion abnormality containing the adiponectin receptor agonist as an active ingredient The present invention relates to a therapeutic agent and / or a preventive agent for diseases. The present invention also relates to a food composition for adiponectin receptor operation and use thereof. Specifically, the present invention relates to a carotenoid derived from tomato, or at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin, or tomato. An adiponectin receptor-acting food composition containing an extract extracted with a mixed solvent of methanol and methyl tert-butyl ether as an active ingredient, adiponectin secretion containing the adiponectin receptor-acting food composition The present invention relates to a food composition for treatment and / or prevention of diseases caused by abnormalities.
アディポネクチンは、脂肪細胞から分泌されるホルモンで、インスリン感受性の亢進、動脈硬化の抑制、抗炎症の抑制などの作用が知られている。運動不足などから肥満になった人や、２型糖尿病の人では、脂肪細胞から分泌されるアディポネクチンが低下するため、アディポネクチンは、肥満から引き起こされるインスリン抵抗性に関わる因子として注目されている。 Adiponectin is a hormone secreted from adipocytes and is known to have actions such as increased insulin sensitivity, suppression of arteriosclerosis, and suppression of anti-inflammatory. In a person who becomes obese due to lack of exercise or a person with type 2 diabetes, adiponectin secreted from adipocytes decreases, and thus adiponectin is attracting attention as a factor related to insulin resistance caused by obesity.
アディポネクチンの作用を細胞内に伝える分子である、アディポネクチン受容体（以下、ＡｄｉｐｏＲとも称する）が同定されている。遺伝的素養や肥満等により既にアディポネクチンの分泌に異常を来している場合、アディポネクチン自体の分泌を促すのではなく、ＡｄｉｐｏＲを直接的に活性させることが重要との報告がある（非特許文献１）。 An adiponectin receptor (hereinafter also referred to as AdipoR), which is a molecule that transmits the action of adiponectin into cells, has been identified. There has been a report that it is important to activate AdipoR directly rather than to promote secretion of adiponectin itself when abnormal secretion of adiponectin has already occurred due to genetic predisposition or obesity (Non-patent Document 1). ).
一方、リコピンやβ−カロテンは、トマト等に含まれている天然に存在するカロテノイド化合物の一種であって、様々な疾病に対して予防的又は治療的に働くことが知られている。 On the other hand, lycopene and β-carotene are types of naturally occurring carotenoid compounds contained in tomatoes and the like, and are known to work preventively or therapeutically on various diseases.
リコピンは、アディポネクチンの産生を促進すること（特許文献１）や、β−カロテンがアディポネクチン受容体の発現を増加させること（特許文献２）が知られている。しかし、リコピンやβ−カロテンを含むカロテノイドが、ＡｄｉｐｏＲに直接作用してＡｄｉｐｏＲを活性化させることは知られていない。 Lycopene is known to promote the production of adiponectin (Patent Document 1), and β-carotene increases the expression of an adiponectin receptor (Patent Document 2). However, it is not known that carotenoids including lycopene and β-carotene act directly on AdipoR to activate AdipoR.
本発明は上記事情に鑑みてなされたものであって、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療又は予防に有用な、アディポネクチン受容体作動薬、及びアディポネクチン受容体作動用食品組成物を提供することを課題とする。 The present invention has been made in view of the above circumstances, and is useful for the treatment or prevention of diseases such as type 2 diabetes and obesity caused by adiponectin reduction, and food for adiponectin receptor operation It is an object to provide a composition.
本発明者らは、鋭意研究の結果、リコピンやβ−カロテン等のトマト由来のカロテノイド、及び、トルレン、フコキサンチン等のカロテノイド、並びにトマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物がＡｄｉｐｏＲに直接作用し、ＡｄｉｐｏＲを活性化させる、ＡｄｉｐｏＲ作動薬として機能することを見出し、本発明を完成するに至った。すなわち、本発明は、以下の［１］〜［１３］に関する。 As a result of earnest research, the present inventors have used carotenoids derived from tomatoes such as lycopene and β-carotene, carotenoids such as tolulene and fucoxanthin, and a mixed solvent of methanol and methyl tert-butyl ether from tomatoes. It was found that the extracted extract acts directly on AdipoR and activates AdipoR to function as an AdipoR agonist, and the present invention has been completed. That is, the present invention relates to the following [1] to [13].
［１］ トマト由来のカロテノイドを有効成分として含有する、アディポネクチン受容体作動薬。
［２］ 前記トマト由来のカロテノイドが、フィトエン、フィトフルエン、β−カロテン、リコピン、及びα−カロテンからなる群から選ばれる少なくとも１種である、［１］に記載のアディポネクチン受容体作動薬。
［３］ フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、アディポネクチン受容体作動薬。
［４］ 前記β−カロテン又は前記リコピンが、シス異性体である、［２］又は［３］に記載のアディポネクチン受容体作動薬。
［５］ トマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、アディポネクチン受容体作動薬。
［６］ ［１］〜［５］のいずれか一項に記載のアディポネクチン受容体作動薬を有効成分として含有する、アディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤。
［７］ トマト由来のカロテノイドを有効成分として含有する、アディポネクチン受容体作動用食品組成物。
［８］ 前記トマト由来のカロテノイドが、フィトエン、フィトフルエン、β−カロテン、リコピン、及びα−カロテンからなる群から選ばれる少なくとも１種である、［７］に記載のアディポネクチン受容体作動用食品組成物。
［９］ フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、アディポネクチン受容体作動用食品組成物。
［１０］ 前記β−カロテン又は前記リコピンが、シス異性体である、［８］又は［９］に記載のアディポネクチン受容体作動用食品組成物。
［１１］ トマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、アディポネクチン受容体作動用食品組成物。
［１２］ ［７］〜［１１］のいずれか一項に記載のアディポネクチン受容体作動用食品組成物を含有する、アディポネクチン分泌異常に起因する疾患の治療及び／又は予防用食品組成物。
［１３］ 前記食品組成物が、健康食品、機能性表示食品、特別用途食品、病者用食品、栄養補助食品、サプリメント、又は特定保健用食品である、［７］〜［１２］のいずれか一項に記載の食品組成物。
[1] An adiponectin receptor agonist containing a carotenoid derived from tomato as an active ingredient.
[2] The adiponectin receptor agonist according to [1], wherein the tomato-derived carotenoid is at least one selected from the group consisting of phytoene, phytofluene, β-carotene, lycopene, and α-carotene.
[3] An adiponectin receptor agonist comprising as an active ingredient at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin.
[4] The adiponectin receptor agonist according to [2] or [3], wherein the β-carotene or the lycopene is a cis isomer.
[5] An adiponectin receptor agonist containing, as an active ingredient, an extract extracted from tomato using a mixed solvent of methanol and methyl tert-butyl ether.
[6] A therapeutic and / or prophylactic agent for a disease caused by abnormal adiponectin secretion, comprising the adiponectin receptor agonist according to any one of [1] to [5] as an active ingredient.
[7] A food composition for adiponectin receptor operation comprising a carotenoid derived from tomato as an active ingredient.
[8] The food composition for adiponectin receptor operation according to [7], wherein the tomato-derived carotenoid is at least one selected from the group consisting of phytoene, phytofluene, β-carotene, lycopene, and α-carotene. object.
[9] A food composition for adiponectin receptor operation comprising, as an active ingredient, at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene and fucoxanthin.
[10] The food composition for actuating an adiponectin receptor according to [8] or [9], wherein the β-carotene or the lycopene is a cis isomer.
[11] A food composition for working adiponectin receptor, comprising as an active ingredient an extract extracted from tomato using a mixed solvent of methanol and methyl tert-butyl ether.
[12] A food composition for treatment and / or prevention of a disease caused by abnormal adiponectin secretion, comprising the food composition for adiponectin receptor operation according to any one of [7] to [11].
[13] Any one of [7] to [12], wherein the food composition is a health food, a functional label food, a special-purpose food, a food for a sick person, a dietary supplement, a supplement, or a food for specified health use The food composition according to one item.
本発明に係る、トマト由来のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動薬は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤として有用である。また、本発明に係る、トマト由来のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療及び／又は予防用食品組成物として有用である。
本発明に係る、フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、アディポネクチン受容体作動薬は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤として有用である。また、本発明に係る、フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療及び／又は予防用食品組成物として有用である。
本発明に係る、トマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物（以下、トマトのＭＴＢＥ抽出物とも称する）を有効成分として含有する、アディポネクチン受容体作動薬は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤として有用である。また、本発明に係る、トマトのＭＴＢＥ抽出物を有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療及び／又は予防用食品組成物として有用である。
本発明のアディポネクチン作動薬及びアディポネクチン作動用食品組成物は、アディポネクチンの産生を促進したり、ＡｄｉｐｏＲの発現を促進したりしても、アディポネクチンの効果を期待することができない、遺伝的素養によりアディポネクチン分泌に異常を来している患者に対しても、ＡｄｉｐｏＲに作用して、ＡｄｉｐｏＲを直接活性化させることができるため、アディポネクチン分泌異常に起因する２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤、並びに前記疾患の治療用食品組成物及び／又は予防用食品組成物として有用である。
The AdipoR agonist containing a tomato-derived carotenoid as an active ingredient according to the present invention has an excellent AdipoR activation action, and is a therapeutic agent for diseases such as type 2 diabetes and obesity caused by a decrease in adiponectin and / or Or it is useful as a preventive agent. Moreover, the food composition for AdipoR operation | movement which contains the carotenoid derived from a tomato as an active ingredient based on this invention has the outstanding AdipoR activation effect | action, and diseases, such as type 2 diabetes and obesity caused by the fall of adiponectin It is useful as a food composition for treatment and / or prevention.
An adiponectin receptor agonist containing as an active ingredient at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin according to the present invention, It has an excellent AdipoR activation action and is useful as a therapeutic and / or prophylactic agent for diseases such as type 2 diabetes and obesity caused by adiponectin reduction. The food composition for AdipoR operation according to the present invention, which contains at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin as an active ingredient. The product has an excellent AdipoR activation effect and is useful as a food composition for treatment and / or prevention of diseases such as type 2 diabetes and obesity caused by a decrease in adiponectin.
An adiponectin receptor agonist comprising, as an active ingredient, an extract extracted from tomato using a mixed solvent of methanol and methyl tert-butyl ether (hereinafter also referred to as MTBE extract of tomato) according to the present invention. It has an excellent AdipoR activation action, and is useful as a therapeutic and / or prophylactic agent for diseases such as type 2 diabetes and obesity caused by a decrease in adiponectin. Moreover, the food composition for AdipoR operation | movement which contains the MTBE extract of a tomato as an active ingredient based on this invention has the outstanding AdipoR activation effect | action, type 2 diabetes, obesity, etc. which are caused by the fall of adiponectin It is useful as a food composition for treatment and / or prevention of diseases.
The adiponectin agonist and the food composition for adiponectin operation of the present invention cannot expect the effect of adiponectin even if the production of adiponectin is promoted or the expression of AdipoR is promoted. Since it can act on AdipoR and directly activate AdipoR even for patients who have abnormalities, therapeutic agents for diseases such as type 2 diabetes and obesity caused by abnormal adiponectin secretion and / or It is useful as a prophylactic agent, and a food composition for treating the disease and / or a food composition for prevention.
以下、本発明について詳しく説明する。
≪トマト由来のカロテノイド≫
本発明において用いられるトマト由来のカロテノイドとしては、トマトに含まれるカロテノイドであれば、特に制限はないが、例えば、フィトエン、フィトフルエン、β−カロテン、リコピン、α−カロテン等が挙げられるが、β−カロテン及びリコピンが好ましい。
The present invention will be described in detail below.
≪Tomato-derived carotenoid≫
The carotenoid derived from tomato used in the present invention is not particularly limited as long as it is a carotenoid contained in tomato, and examples thereof include phytoene, phytofluene, β-carotene, lycopene, α-carotene, and the like. -Carotene and lycopene are preferred.
本発明において用いられるトマト由来のカロテノイドは特に限定されず、天然の成分であっても、合成されたものであってもよい。また、トマト由来のカロテノイドが体内で吸収・分解された際に生じるものであってもよい。例えば、β−カロテンの代わりに、β−カロテンが体内で吸収分解された際に生じるレチナール、レチノイン酸の形態で用いてもよい。 The carotenoid derived from tomato used in the present invention is not particularly limited, and may be a natural component or a synthesized one. Further, it may be produced when tomato-derived carotenoid is absorbed and decomposed in the body. For example, instead of β-carotene, it may be used in the form of retinal or retinoic acid produced when β-carotene is absorbed and decomposed in the body.
β−カロテンは、下記構造を有する分子量５３６．８７のカロテノイドであり、水には殆ど溶けない脂溶性の橙色色素である。 β-carotene is a carotenoid having a molecular weight of 536.87 having the following structure, and is a fat-soluble orange pigment that hardly dissolves in water.
本発明において用いられるβ−カロテンは、異性体が存在する。該異性体としては、オールトランス異性体（以下、オールトランス体ともいう）と、１１個の共役π結合のうち、少なくとも１個にシス型を含む、シス異性体（以下、シス体ともいう）等が挙げられる。該シス異性体としては、５−シス体、９−シス体、１３−シス体等が挙げられる。本発明において用いられるβ−カロテンは、これらのβ−カロテンのいずれであってもよいが、シス体であることが好ましい。 The β-carotene used in the present invention has an isomer. The isomers include an all-trans isomer (hereinafter also referred to as an all-trans isomer) and a cis isomer (hereinafter also referred to as a cis-isomer) containing at least one cis form among 11 conjugated π bonds. Etc. Examples of the cis isomer include 5-cis isomer, 9-cis isomer, 13-cis isomer and the like. The β-carotene used in the present invention may be any of these β-carotenes, but is preferably a cis isomer.
リコピンは、下記構造を有する分子量５３６．８７のカロテノイドであり、水には殆ど溶けない脂溶性の赤色色素である。 Lycopene is a carotenoid with a molecular weight of 536.87 having the following structure, and is a fat-soluble red pigment that is hardly soluble in water.
本発明において用いられるリコピンは、異性体が存在する。該異性体としては、オールトランス異性体（以下、オールトランス体ともいう）と、１１個の共役π結合のうち、少なくとも１個にシス型を含む、シス異性体（以下、シス体ともいう）等が挙げられる。該シス異性体としては、５−シス体、９−シス体、１３−シス体等が挙げられる。本発明において用いられるリコピンは、これらのリコピンのいずれであってもよいが、シス体であることが好ましい。 The lycopene used in the present invention has an isomer. The isomers include an all-trans isomer (hereinafter also referred to as an all-trans isomer) and a cis isomer (hereinafter also referred to as a cis-isomer) containing at least one cis form among 11 conjugated π bonds. Etc. Examples of the cis isomer include 5-cis isomer, 9-cis isomer, 13-cis isomer and the like. The lycopene used in the present invention may be any of these lycopenes, but is preferably a cis isomer.
リコピンは、天然においては、トマト、柿、スイカ、ピンクグレープフルーツなどの天然物に含まれており、本発明において用いられるリコピンは、これらの天然物から分離及び抽出されたのものであってもよい。 Lycopene is naturally contained in natural products such as tomatoes, strawberries, watermelons, pink grapefruits, etc., and the lycopene used in the present invention may be separated and extracted from these natural products.
また、本発明において用いられるリコピンは、天然物からの抽出物を必要に応じて適宜精製したものでもよいし、合成品であってもよい。 The lycopene used in the present invention may be a product obtained by appropriately purifying an extract from a natural product as necessary, or may be a synthetic product.
また、本発明において用いられるリコピンは、リコピン誘導体であってもよい。該リコピンの誘導体としては、例えば、レチノイン酸のようなカロテノイド、合成アシクロ−レチノイン酸、１−ＨＯ−３’，４’−ジデヒドロリコピン、３，１’−（ＨＯ）２−γ−カロテン、１，１’−（ＨＯ）２−３，４，３’，４’−テトラデヒドロリコピン、１，１’−（ＨＯ）２−３，４−ジデヒドロリコピン等が挙げられ、常法に従い、製造することができる。 The lycopene used in the present invention may be a lycopene derivative. Examples of the lycopene derivative include carotenoids such as retinoic acid, synthetic acyclo-retinoic acid, 1-HO-3 ′, 4′-didehydrolycopene, 3,1 ′-(HO) 2 -γ-carotene, 1,1 ′-(HO) 2 -3,4,3 ′, 4′-tetradehydrolycopene, 1,1 ′-(HO) 2 3,4-didehydrolycopene, etc. Can be manufactured.
本発明において用いられるリコピンの形態の一つとしては、トマト加工品から抽出された脂溶性抽出物が挙げられる。トマト加工品としては、トマトペースト、トマトピューレ、トマトジュース、トマトパルプ等が挙げられる。該トマト加工品から抽出された脂溶性抽出物は、当該脂溶性抽出物を含む組成物中における安定性、品質、生産性の点から特に好ましい。
ここで、トマト加工品から抽出された脂溶性抽出物とは、トマト加工品から、有機溶剤や油を用いて抽出された抽出物や超臨界抽出法によって抽出された抽出物を意味する。脂溶性抽出物であるリコピンとしては、リコピン含有オイル又はオレオレジンとして広く市販されているトマト抽出物を用いることができ、例えば、サンブライト（株）より販売されているＬｙｃ−Ｏ−Ｍａｔｏ １５％、Ｌｙｃ−Ｏ−Ｍａｔｏ ６％、協和発酵バイオ（株）より販売されているリコピン１８等が挙げられる。
One of the forms of lycopene used in the present invention is a fat-soluble extract extracted from processed tomato products. Examples of processed tomato products include tomato paste, tomato puree, tomato juice, and tomato pulp. The fat-soluble extract extracted from the processed tomato product is particularly preferable in terms of stability, quality, and productivity in the composition containing the fat-soluble extract.
Here, the fat-soluble extract extracted from the processed tomato product means an extract extracted from the processed tomato product using an organic solvent or oil, or an extract extracted by a supercritical extraction method. As the lycopene which is a fat-soluble extract, a tomato extract widely marketed as lycopene-containing oil or oleoresin can be used. For example, Lyc-O-Mato 15% sold by Sunbright Co., Ltd. Lycopene 18 sold by Lyc-O-Mato 6%, Kyowa Hakko Bio Co., Ltd., and the like.
≪その他のカロテノイド≫
本発明において用いられるカロテノイドとしては、前記トマト由来のカロテノイド以外に、トルレン、フコキサンチン等が挙げられる。
本発明において用いられるトルレン、及びフコキサンチンは特に限定されず、天然の成分であっても、合成されたものであってもよい。
≪Other carotenoids≫
Examples of the carotenoid used in the present invention include tolylene, fucoxanthin and the like in addition to the tomato-derived carotenoid.
The tolylene and fucoxanthin used in the present invention are not particularly limited, and may be natural components or synthesized ones.
≪トマトのＭＴＢＥ抽出物≫
本発明において用いられる、トマトのＭＴＢＥ抽出物としては、トマトから、メタノール：メチルｔｅｒｔ−ブチルエーテル＝１：３の溶媒を用いて抽出された抽出物等が挙げられる。使用されるトマトとしては、トマトそのものであっても、前記トマト加工品であってもよい。トマトのＭＴＢＥ抽出物は、当該抽出物をさらに濃縮等の処理や精製を行ったものであってもよい。トマトのＭＴＢＥ抽出物は、カロテノイド等の脂溶性成分を多く含む。それに対し、トマトを、８０％メタノール水溶液（以下、８０％メタノールとも称する）で抽出した抽出物は、トマトの水溶性成分を多く含む。
トマトのＭＴＢＥ抽出物は、例えば、トマトに、メタノール:メチルｔｅｒｔ−ブチルエーテル＝１：３の溶媒を添加し、ビーズ破砕機等を用いて溶媒内でトマトを破砕した後、超音波処理を行い、得られたトマト破砕物にメタノール：水＝１：３の溶媒を加えて混和して遠心分離し、得られる上清を乾固させること等により得ることができる。
≪MTBE extract of tomato≫
Examples of the MTBE extract of tomato used in the present invention include an extract extracted from tomato using a solvent of methanol: methyl tert-butyl ether = 1: 3. The tomato used may be the tomato itself or the processed tomato product. The MTBE extract of tomato may be one obtained by further subjecting the extract to a treatment such as concentration or purification. The MTBE extract of tomato contains a lot of fat-soluble components such as carotenoids. In contrast, an extract obtained by extracting tomato with an 80% aqueous methanol solution (hereinafter also referred to as 80% methanol) contains a large amount of water-soluble components of tomato.
MTBE extract of tomato is, for example, adding a solvent of methanol: methyl tert-butyl ether = 1: 3 to tomato, crushing tomato in the solvent using a bead crusher or the like, then performing ultrasonic treatment, The obtained tomato crushed product can be obtained by adding a solvent of methanol: water = 1: 3, mixing and centrifuging, and drying the resulting supernatant.
≪ＡｄｉｐｏＲ作動薬≫
トマト由来のカロテノイド、トルレン、及びフコキサンチンは、ＡｄｉｐｏＲを活性化させ、ＡｄｉｐｏＲ作動薬として機能する。また、トマトのＭＴＢＥ抽出物は、ＡｄｉｐｏＲを活性化させ、ＡｄｉｐｏＲ作動薬として機能する。従って、トマト由来のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動薬、フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動薬、及びトマトのＭＴＢＥ抽出物を有効成分として含有する、ＡｄｉｐｏＲ作動薬は、ＡｄｉｐｏＲが活性化されないことにより引き起こされる状態又は疾病の治療及び／又は予防に用いることができる。例えば、インスリン抵抗性の改善、ＴＮＦ−α産生の抑制、及び２型糖尿病、動脈硬化、冠動脈疾患、腎不全、心筋梗塞、高血圧、肝線維化、肥満等の治療及び／又は予防に用いることができる。
≪AdipoR agonist≫
Tomato-derived carotenoids, tolylene, and fucoxanthin activate AdipoR and function as AdipoR agonists. In addition, MTBE extract of tomato activates AdipoR and functions as an AdipoR agonist. Accordingly, the active ingredient contains at least one carotenoid selected from the group consisting of an AdipoR agonist, phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene and fucoxanthin, containing a carotenoid derived from tomato as an active ingredient. The AdipoR agonist and the AdipoR agonist containing the MTBE extract of tomato as active ingredients can be used for the treatment and / or prevention of a condition or disease caused by the fact that AdipoR is not activated. For example, it can be used to improve insulin resistance, suppress TNF-α production, and treat and / or prevent type 2 diabetes, arteriosclerosis, coronary artery disease, renal failure, myocardial infarction, hypertension, liver fibrosis, obesity and the like. it can.
また、本発明のＡｄｉｐｏＲ作動薬は、アディポネクチンの産生を促進したり、ＡｄｉｐｏＲの発現を促進したりしても、アディポネクチンの効果を期待することができない、遺伝的素養によりアディポネクチン分泌に異常を来している患者に対しても、ＡｄｉｐｏＲに作用して、ＡｄｉｐｏＲを直接活性化させることができるため、アディポネクチン分泌異常に起因する２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤として用いることができる。 In addition, the AdipoR agonist of the present invention cannot be expected to have an effect of adiponectin even if the production of adiponectin is promoted or the expression of AdipoR is promoted. Can also act directly on AdipoR to directly activate AdipoR, so it can be used as a therapeutic and / or prophylactic agent for diseases such as type 2 diabetes and obesity caused by abnormal adiponectin secretion Can do.
トマト由来のカロテノイド、トルレン、フコキサンチン、及びトマトのＭＴＢＥ抽出物は、そのままでＡｄｉｐｏＲ作動薬とすることができるし、さらに他の任意成分を配合してＡｄｉｐｏＲ作動薬としてもよい。このような任意成分は、ＡｄｉｐｏＲの活性化作用が期待され、かつ安全性が確認されているものを特に制限なく用いることができる。 Tomato-derived carotenoids, tolulene, fucoxanthin, and MTBE extract of tomato can be used as they are as AdipoR agonists, and other optional components can be added to make AdipoR agonists. As such optional components, those that are expected to activate AdipoR and have been confirmed to be safe can be used without particular limitation.
本発明に係るＡｄｉｐｏＲ作動薬の投与形態としては、例えば錠剤、被覆錠剤、カプセル剤、顆粒剤、散剤、溶液、シロップ剤、乳液等による経口投与を挙げることができる。これらの各種製剤は、常法に従って主薬である、トマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物に加えて、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤などの医薬等の製剤技術分野において通常使用しうる既知の補助剤を用いて製剤化することができる。 Examples of the administration form of the AdipoR agonist according to the present invention include oral administration such as tablets, coated tablets, capsules, granules, powders, solutions, syrups, and emulsions. These various preparations, in addition to the tomato-derived carotenoids, tolulene, fucoxanthin, or MTBE extract of tomato, which are the main agents according to conventional methods, excipients, binders, disintegrants, lubricants, colorants, It can be formulated using known adjuvants that can be generally used in the field of pharmaceutical technology such as pharmaceuticals such as flavoring agents, solubilizing agents, suspension agents, and coating agents.
本発明のＡｄｉｐｏＲ作動薬におけるトマト由来のカロテノイド、トルレン、フコキサンチン、及びトマトのＭＴＢＥ抽出物の含有量は、剤型によって異なるため特に限定されない。 In the AdipoR agonist of the present invention, the contents of tomato-derived carotenoids, tolylene, fucoxanthin, and tomato MTBE extract are not particularly limited because they differ depending on the dosage form.
本発明のＡｄｉｐｏＲ作動薬の投与量は、個々の有効成分の活性、患者の性別、症状、年齢、投与方法によって異なるが、例えば、トマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物を、通常、成人１人、１日当たり、５〜５００ｍｇ、好ましくは、４０ｍｇ〜２００ｍｇ投与することができる量である。例えば、ＡｄｉｐｏＲ作動薬全量に対して、トマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物を好ましくは１〜９５％質量％、より好ましくは、１０〜４０質量％の割合とする。 The dose of the AdipoR agonist of the present invention varies depending on the activity of the individual active ingredient, the patient's sex, symptoms, age, and administration method. For example, a carotenoid derived from tomato, tolylene, fucoxanthin, or MTBE extract of tomato Is usually an amount that can be administered from 5 to 500 mg, preferably from 40 mg to 200 mg per adult per day. For example, the tomato-derived carotenoid, tolylene, fucoxanthin, or MTBE extract of tomato is preferably 1 to 95% by mass, more preferably 10 to 40% by mass with respect to the total amount of AdipoR agonist.
本発明のＡｄｉｐｏＲ作動薬を投与する対象は、動物、中でも哺乳類が挙げられる。哺乳類としては、特に制限はないが、例えば、ヒト、イヌ、ネコ、ウシ、ウマ等が挙げられ、ヒトであることが好ましい。また、本発明のＡｄｉｐｏＲ作動薬は、ＡｄｉｐｏＲが活性化されないことに伴う疾患に対する予防剤として、ＡｄｉｐｏＲが活性化されないことに伴う疾患を発症していない上記対象に投与することもできる。 Subjects to which the AdipoR agonist of the present invention is administered include animals, especially mammals. The mammal is not particularly limited, and examples thereof include humans, dogs, cats, cows, horses and the like, and humans are preferable. In addition, the AdipoR agonist of the present invention can be administered to the above-mentioned subject who has not developed a disease associated with AdipoR not being activated as a preventive agent for a disease associated with AdipoR not being activated.
本発明のＡｄｉｐｏＲ作動薬のＡｄｉｐｏＲ活性化作用の測定は、ＡｄｉｐｏＲが活性化されたことに伴う作用を測定することであれば特に制限はないが、例えば、アディポネクチンがＡｄｉｐｏＲに結合した際の下流シグナルである、ＡＭＰキナーゼ（以下、ＡＭＰＫと称する）のリン酸化を測定することにより行うことができる。被検物質投与下におけるリン酸化したＡＭＰＫ（ｐＡＭＰＫ）の量と、被検物質非投与下でのリン酸化したＡＭＰＫの量との比（ｐＡＭＰＫ／ＡＭＰＫ比）が高くなれば当該被検物質はＡｄｉｐｏＲ活性化作用を有すると評価することができる。 The measurement of the AdipoR activation action of the AdipoR agonist of the present invention is not particularly limited as long as the action associated with the activation of AdipoR is measured, but for example, a downstream signal when adiponectin binds to AdipoR It can be carried out by measuring phosphorylation of AMP kinase (hereinafter referred to as AMPK). If the ratio (pAMPK / AMPK ratio) between the amount of phosphorylated AMPK (pAMPK) under administration of the test substance and the amount of phosphorylated AMPK under non-test substance administration (pAMPK / AMPK ratio) is high, the test substance is AdipoR. It can be evaluated as having an activating effect.
また、前記ＡＭＰＫのリン酸化は、ＡｄｉｐｏＲの活性化以外でも起こるため、前記ＡＭＰＫのリン酸化が、ＡｄｉｐｏＲを介して生じていることの判断は、ｓｉＲＮＡによりＡｄｉｐｏＲをノックダウンした系におけるＡＭＰＫのリン酸化を測定し、ＡｄｉｐｏＲをノックダウンしていない系で認められるＡＭＰＫのリン酸化が、ＡｄｉｐｏＲをノックダウンした系で認められるか否かを確認することにより行うことできる。例えば、ＡｄｉｐｏＲノックダウンしていない系で認められるＡＭＰＫのリン酸化が、ＡｄｉｐｏＲをノックダウンした系で認められない場合は、ＡＭＰＫのリン酸化は、ＡｄｉｐｏＲの活性化により生じたものと判断することができる。 In addition, since the phosphorylation of AMPK occurs other than the activation of AdipoR, the determination that the phosphorylation of AMPK occurs via AdipoR is based on the phosphorylation of AMPK in a system in which AdipoR is knocked down by siRNA. And AMPK phosphorylation observed in a system not knocking down AdipoR can be confirmed by confirming whether it is observed in a system knocking down AdipoR. For example, if AMPK phosphorylation observed in a system not knocked down by AdipoR is not observed in a system knocked down by AdipoR, it can be determined that phosphorylation of AMPK was caused by activation of AdipoR. it can.
≪アディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤≫
本発明のＡｄｉｐｏＲ作動薬は、ＡｄｉｐｏＲを直接活性化することができるため、本発明のＡｄｉｐｏＲ作動薬は、アディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤の有効成分として用いることができる。
本発明によって治療或いは予防されるアディポネクチン分泌異常に起因する疾患は、アディポネクチンが分泌異常により、分泌されない、或いは、分泌されても少量しか分泌されないため、ＡｄｉｐｏＲが活性化されないことにより引き起こされる疾患であれば特に制限はないが、例えば、アディポネクチンの産生を促進したり、ＡｄｉｐｏＲの発現を促進したりしても、アディポネクチンの効果を期待することができない、遺伝的素養によりアディポネクチン分泌が異常となっていることに伴う疾患を挙げることができる。
≪Therapeutic and / or prophylactic agent for diseases caused by abnormal adiponectin secretion≫
Since the AdipoR agonist of the present invention can directly activate AdipoR, the AdipoR agonist of the present invention can be used as an active ingredient of a therapeutic and / or prophylactic agent for diseases caused by abnormal adiponectin secretion. .
The disease caused by abnormal adiponectin secretion to be treated or prevented by the present invention is a disease caused by adiponectin not being activated because adiponectin is not secreted due to abnormal secretion or is secreted only in a small amount even if secreted. Although there is no particular limitation, for example, even if the production of adiponectin or the expression of AdipoR is promoted, the effect of adiponectin cannot be expected. Adiponectin secretion is abnormal due to genetic predisposition Mention of diseases associated therewith can be mentioned.
本発明のアディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤の投与形態としては、例えば錠剤、被覆錠剤、カプセル剤、顆粒剤、散剤、溶液、シロップ剤、乳液等による経口投与を挙げることができる。これらの各種製剤は、常法に従って主薬であるトマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物に加えて、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤などの医薬等の製剤技術分野において通常使用しうる既知の補助剤を用いて製剤化することができる。 Examples of the administration form of the therapeutic and / or prophylactic agent for diseases caused by abnormal secretion of adiponectin according to the present invention include oral administration such as tablets, coated tablets, capsules, granules, powders, solutions, syrups, and emulsions. be able to. These various preparations are prepared in accordance with conventional methods, in addition to the tomato-derived carotenoids, tolulene, fucoxanthin, or tomato MTBE extract, excipients, binders, disintegrants, lubricants, coloring agents, taste masking It can be formulated using known adjuvants that can be generally used in the pharmaceutical technology field such as pharmaceuticals such as flavoring agents, solubilizers, suspension agents, and coating agents.
本発明のアディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤におけるトマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物の含有量は、剤型によって異なるが、一般にアディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤の全質量に対して、１質量％〜９５質量％であることが好ましく、１０〜４０質量％であることがより好ましい。 The content of the MTBE extract of tomato-derived carotenoid, tolylene, fucoxanthin, or tomato in the therapeutic and / or preventive agent for diseases caused by abnormal adiponectin secretion of the present invention varies depending on the dosage form, but in general, abnormal adiponectin secretion It is preferably 1% by mass to 95% by mass and more preferably 10% by mass to 40% by mass with respect to the total mass of the therapeutic agent and / or the preventive agent for diseases caused by.
本発明のアディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤の投与量は、個々の有効成分の活性、患者の性別、症状、年齢、投与方法によって異なるが、例えば、トマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物を、通常、成人１人、１日当たり、５〜５００ｍｇ、好ましくは、４０ｍｇ〜２００ｍｇ投与することができる量である。例えば、アディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤全量に対して、トマト由来のカロテノイド、トルレン、フコキサンチン、又はトマトのＭＴＢＥ抽出物を好ましくは１〜９５％質量％、より好ましくは、１０〜４０質量％の割合とする。 The dose of the therapeutic agent and / or prophylactic agent for diseases caused by abnormal secretion of adiponectin of the present invention varies depending on the activity of individual active ingredients, patient sex, symptoms, age, and administration method. For example, carotenoids derived from tomato , Tolylene, fucoxanthin, or tomato MTBE extract is usually an amount that can be administered to an adult per person per day, 5 to 500 mg, preferably 40 mg to 200 mg. For example, the tomato-derived carotenoid, tolylene, fucoxanthin, or MTBE extract of tomato is preferably 1 to 95% by mass, more preferably, based on the total amount of therapeutic and / or preventive agent for diseases caused by abnormal adiponectin secretion Is a ratio of 10 to 40% by mass.
本発明のアディポネクチン分泌異常に起因する疾患の治療剤及び／又は予防剤を投与する対象は、動物、中でも哺乳類が挙げられる。哺乳類としては、特に制限はないが、例えば、ヒト、イヌ、ネコ、ウシ、ウマ等が挙げられ、ヒトであることが好ましい。 The subject to which the therapeutic and / or prophylactic agent for a disease caused by abnormal adiponectin secretion of the present invention is administered includes animals, particularly mammals. The mammal is not particularly limited, and examples thereof include humans, dogs, cats, cows, horses and the like, and humans are preferable.
≪食品組成物≫
本発明により、トマト由来のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物、及びフィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイドを有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物、及びトマトのＭＴＢＥ抽出物を有効成分として含有するＡｄｉｐｏＲ作動用食品組成物を提供することができる。本発明に係るトマト由来のカロテノイド、トルレン、フコキサンチン及びトマトのＭＴＢＥ抽出物は、ＡｄｉｐｏＲ活性化作用を有するため、ＡｄｉｐｏＲ作動用食品組成物の有効成分として、各種食品組成物に含有させることができる。本発明において、食品組成物には、食品だけでなく飲料も含む。
≪Food composition≫
According to the present invention, a food composition for AdipoR operation containing a carotenoid derived from tomato as an active ingredient, and at least one selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene and fucoxanthin The food composition for AdipoR operation | movement which contains the seed carotenoid as an active ingredient, and the food composition for AdipoR operation | movement which contains the MTBE extract of a tomato as an active ingredient can be provided. The tomato-derived carotenoids, tolulene, fucoxanthin and tomato MTBE extract according to the present invention have an AdipoR activating action, and therefore can be contained in various food compositions as active ingredients of AdipoR working food compositions. . In the present invention, the food composition includes not only food but also beverages.
本発明の食品組成物において、トマト由来のカロテノイドは、フィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン等が挙げられ、β−カロテン及びリコピンが好ましく用いられる。 In the food composition of the present invention, examples of the carotenoid derived from tomato include phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene and the like, and β-carotene and lycopene are preferably used.
本発明の食品組成物において、トマトのＭＴＢＥ抽出物としては、トマトから、メタノール：メチルｔｅｒｔ−ブチルエーテル＝１：３の溶媒を用いて抽出された抽出物等が挙げられる。前記トマトとしては、トマトそのものであっても、前記トマト加工品であってもよい。トマトのＭＴＢＥ抽出物は、当該抽出物をさらに濃縮等の処理や精製を行ったものであってもよい。トマトのＭＴＢＥ抽出物は、カロテノイド等の脂溶性成分を多く含む。 In the food composition of the present invention, the MTBE extract of tomato includes an extract extracted from tomato using a solvent of methanol: methyl tert-butyl ether = 1: 3. The tomato may be the tomato itself or the processed tomato product. The MTBE extract of tomato may be one obtained by further subjecting the extract to a treatment such as concentration or purification. The MTBE extract of tomato contains a lot of fat-soluble components such as carotenoids.
本発明のＡｄｉｐｏＲ作動用食品組成物により治療及び／又は予防することができる疾患としては、ＡｄｉｐｏＲが活性化されないことにより引き起こされる状態又は疾病であれば特に制限はないが、例えば、インスリン抵抗性の改善、ＴＮＦ−α産生の抑制、及び２型糖尿病、動脈硬化、冠動脈疾患、腎不全、心筋梗塞、高血圧、肝線維化、肥満等を挙げることができる。 The disease that can be treated and / or prevented by the AdipoR working food composition of the present invention is not particularly limited as long as it is a condition or disease caused by the fact that AdipoR is not activated. Examples include improvement, suppression of TNF-α production, type 2 diabetes, arteriosclerosis, coronary artery disease, renal failure, myocardial infarction, hypertension, liver fibrosis, obesity and the like.
また、本発明のＡｄｉｐｏＲ作動用食品組成物は、アディポネクチンの産生を促進したり、ＡｄｉｐｏＲの発現を促進したりしても、アディポネクチンの効果を期待することができない、遺伝的素養によりアディポネクチン分泌に異常を来している患者に対しても、ＡｄｉｐｏＲに作用して、ＡｄｉｐｏＲを直接活性化させることができるため、アディポネクチン分泌異常による２型糖尿病や肥満等の疾患の治療及び／又は予防用食品組成物として用いることができる。 In addition, the food composition for AdipoR operation of the present invention cannot be expected to have an effect of adiponectin even if it promotes the production of adiponectin or promotes the expression of AdipoR. Can act directly on AdipoR to directly activate AdipoR, and therefore a food composition for treatment and / or prevention of diseases such as type 2 diabetes and obesity caused by abnormal adiponectin secretion Can be used as
トマト由来のカロテノイド、トルレン、フコキサンチン、及びトマトのＭＴＢＥ抽出物は、そのままでＡｄｉｐｏＲ作動用食品組成物とすることができるし、さらに他の任意成分を配合してＡｄｉｐｏＲ作動用食品組成物としてもよい。このような任意成分は、ＡｄｉｐｏＲを活性化作用が期待され、かつ安全性が確認されているものを特に制限なく用いることができる。 Carotenoids derived from tomatoes, tolylene, fucoxanthin, and MTBE extract of tomatoes can be used as they are as food compositions for AdipoR operation, and can also be blended with other optional ingredients as food compositions for AdipoR operation. Good. As such optional components, those which are expected to activate AdipoR and have been confirmed to be safe can be used without particular limitation.
本発明のＡｄｉｐｏＲ作動用食品組成物を摂取させる対象は、動物、中でも哺乳類が挙げられる。哺乳類としては、特に制限はないが、例えば、ヒト、イヌ、ネコ、ウシ、ウマ等が挙げられ、ヒトであることが好ましい。また、本発明のＡｄｉｐｏＲ作動用食品組成物は、ＡｄｉｐｏＲが活性化されないことに伴う疾患に対する予防用食品組成物として、ＡｄｉｐｏＲが活性化されないことに伴う疾患を発症していない上記対象に摂取させることもできる。 Examples of the subject ingesting the food composition for AdipoR operation of the present invention include animals, particularly mammals. The mammal is not particularly limited, and examples thereof include humans, dogs, cats, cows, horses and the like, and humans are preferable. Moreover, the food composition for AdipoR operation of the present invention is ingested by the above-mentioned subject who has not developed a disease associated with AdipoR not being activated, as a food composition for prevention of a disease associated with AdipoR not being activated. You can also.
本発明のＡｄｉｐｏＲ作動用食品組成物は、ＡｄｉｐｏＲを直接活性化することができるため、本発明のＡｄｉｐｏＲ作動用食品組成物は、アディポネクチン分泌異常に起因する疾患の治療及び／又は予防用食品組成物の有効成分として用いることができる。
本発明によって治療或いは予防されるアディポネクチン分泌異常に起因する疾患は、アディポネクチンが分泌異常により、分泌されない、或いは、分泌されても少量しか分泌されないため、ＡｄｉｐｏＲが活性化されないことにより引き起こされる疾患であれば特に制限はないが、例えば、アディポネクチンの産生を促進したり、ＡｄｉｐｏＲの発現を促進したりしても、アディポネクチンの効果を期待することができない、遺伝的素養によりアディポネクチン分泌が異常となっていることに伴う疾患を挙げることができる。
Since the food composition for AdipoR operation of the present invention can directly activate AdipoR, the food composition for AdipoR operation of the present invention is a food composition for treatment and / or prevention of diseases caused by abnormal adiponectin secretion. It can be used as an active ingredient.
The disease caused by abnormal adiponectin secretion to be treated or prevented by the present invention is a disease caused by adiponectin not being activated because adiponectin is not secreted due to abnormal secretion or is secreted only in a small amount even if secreted. Although there is no particular limitation, for example, even if the production of adiponectin or the expression of AdipoR is promoted, the effect of adiponectin cannot be expected. Adiponectin secretion is abnormal due to genetic predisposition Mention of diseases associated therewith can be mentioned.
本発明のＡｄｉｐｏＲ作動用食品組成物、及びアディポネクチン分泌異常に起因する疾患の治療及び／又は予防用食品組成物（以下、本発明の食品組成物と総称する）としては、特に限定されないが、例えば、各種飲料、ヨーグルト、チーズ、バター、乳酸菌発酵品等の各種乳製品、流動食、ゼリー、キャンディ、レトルト食品、錠菓、クッキー、カステラ、パン、ビスケット、などが挙げられる。また、健康食品、機能性表示食品、特別用途食品、病者用食品、栄養補助食品、サプリメント又は特定保健用食品等として使用することもできる。 The food composition for AdipoR operation of the present invention and the food composition for treatment and / or prevention of diseases caused by abnormal adiponectin secretion (hereinafter collectively referred to as the food composition of the present invention) are not particularly limited, for example And various dairy products such as various beverages, yogurt, cheese, butter and lactic acid bacteria fermented products, liquid food, jelly, candy, retort food, tablet confectionery, cookies, castella, bread and biscuits. Moreover, it can also be used as a health food, a functional label food, a special-purpose food, a food for a sick person, a dietary supplement, a supplement, or a food for specified health use.
本発明の食品組成物には、可食性の、炭水化物、蛋白質、脂質、ビタミン類、ミネラル類、糖質（ブドウ糖、等）、天然又は人工甘味剤、クエン酸、炭酸水、果汁、安定剤、保存剤、結合剤、増粘剤、乳化剤などを適宜配合することができる。 The food composition of the present invention includes edible carbohydrates, proteins, lipids, vitamins, minerals, carbohydrates (glucose, etc.), natural or artificial sweeteners, citric acid, carbonated water, fruit juice, stabilizers, Preservatives, binders, thickeners, emulsifiers and the like can be appropriately blended.
本発明の食品組成物の摂取量は、その形態によって異なるが、トマト由来のカロテノイド、トルレン、フコキサンチン又はトマトのＭＴＢＥ抽出物を、１通常、成人１人、１日当たり、５〜５００ｍｇ、好ましくは、４０ｍｇ〜２００ｍｇ投与することができる量である。例えば、ＡｄｉｐｏＲ作動用食品組成物１００ｇ中に、トマト由来のカロテノイド、トルレン、フコキサンチン又はトマトのＭＴＢＥ抽出物を好ましくは５〜５００ｍｇ、より好ましくは、４０〜２００ｍｇ含有させる。なお、トマトを主成分とした食品組成物にＡｄｉｐｏＲ作動薬を配合する場合には、トマト中のカロテノイドの量に合わせて上記トマト由来のカロテノイド量となるように、ＡｄｉｐｏＲ作動薬の含有量を調節することができる。 Although the intake of the food composition of the present invention varies depending on the form, the MTBE extract of tomato-derived carotenoid, tolylene, fucoxanthin or tomato is usually 5 to 500 mg per day, preferably 1 adult, 1 day. , 40 mg to 200 mg can be administered. For example, the MTBE extract of tomato-derived carotenoid, tolylene, fucoxanthin or tomato is preferably contained in 5 to 500 mg, more preferably 40 to 200 mg in 100 g of AdipoR working food composition. In addition, when an AdipoR agonist is added to a food composition mainly composed of tomatoes, the content of the AdipoR agonist is adjusted so that the amount of carotenoid derived from the tomato is the same as the amount of carotenoid in the tomato. can do.
本発明の食品組成物の摂取回数は、特に限定されないが、好ましくは１日１〜３回であり、必要に応じて摂取回数を増減してもよい。なお、「１日当り」とは、本発明の食品組成物の形態によって異なるが、表示される１日の摂取目安量や、通常１度で消費する飲みきりタイプの飲料であれば１本当りに含まれる量を指すものである。 The number of intakes of the food composition of the present invention is not particularly limited, but is preferably 1 to 3 times a day, and the number of intakes may be increased or decreased as necessary. Note that “per day” varies depending on the form of the food composition of the present invention. However, the displayed daily intake standard amount or a drink-type beverage that is normally consumed at a time is usually per serving. It refers to the amount contained.
上記の食品組成物は、ＡｄｉｐｏＲ活性化による、ＡｄｉｐｏＲが活性化されないことに伴う各種疾患の治療及び／又は予防作用を有する旨の表示をした食品組成物であってもよい。前記ＡｄｉｐｏＲが活性化されないことに伴う各種疾患に対する治療及び／又は予防作用を有する旨の表示をした食品組成物としては、例えば、遺伝的素養による、アディポネクチン分泌異常に起因する各種疾患に対して治療及び／又は予防作用を有する旨の表示を付した食品組成物等が挙げられる。 The food composition described above may be a food composition showing that it has a therapeutic and / or preventive action for various diseases associated with AdipoR being not activated by AdipoR activation. Examples of the food composition showing that it has a therapeutic and / or preventive action against various diseases associated with the inactivation of AdipoR include, for example, treatment for various diseases caused by abnormal adiponectin secretion due to genetics And / or a food composition with a label indicating that it has a preventive action.
以下、実施例により本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to a following example.
［実施例１］
１０％ウシ胎児血清、１％ペニシリン−ストレプトマイシン（以下、Ｐ／Ｓと略記する）を加えた高グルコースダルベッコ改変イーグル培地（以下、ＤＭＥＭと略記する）を使用し、マウス筋芽細胞株Ｃ２Ｃ１２を１２ウェルプレートに２×１０５細胞／ウェルで播種した。３日後、２％ウマ血清、１％Ｐ／Ｓを含むＤＭＥＭを分化誘導培地として使用して培地交換を行った。その後、２日おきに分化誘導培地の交換を行い、５日間分化誘導を行った。５日後、無血清のＤＭＥＭで一晩培養した。
[Example 1]
Using a high glucose Dulbecco's modified Eagle's medium (hereinafter abbreviated as DMEM) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (hereinafter abbreviated as P / S), a mouse myoblast cell line C2C12 was treated with 12 Well plates were seeded at 2 × 10 5 cells / well. Three days later, the medium was changed using DMEM containing 2% horse serum and 1% P / S as a differentiation-inducing medium. Thereafter, the differentiation induction medium was changed every 2 days, and differentiation induction was performed for 5 days. After 5 days, the cells were cultured overnight in serum-free DMEM.
一晩培養後、Ｃ２Ｃ１２の培養液を除去し、被験薬として、フィトエン、フィトフルエン、β−カロテン（オールトランス体）、トルレン、リコピン（オールトランス体）及びカロテノイドと類似構造を有するレチノール及びゲラニルゲラニオール（ＧＧＯＨ）、並びに、陽性コントロールとしてＡｄｉｐｏＲを活性化することが知られている下記構造式で表されるアディポロン（ＡｄｉｐｏＲｏｎ；Ｎａｔｕｒｅ ５０３：４９４−４９９ ２０１３）を用い、各被験薬を１μＭ（アディポロンは１μＭと５０μＭ）となるように溶解した無血清のＤＭＥＭを添加して１０分間培養することで、被験薬をＣ２Ｃ１２に１０分間反応させた。なお、各被験薬の溶媒として０．２％Ｔｗｅｅｎ−２０を含むテトラヒドロフランを使用し、ＤＭＥＭ中の溶媒の最終濃度が０．０５％になるようにして各被験薬を添加した。コントロールとしては、０．０５％の溶媒のみを含むＤＭＥＭを用いた。 After overnight culture, the culture solution of C2C12 was removed, and retinol and geranylgeraniol having similar structures as phytoene, phytofluene, β-carotene (all-trans form), tolylene, lycopene (all-trans form) and carotenoids were used as test drugs. (GGOH), and adipolone (AdipoRon; Nature 503: 494-499 2013) represented by the following structural formula known to activate AdipoR as a positive control, and 1 μM of each test drug (Adipolone is The test drug was reacted with C2C12 for 10 minutes by adding serum-free DMEM dissolved to 1 μM and 50 μM) and culturing for 10 minutes. Tetrahydrofuran containing 0.2% Tween-20 was used as a solvent for each test drug, and each test drug was added so that the final concentration of the solvent in DMEM was 0.05%. As a control, DMEM containing only 0.05% solvent was used.
反応後、Ｃ２Ｃ１２をリン酸緩衝生理食塩水（Ｐｈｏｓｐｈａｔｅ ｂｕｆｆｅｒｅｄ ｓａｌｉｎｅ；ＰＢＳ）で洗浄し、細胞溶解液（５０ｍＭ Ｔｒｉｓ−ＨＣｌ、５ｍＭ ＥＤＴＡ、１５０ｍＭ ＮａＣｌ、０．５％ Ｎｏｎｉｄｅｔ Ｐ−４０、１％ ｐｒｏｔｅａｓｅ ｉｎｈｉｂｉｔｏｒ、１％ ｐｈｏｓｐｈａｔａｓｅ ｉｎｈｉｂｉｔｏｒ）を添加した。続いて、氷上でスクレイパーにて細胞を回収し、超音波処理により細胞を破砕した。得られた細胞破砕物を遠心分離し、上清をタンパク質溶液として回収した。回収タンパク質の濃度を測定後、タンパク質溶液に等量のＳＤＳサンプルバッファー（１２５ｍＭ Ｔｒｉｓ−ＨＣｌ（ｐＨ ６．８）、４％ ＳＤＳ、１０％ スクロース、１０％ ２−メルカプトエタノール、０．０１％ ブロモフェノールブルー）を加えて混合し、沸騰水中で３分間煮沸処理したものを、泳動用サンプルとして以降のウエスタンブロットまで−３０℃にて保存した。 After the reaction, C2C12 was washed with phosphate buffered saline (PBS), and cell lysate (50 mM Tris-HCl, 5 mM EDTA, 150 mM NaCl, 0.5% Nonidet P-40, 1% protease inhibitor). 1% phosphatase inhibitor) was added. Subsequently, the cells were collected with a scraper on ice, and the cells were disrupted by ultrasonic treatment. The obtained cell lysate was centrifuged, and the supernatant was recovered as a protein solution. After measuring the concentration of the recovered protein, an equal amount of SDS sample buffer (125 mM Tris-HCl (pH 6.8), 4% SDS, 10% sucrose, 10% 2-mercaptoethanol, 0.01% bromophenol is added to the protein solution. Blue) was added, mixed, and boiled in boiling water for 3 minutes, and stored at −30 ° C. as a sample for electrophoresis until subsequent Western blotting.
泳動用サンプルを、各サンプルのタンパク質量が１０μｇになるようにして１０％アクリルアミドゲルを用いたポリアクリルアミドゲル電気泳動（ＳＤＳ−ＰＡＧＥ）に供した。タンパク質をＰＶＤＦ膜に転写後、１次抗体として抗ｐＡＭＰＫ抗体（Ｃｅｌｌ ｓｉｇｎａｌｉｎｇ社製、＃２５３５）または抗ＡＭＰＫ抗体（Ｃｅｌｌ ｓｉｇｎａｌｉｎｇ社製、＃５８３１）、２次抗体としてＨＲＰ標識抗ウサギＩｇＧ抗体（Ｓａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ社製、＃ｓｃ−２００４）、及び検出試薬としてＭｉｌｌｉｐｏｒｅ Ｉｍｍｏｂｉｌｏｎ Ｗｅｓｔｅｒｎを用いて、リン酸化されたＡＭＰＫ（ｐＡＭＰＫ）又はＡＭＰＫを検出した。検出されたバンドの画像から、画像解析ソフト（ＩｍａｇｅＪ、ＮＩＨ）を用いてｐＡＭＰＫ及びＡＭＰＫの発現量を定量化し、ＡＭＰＫリン酸化活性の指標としてｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図１に示す。 Samples for electrophoresis were subjected to polyacrylamide gel electrophoresis (SDS-PAGE) using 10% acrylamide gel so that the amount of protein in each sample was 10 μg. After transferring the protein to a PVDF membrane, an anti-pAMPK antibody (Cell Signaling, # 2535) or an anti-AMPK antibody (Cell Signaling, # 5831) is used as a primary antibody, and an HRP-labeled anti-rabbit IgG antibody (Santa) is used as a secondary antibody. Phosphorylated AMPK (pAMPK) or AMPK was detected using Cruz Biotechnology, # sc-2004) and Millipore Immobilon Western as a detection reagent. From the detected band image, the expression levels of pAMPK and AMPK were quantified using image analysis software (ImageJ, NIH), and the pAMPK / AMPK ratio was calculated as an index of AMPK phosphorylation activity. The result is shown in FIG.
図１に示したように、フィトエン、フィトフルエン、β−カロテン（オールトランス体）、トルレン、リコピン（オールトランス体）及び陽性コントロールであるアディポロンは、ｐＡＭＰＫ／ＡＭＰＫ比を上昇させ、ＡＭＰＫをリン酸化させることが確認された。それに対し、レチノール及びゲラニルゲラニオール（ＧＧＯＨ）は、ｐＡＭＰＫ／ＡＭＰＫ比を上昇させず、ＡＭＰＫをリン酸化させないことが確認された。 As shown in FIG. 1, phytoene, phytofluene, β-carotene (all-trans form), tolylene, lycopene (all-trans form) and positive control adipolone increase the pAMPK / AMPK ratio and phosphorylate AMPK. It was confirmed that On the other hand, it was confirmed that retinol and geranylgeraniol (GGOH) do not increase the pAMPK / AMPK ratio and do not phosphorylate AMPK.
［実施例２］
被験薬として、α−カロテン及びフコキサンチンを用い、実施例１と同様にして、ｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図２に示す。
図２に示したように、α−カロテン及びフコキサンチンは、ｐＡＭＰＫ／ＡＭＰＫ比を上昇させ、ＡＭＰＫをリン酸化させることが確認された。
[Example 2]
As the test drug, α-carotene and fucoxanthin were used, and the pAMPK / AMPK ratio was calculated in the same manner as in Example 1. The result is shown in FIG.
As shown in FIG. 2, it was confirmed that α-carotene and fucoxanthin increase the pAMPK / AMPK ratio and phosphorylate AMPK.
［実施例３］
実施例１で分化誘導して３日目のマウス筋芽細胞株Ｃ２Ｃ１２を、２％ウマ血清を含むＤＭＥＭで１回洗浄後、ＤＭＥＭを６００μＬ／ウェル加えた。
Ｏｐｔｉ−ＭＥＭ Ｉ Ｒｅｄｕｃｅｄ Ｓｅｒｕｍ Ｍｅｄｉｕｍ（ｉｎｖｉｔｒｏｇｅｎ社製、以下、Ｏｐｔｉ−ＭＥＭと略記する）６０μＬにＬｉｐｏｆｅｃｔａｍｉｎｅ ２０００（ｉｎｖｉｔｒｏｇｅｎ社製）を５μＬ添加し、５分間室温にて静置した。
一方、別のＯｐｔｉ−ＭＥＭ ６０μＬに、配列番号１で表される塩基配列からなるセンス鎖と、配列番号２で表されるアンチセンス鎖とからなるｓｉＲＮＡ（ＱＩＡＧＥＮ社製、Ｍｍ＿Ａｄｉｐｏｒ１＿３、＃ＳＩ００８９０３０９）またはコントロールｓｉＲＮＡ（ＳＩＧＭＡ−ＡＬＤＲＩＣＨ社製、ＭＩＳＳＩＯＮ ｓｉＲＮＡ Ｕｎｉｖｅｒｓａｌ Ｎｅｇａｔｉｖｅ Ｃｏｎｔｒｏｌ、＃ＳＩＣ−００１）を６０ｐｍｏｌ添加し、ここに５分間静置した前述のＬｉｐｏｆｅｃｔａｍｉｎｅ ２０００含有Ｏｐｔｉ−ＭＥＭ ６０μＬを加え緩やかに混和して２０分間室温で静置した。
２０分後、計１２０μＬの上記Ｏｐｔｉ−ＭＥＭを、前述の６００μＬ／ウェルのＤＭＥＭで培養中のＣ２Ｃ１２に添加し、２日間培養した。２日後、実施例１と同様の方法で、β−カロテン（オールトランス体）をＣ２Ｃ１２に１０分間反応させ、ｐＡＭＰＫ及びＡＭＰＫの発現量の定量及びＡＭＰＫリン酸化活性の算出を行った。
[Example 3]
The mouse myoblast cell line C2C12 of which differentiation was induced in Example 1 was washed once with DMEM containing 2% horse serum, and then DMEM was added at 600 μL / well.
5 μL of Lipofectamine 2000 (manufactured by Invitrogen) was added to 60 μL of Opti-MEM I Reduced Serum Medium (manufactured by Invitrogen, hereinafter abbreviated as Opti-MEM), and allowed to stand at room temperature for 5 minutes.
On the other hand, in another Opti-MEM 60 μL, siRNA consisting of a sense strand consisting of the base sequence represented by SEQ ID NO: 1 and an antisense strand represented by SEQ ID NO: 2 (manufactured by QIAGEN, Mm_Adipor1_3, # SI00890309) or 60 pmol of control siRNA (manufactured by SIGMA-ALDRICH, MISSION siRNA Universal Negative Control, # SIC-001) was added, and the above-mentioned Lipofectamine 2000-containing Opti-MEM 60 μL, which was allowed to stand for 5 minutes, was gently mixed for 20 minutes. Allowed to stand at room temperature.
After 20 minutes, a total of 120 μL of the Opti-MEM was added to the C2C12 being cultured in the above-mentioned 600 μL / well of DMEM and cultured for 2 days. Two days later, β-carotene (all-trans form) was reacted with C2C12 for 10 minutes in the same manner as in Example 1, and the expression levels of pAMPK and AMPK were quantified and the AMPK phosphorylation activity was calculated.
その結果を図３に示す。図３において、「コントロール ｓｉＲＮＡ」は、ＡｄｉｐｏＲをノックダウンしない系でのｐＡＭＰＫ／ＡＭＰＫ比、「ＡｄｉｐｏＲ ｓｉＲＮＡ」は、ＡｄｉｐｏＲをｓｉＲＮＡによりノックダウンした系でのｐＡＭＰＫ／ＡＭＰＫ比をそれぞれ示す。
図３に示したように、ｐＡＭＰＫ／ＡＭＰＫ比は、β−カロテン（オールトランス体）の添加により上昇し、当該β−カロテンにより上昇したｐＡＭＰＫ／ＡＭＰＫ比は、ＡｄｉｐｏＲのノックダウンにより抑制された。
このことから、実施例１で見られた、β−カロテン（オールトランス体）によるＡＭＰＫのリン酸化は、ＡｄｉｐｏＲの活性化によるものであることが明らかとなった。
The result is shown in FIG. In FIG. 3, “control siRNA” indicates the pAMPK / AMPK ratio in a system that does not knock down AdipoR, and “AdipoR siRNA” indicates the pAMPK / AMPK ratio in a system in which AdipoR is knocked down by siRNA.
As shown in FIG. 3, the pAMPK / AMPK ratio was increased by the addition of β-carotene (all-trans form), and the pAMPK / AMPK ratio increased by the β-carotene was suppressed by knockdown of AdipoR.
From this, it became clear that phosphorylation of AMPK by β-carotene (all-trans form) seen in Example 1 was due to activation of AdipoR.
［実施例４］
β−カロテン（オールトランス体）の代わりに、リコピン（オールトランス体）を用い、実施例３と同様にして、ｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図４に示す。図４に示したように、ｐＡＭＰＫ／ＡＭＰＫ比は、リコピン（オールトランス体）の添加により上昇し、当該リコピンの添加により上昇したｐＡＭＰＫ／ＡＭＰＫ比は、ＡｄｉｐｏＲのノックダウンにより抑制された。
このことから、実施例１で見られた、リコピン（オールトランス体）によるＡＭＰＫのリン酸化は、ＡｄｉｐｏＲの活性化によるものであることが明らかとなった。
[Example 4]
A pAMPK / AMPK ratio was calculated in the same manner as in Example 3 except that lycopene (all-trans form) was used instead of β-carotene (all-trans form). The result is shown in FIG. As shown in FIG. 4, the pAMPK / AMPK ratio was increased by the addition of lycopene (all-trans form), and the pAMPK / AMPK ratio increased by the addition of the lycopene was suppressed by knockdown of AdipoR.
From this, it became clear that phosphorylation of AMPK by lycopene (all-trans form) seen in Example 1 was due to activation of AdipoR.
［実施例５］
（トマトのＭＴＢＥ抽出物の製造）
液体窒素を用いて凍結破砕したトマトを、氷上にて蓋付きのチューブに約１５０ｍｇ秤量し、トマト１５０ｍｇに対してメタノール: メチルｔｅｒｔ−ブチルエーテル＝１：３の溶媒を６００μＬ添加した。ビーズ破砕機を用いて溶媒内でトマトを破砕した後、２分間超音波処理を行った。トマト破砕物から色が抜けていることを確認後、チューブにメタノール：水＝１：３の溶媒を６００μＬ加え転倒混和し、４℃、１００００Ｇで５分間遠心分離した。溶液が２層に分離していることを確認後、橙色の上清を回収した。これを遠心エバポレーターにより乾固させることによりトマトのＭＴＢＥ抽出物を得た。
[Example 5]
(Manufacture of MTBE extract of tomato)
About 150 mg of tomato frozen and crushed using liquid nitrogen was weighed in a tube with a lid on ice, and 600 μL of a solvent of methanol: methyl tert-butyl ether = 1: 3 was added to 150 mg of tomato. After crushing tomatoes in a solvent using a bead crusher, sonication was performed for 2 minutes. After confirming that the color was removed from the crushed tomato, 600 μL of methanol: water = 1: 3 solvent was added to the tube and mixed by inversion, followed by centrifugation at 4 ° C. and 10,000 G for 5 minutes. After confirming that the solution was separated into two layers, the orange supernatant was recovered. This was dried with a centrifugal evaporator to obtain an MTBE extract of tomato.
（トマトの８０％メタノール抽出物の製造）
液体窒素を用いて凍結破砕したトマトを７２時間凍結乾燥させた。その乾燥粉末約５０ｍｇを蓋付きのチューブに秤量し、トマト５０ｍｇに対して８０％メタノールを１ｍＬ添加した。ビーズ破砕機を用いて８０％メタノール中でトマトを破砕した後、１５，０００ｒｐｍ、４℃で１０分間遠心分離し、上清を回収した。回収した上清の一部を新しいチューブに移し、上清と等量の水を加えた後、転倒混和した。さらに、上清の１．２倍量のメタノール: メチルｔｅｒｔ−ブチルエーテル＝１：３の溶媒を加え、転倒混和後、４℃、１００００Ｇ、５分間遠心分離した。溶液が２層に分離していることを確認後、橙色の上清を除去し、下層の溶液を回収した。これを遠心エバポレーターにより乾固させることでトマトの８０％メタノール抽出物を得た。
(Production of 80% methanol extract of tomato)
Tomatoes frozen and crushed using liquid nitrogen were lyophilized for 72 hours. About 50 mg of the dried powder was weighed into a tube with a lid, and 1 mL of 80% methanol was added to 50 mg of tomato. After crushing tomatoes in 80% methanol using a bead crusher, the tomato was centrifuged at 15,000 rpm and 4 ° C. for 10 minutes, and the supernatant was collected. A part of the collected supernatant was transferred to a new tube, and the same amount of water as the supernatant was added, and then mixed by inversion. Furthermore, 1.2 times the amount of the supernatant, methanol: methyl tert-butyl ether = 1: 3 solvent was added, and the mixture was mixed by inversion, followed by centrifugation at 4 ° C. and 10,000 G for 5 minutes. After confirming that the solution was separated into two layers, the orange supernatant was removed, and the lower layer solution was recovered. This was dried by a centrifugal evaporator to obtain an 80% methanol extract of tomato.
（各抽出物のＡＭＰＫリン酸化活性の評価）
１０％ウシ胎児血清、１％Ｐ／Ｓを加えた高グルコースＤＭＥＭを使用し、マウス筋芽細胞株Ｃ２Ｃ１２を１２ウェルプレートに２×１０５細胞／ウェルで播種した。３日後、２％ウマ血清、１％Ｐ／Ｓを含むＤＭＥＭを分化誘導培地として使用して培地交換を行った。その後、２日おきに分化誘導培地の交換を行い、５日間分化誘導を行った。５日後、無血清のＤＭＥＭで一晩培養した。
(Evaluation of AMPK phosphorylation activity of each extract)
Using a high glucose DMEM supplemented with 10% fetal bovine serum and 1% P / S, the mouse myoblast cell line C2C12 was seeded in a 12-well plate at 2 × 10 5 cells / well. Three days later, the medium was changed using DMEM containing 2% horse serum and 1% P / S as a differentiation-inducing medium. Thereafter, the differentiation induction medium was changed every 2 days, and differentiation induction was performed for 5 days. After 5 days, the cells were cultured overnight in serum-free DMEM.
一晩培養後、Ｃ２Ｃ１２の培養液を除去し、被験薬として、上記で得られたトマトのＭＴＢＥ抽出物、トマトの８０％メタノール抽出物、並びに、陽性コントロールとしてアディポロン（ＡｄｉｐｏＲｏｎ）を用い、各被験薬を１μＭ（アディポロンは５０μＭ）となるように溶解した無血清のＤＭＥＭを添加して１０分間培養することで、被験薬をＣ２Ｃ１２に１０分間反応させた。なお、トマトのＭＴＢＥ抽出物の溶媒としてジメチルスルホキシド（ＤＭＳＯ）を、トマトの８０％メタノール抽出物の溶媒として水を、それぞれ使用し、ＤＭＥＭ中の溶媒の最終濃度が１．０％になるようにして各被験薬を添加した。コントロールとしては、各抽出物に用いたものと同じ溶媒を１．０％含むＤＭＥＭを用いた。アディポロンの溶媒にはＤＭＳＯを用いた。
反応後、実施例１と同様にして、ポリアクリルアミドゲル電気泳動（ＳＤＳ−ＰＡＧＥ）を行い、リン酸化されたＡＭＰＫ（ｐＡＭＰＫ）又はＡＭＰＫを検出した。検出されたバンドの画像から、画像解析ソフト（ＩｍａｇｅＪ、ＮＩＨ）を用いてｐＡＭＰＫ及びＡＭＰＫの発現量を定量化し、ＡＭＰＫリン酸化活性の指標としてｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図５に示す。
図５に示したように、トマトのＭＴＢＥ抽出物及び陽性コントロールであるアディポロンは、ｐＡＭＰＫ／ＡＭＰＫ比を上昇させ、ＡＭＰＫをリン酸化させることが確認された。それに対し、トマトの８０％メタノール抽出物は、ｐＡＭＰＫ／ＡＭＰＫ比を上昇させず、ＡＭＰＫをリン酸化させないことが確認された。
After overnight culture, the C2C12 culture solution was removed and each test was conducted using MTBE extract of tomato obtained above, 80% methanol extract of tomato as a test drug, and AdipoRon as a positive control. The test drug was allowed to react with C2C12 for 10 minutes by adding serum-free DMEM in which the drug was dissolved at 1 μM (adipolone was 50 μM) and culturing for 10 minutes. It should be noted that dimethyl sulfoxide (DMSO) is used as a solvent for MTBE extract of tomato and water is used as a solvent of 80% methanol extract of tomato so that the final concentration of the solvent in DMEM is 1.0%. Each test drug was added. As a control, DMEM containing 1.0% of the same solvent as used for each extract was used. DMSO was used as a solvent for adipolone.
After the reaction, polyacrylamide gel electrophoresis (SDS-PAGE) was performed in the same manner as in Example 1 to detect phosphorylated AMPK (pAMPK) or AMPK. From the detected band image, the expression levels of pAMPK and AMPK were quantified using image analysis software (ImageJ, NIH), and the pAMPK / AMPK ratio was calculated as an index of AMPK phosphorylation activity. The result is shown in FIG.
As shown in FIG. 5, it was confirmed that MTBE extract of tomato and adipolone as a positive control increased the pAMPK / AMPK ratio and phosphorylated AMPK. On the other hand, it was confirmed that 80% methanol extract of tomato does not raise the pAMPK / AMPK ratio and does not phosphorylate AMPK.
［実施例６］
β−カロテン（オールトランス体）の代わりに、実施例５で得られたトマトのＭＴＢＥ抽出物を１００μｇ／ｍＬ用いる以外は、実施例３と同様にして、ｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図６に示す。
図６に示したように、ｐＡＭＰＫ／ＡＭＰＫ比は、トマトのＭＴＢＥ抽出物の添加により上昇し、当該ＭＴＢＥ抽出物により上昇したｐＡＭＰＫ／ＡＭＰＫ比は、ＡｄｉｐｏＲのノックダウンにより抑制された。
このことから、実施例５で見られた、トマトのＭＴＢＥ抽出物によるＡＭＰＫのリン酸化は、ＡｄｉｐｏＲの活性化によるものであることが明らかとなった。
[Example 6]
The pAMPK / AMPK ratio was calculated in the same manner as in Example 3 except that 100 μg / mL of the MTBE extract of tomato obtained in Example 5 was used instead of β-carotene (all-trans form). The result is shown in FIG.
As shown in FIG. 6, the pAMPK / AMPK ratio was increased by the addition of tomato MTBE extract, and the pAMPK / AMPK ratio increased by the MTBE extract was suppressed by knockdown of AdipoR.
From this, it became clear that phosphorylation of AMPK by the MTBE extract of tomato seen in Example 5 was due to activation of AdipoR.
［実施例７］
（シス体リコピンの調製）
リコピン（オールトランス体；以下、オールトランスリコピンともいう）をクロロホルムに溶解し、５０℃で一晩加温した。加温後、遠心濃縮器でクロロホルムを留去し乾固させ、−８０℃にて冷凍保存した。
上記で得られた乾固物をメタノール: メチルｔｅｒｔ−ブチルエーテル＝１：１の溶媒に溶解し、分取ＨＰＬＣ（Ｐｒｏｍｉｎｅｎｃｅシステム、島津製作所）を用いて、シス体リコピン（以下、シスリコピンともいう）である、１３−シスリコピンを分取後、乾固させた。
[Example 7]
(Preparation of cis lycopene)
Lycopene (all-trans isomer; hereinafter, also referred to as all-trans-lycopene) was dissolved in chloroform and heated at 50 ° C. overnight. After heating, chloroform was distilled off with a centrifugal concentrator to dryness, and stored frozen at -80 ° C.
The dried product obtained above is dissolved in a solvent of methanol: methyl tert-butyl ether = 1: 1, and cis-lycopene (hereinafter, also referred to as cis-lycopene) using preparative HPLC (Prominence system, Shimadzu Corporation). After separating 13-cis lycopene, the mixture was dried.
（シスリコピンのＡＭＰＫリン酸化活性の評価）
被験薬として、オールトランスリコピン、及び、上記で得られた１３−シスリコピンを、それぞれ０．２％Ｔｗｅｅｎ−２０を含むテトラヒドロフランに溶解したものを用い、実施例１と同様にして、ｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図７に示す。
図７に示したように、１３−シスリコピンは、オールトランスリコピンよりも強くｐＡＭＰＫ／ＡＭＰＫ比を上昇させ、シスリコピンは、オールトランスリコピンよりも強くＡＭＰＫをリン酸化させることが確認された。
(Evaluation of AMPK phosphorylation activity of cis-lycopene)
As test drugs, all-trans lycopene and 13-cis lycopene obtained above were dissolved in tetrahydrofuran each containing 0.2% Tween-20, and the same as in Example 1, pAMPK / AMPK The ratio was calculated. The result is shown in FIG.
As shown in FIG. 7, it was confirmed that 13-cis lycopene increases the pAMPK / AMPK ratio more strongly than all-trans lycopene, and cis-lycopene phosphorylates AMPK more strongly than all-trans lycopene.
［実施例８］
（シス体β−カロテンのＡＭＰＫリン酸化活性の評価）
被験薬として、β−カロテン（オールトランス体；以下、オールトランスβ−カロテンともいう）及び、シス体β−カロテン（以下、シスβ−カロテンともいう）である、９−シスβ−カロテン及び１３−シスβ−カロテンを用い、実施例１と同様にして、ｐＡＭＰＫ／ＡＭＰＫ比を算出した。その結果を図８に示す。
図８に示したように、９−シスβ−カロテン及び１３−シスβ−カロテンは、オールトランスβ−カロテンよりも強くｐＡＭＰＫ／ＡＭＰＫ比を上昇させ、シスβ−カロテンは、オールトランスβ−カロテンよりも強くＡＭＰＫをリン酸化させることが確認された。
[Example 8]
(Evaluation of AMPK phosphorylation activity of cis-form β-carotene)
As test drugs, 9-cis β-carotene and 13 which are β-carotene (all-trans form; hereinafter also referred to as all-trans β-carotene) and cis-form β-carotene (hereinafter also referred to as cis β-carotene). -The pAMPK / AMPK ratio was calculated in the same manner as in Example 1 using cis β-carotene. The result is shown in FIG.
As shown in FIG. 8, 9-cis β-carotene and 13-cis β-carotene increase the pAMPK / AMPK ratio more strongly than all-trans β-carotene, and cis β-carotene is all-trans β-carotene. It was confirmed that AMPK was phosphorylated more strongly than that.
本発明に係るトマト由来のカロテノイド、又はフィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイド、或いはトマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、ＡｄｉｐｏＲ作動薬は、優れたＡｄｉｐｏＲ活性化作用を有し、アディポネクチンの低下により引き起こされる２型糖尿病や肥満等の疾患の治療剤及び／又は予防剤として利用可能である。また、本発明に係るトマト由来のカロテノイド、又はフィトエン、フィトフルエン、β−カロテン、トルレン、リコピン、α−カロテン、及びフコキサンチンからなる群から選ばれる少なくとも１種のカロテノイド、或いはトマトから、メタノールとメチルｔｅｒｔ−ブチルエーテルとの混合溶媒を用いて抽出された抽出物を有効成分として含有する、ＡｄｉｐｏＲ作動用食品組成物は、優れたＡｄｉｐｏＲ活性化作用を有し、２型糖尿病や肥満等の疾患の治療及び／又は予防用食品組成物として利用可能である。 Tomato-derived carotenoid according to the present invention, or at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin, or tomato, methanol and methyl tert -AdipoR agonist containing an extract extracted using a mixed solvent with butyl ether as an active ingredient has an excellent AdipoR activation action, and diseases such as type 2 diabetes and obesity caused by adiponectin decrease It can be used as a therapeutic and / or prophylactic agent. Further, from the tomato-derived carotenoid according to the present invention, or at least one carotenoid selected from the group consisting of phytoene, phytofluene, β-carotene, tolylene, lycopene, α-carotene, and fucoxanthin, or tomato, and methanol The food composition for AdipoR operation, which contains an extract extracted using a mixed solvent with methyl tert-butyl ether as an active ingredient, has an excellent AdipoR activation action, and is effective for diseases such as type 2 diabetes and obesity. It can be used as a food composition for treatment and / or prevention.
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