JP2015117207A - Fat accumulation inhibitor - Google Patents
Fat accumulation inhibitor Download PDFInfo
- Publication number
- JP2015117207A JP2015117207A JP2013261944A JP2013261944A JP2015117207A JP 2015117207 A JP2015117207 A JP 2015117207A JP 2013261944 A JP2013261944 A JP 2013261944A JP 2013261944 A JP2013261944 A JP 2013261944A JP 2015117207 A JP2015117207 A JP 2015117207A
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- Prior art keywords
- fat accumulation
- fat
- white
- butter oil
- accumulation inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
本発明は、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより善玉アディポカインの産生を促進する作用や、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進する作用を有し、生体内での脂肪蓄積抑制効果に優れ、メタボリックシンドロームの予防や治療に有用で、安定性及び安全性に優れた脂肪蓄積抑制剤に関する。本発明は、さらに該脂肪蓄積抑制剤を含有する、脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料又は脂肪蓄積抑制用医薬品に関する。 The present invention has the effect of promoting the production of good adipokines by promoting the differentiation of white fat precursor cells into small white fat cells, promoting the differentiation of white fat precursor cells into brown fat cells, A fat accumulation inhibitor that has an action to enhance energy metabolism by activating cells, has an excellent fat accumulation suppressing effect in vivo, is useful for prevention and treatment of metabolic syndrome, and has excellent stability and safety. About. The present invention further relates to a food product for inhibiting fat accumulation, a nutrition composition for inhibiting fat accumulation, a feed for inhibiting fat accumulation, or a pharmaceutical product for inhibiting fat accumulation, which further comprises the fat accumulation inhibitor.
近年、我が国のみならず世界的な、生活習慣、特に、食習慣の変化に伴い、先進国を中心とした糖尿病や高血圧、脂質代謝異常症、動脈硬化症等の疾患の増加が大きな社会問題となっている。また、我が国では、循環器系の疾患である心血管疾患と脳血管疾患が死因の約３分の１を占め、その数が年々増加し医療費を圧迫しているため、国政レベルの対策が講じられている。このような生活習慣に起因する疾病は、我が国では生活習慣病と呼ばれており、生体内での過剰な脂肪蓄積がその主要な要因一つと考えられている。また、過剰な脂肪蓄積に伴う肥満に加え、高血圧や高脂血症、耐糖能障害等のリスクファクターが一個人に集積した状態はメタボリックシンドロームとして、広く認識されており、最近では、ヒト以外の哺乳動物、特に、家庭で飼育されているペット等においても、生体内での過剰な脂肪の蓄積が寿命を短縮させることが、動物愛護の観点から大きな社会問題となっている。 In recent years, not only in Japan but also globally, lifestyle changes, especially dietary habits, have led to an increase in diseases such as diabetes, hypertension, dyslipidemia and arteriosclerosis, which are major social problems, mainly in developed countries. It has become. In Japan, cardiovascular and cerebrovascular diseases, which are cardiovascular diseases, account for about one-third of the causes of death, and the number of deaths is increasing year by year, and medical costs are under pressure. Has been taken. Such a disease caused by lifestyle is called a lifestyle-related disease in Japan, and excessive fat accumulation in vivo is considered as one of the main factors. In addition to obesity associated with excessive fat accumulation, risk conditions such as hypertension, hyperlipidemia, and impaired glucose tolerance have been widely recognized as a metabolic syndrome. In animals, particularly pets kept at home, accumulation of excessive fat in the living body shortens the lifespan, which is a big social problem from the viewpoint of animal welfare.
白色脂肪組織は白色脂肪細胞から構成されており、白色脂肪細胞は生体内の過剰なエネルギーを脂肪として蓄える働きを有する。また、白色脂肪細胞に脂肪が蓄積して肥大化するとともに、白色脂肪細胞が分化し、その数が増加した状態は肥満と呼ばれている。したがって、白色脂肪前駆細胞から白色脂肪細胞への分化を抑制し、白色脂肪細胞の数を減少させることによって、生体内の過剰な脂肪の蓄積を抑制することが可能である。また、白色脂肪細胞はアディポネクチンやＴＮＦ−α、レジスチンなどのアディポカインや遊離脂肪酸をはじめとする様々な物質を分泌することが知られている。最近の研究では、肥大化した脂肪細胞のアポトーシスを促進したり、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより、肥大化した脂肪細胞を小型の脂肪細胞に置き換えることによって、アディポネクチン等、インスリン抵抗性を改善する善玉アディポカインの分泌を促進し、ＴＮＦ−αやレジスチン等、インスリン抵抗性を惹起する悪玉アディポカインや遊離脂肪酸等の分泌を抑制して、生体内の過剰な脂肪蓄積を抑制できることが報告されている（特許文献１、２）。
また、褐色脂肪細胞は、白色脂肪細胞と同様に脂肪を貯蔵するものの、ミトコンドリアに存在する脱共役タンパク質１（ｕｎｃｏｕｐｌｉｎｇ ｐｒｏｔｅｉｎ １：ＵＣＰ１）の働きにより、電子伝達系におけるＡＴＰ合成を経ずに脂肪を熱へ変換する。生体内では、白色脂肪細胞によるエネルギーの貯蔵ならびにＡＴＰ合成系を介したエネルギーの補給と、褐色脂肪細胞の熱産生によるエネルギーの消費により、全身のエネルギー消費や体脂肪の調節が行われていると考えられている。最近の研究では、褐色脂肪細胞には胚発生初期時にすでに細胞運命が決定している「既存型」と成人において様々な環境要因等により白色脂肪細胞から分化誘導される「誘導型」の２種類が存在することが分かっている（非特許文献１）。ヒトでは、「既存型」の褐色脂肪細胞は、肩甲骨周辺と首の後ろ、わきの下など限られた場所に少量存在し、加齢とともに減少するが、長期の寒冷刺激やＰＰＡＲγアゴニストの投与などの環境要因等により、成人の白色脂肪組織に存在する白色脂肪前駆細胞が「誘導型」の褐色脂肪細胞に分化することが報告されている。したがって、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進して、生体における過剰な脂肪の蓄積を抑制し、メタボリックシンドローム等を予防または改善することが可能である。
The white adipose tissue is composed of white adipocytes, and the white adipocytes have a function of storing excess energy in the living body as fat. In addition, fat is accumulated in white fat cells to be enlarged, and the state in which white fat cells are differentiated and increased in number is called obesity. Therefore, it is possible to suppress the accumulation of excess fat in the living body by suppressing the differentiation from white fat precursor cells to white fat cells and reducing the number of white fat cells. White adipocytes are known to secrete various substances including adipokines such as adiponectin, TNF-α, resistin, and free fatty acids. Recent studies have shown that by replacing hypertrophic adipocytes with small adipocytes by promoting apoptosis of enlarged adipocytes or by promoting differentiation from white adipose precursor cells to small white adipocytes. Promotes the secretion of good adipokines that improve insulin resistance, such as adiponectin, and suppresses the secretion of bad adipokines and free fatty acids that cause insulin resistance, such as TNF-α and resistin, to increase excess fat in the body It has been reported that accumulation can be suppressed (Patent Documents 1 and 2).
Brown adipocytes store fat in the same way as white adipocytes. However, brown adipocytes do not undergo ATP synthesis in the electron transport system by the action of uncoupling protein 1 (UCP1) present in mitochondria. Convert to heat. In vivo, energy storage and body fat are regulated by whole body by storing energy by white adipocytes, supplementing energy through ATP synthesis system, and consuming energy by heat production of brown adipocytes. It is considered. In recent studies, there are two types of brown adipocytes: the “existing type” whose cell fate has already been determined at the early stage of embryo development and the “induced type” that is induced to differentiate from white adipocytes by various environmental factors in adults. (Non-patent Document 1). In humans, “existing” brown adipocytes are present in small amounts around the scapula, at the back of the neck, under the armpits, and decrease with age, but such as long-term cold stimulation and administration of PPARγ agonists. It has been reported that white adipose precursor cells present in adult white adipose tissue differentiate into “inducible” brown adipocytes due to environmental factors and the like. Therefore, it promotes differentiation from white fat precursor cells to brown adipocytes, or activates brown fat cells to enhance energy metabolism, suppress excessive fat accumulation in the body, prevent metabolic syndrome, etc. Or it can be improved.
従来から、生体内の脂肪の蓄積を抑制する医薬として、肥満治療薬であるオルリスタットや高脂血症の治療薬であるフィブラートなどが知られている。しかし、これらの医薬品を用いた場合、かゆみや食欲不振などの副作用を伴うことがある。また、これらの物質を使用するには医師による処方箋が必要であり、安全性やコストの面から現在のところ飲食品に添加できない状況にある。さらに、生体内の脂肪の蓄積を抑制するためには、生活習慣、特に、食習慣を見直すことが重要であることから、日常的に安全に摂取することが可能で、長期間摂取しても安全上問題のない、脂肪蓄積抑制効果が期待できるような飲食品や飼料の開発が望まれている。 Conventionally, orlistat, which is a therapeutic agent for obesity, and fibrate, which is a therapeutic agent for hyperlipidemia, are known as drugs that suppress the accumulation of fat in the living body. However, these drugs may have side effects such as itching and loss of appetite. Moreover, in order to use these substances, a doctor's prescription is required, and from the viewpoint of safety and cost, it cannot be added to food and drink at present. Furthermore, in order to suppress the accumulation of fat in the living body, it is important to review lifestyle habits, particularly eating habits. There is a demand for the development of foods and drinks and feeds that can be expected to have a fat accumulation-inhibiting effect without safety problems.
牛乳、乳製品は古来より食されてきたことから、日常的に安全に長期間摂取することが可能な食品であり、それらの摂取によって、生体内の脂肪の蓄積が抑制することが疫学調査により報告されている。また、乳に含まれるタンパク質であるκ-カゼインやラクトフェリンには、それぞれ、脂肪細胞における脂肪の蓄積を抑制することや脂質代謝を改善することが知られている（特許文献３、４）。しかしながら、バターオイルに、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより善玉アディポカインの産生を促進する作用や、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進する作用を介した、優れた生体内の脂肪蓄積を抑制する効果があることは知られていない。 Because milk and dairy products have been eaten since ancient times, they are foods that can be consumed safely for a long period of time on a daily basis. It has been reported. In addition, κ-casein and lactoferrin, which are proteins contained in milk, are known to suppress fat accumulation in fat cells and improve lipid metabolism, respectively (Patent Documents 3 and 4). However, butter oil promotes the production of good adipokine by promoting the differentiation from white adipose precursor cells to small white adipocytes, promotes the differentiation from white adipose precursor cells to brown adipocytes, It is not known that there is an excellent effect of suppressing fat accumulation in a living body through the action of enhancing energy metabolism by activating brown adipocytes.
本発明は、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより善玉アディポカインの産生を促進する作用や、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進する作用に優れ、生体内での脂肪の蓄積を抑制し、メタボリックシンドロームの予防または改善に有用で、安定性及び安全性に優れた脂肪蓄積抑制剤、及び該脂肪蓄積抑制剤を配合した脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料又は脂肪蓄積抑制用医薬品を提供することを課題とする。 The present invention has the effect of promoting the production of good adipokines by promoting the differentiation of white fat precursor cells into small white fat cells, promoting the differentiation of white fat precursor cells into brown fat cells, A fat accumulation inhibitor that excels in energy metabolism by activating cells, suppresses fat accumulation in the body, is useful for prevention or improvement of metabolic syndrome, has excellent stability and safety, Another object of the present invention is to provide a fat accumulation-suppressing food and drink, a fat accumulation-suppressing nutritional composition, a fat accumulation-suppressing feed, or a fat accumulation-suppressing pharmaceutical, which contains the fat accumulation inhibitor.
本発明者らは、上記の課題を解決するため鋭意検討を進めたところ、バターオイルに、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより善玉アディポカインの産生を促進する作用や、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進する作用を介した、顕著な生体内の脂肪蓄積抑制効果があることを見出した。
すなわち本発明は、以下の様態を含むものである。
（１）バターオイルを有効成分とする脂肪蓄積抑制剤。
（２）前記バターオイルが牛乳由来であることを特徴とする上記（１）に記載の脂肪蓄積抑制剤。
（３）前記バターオイルを一日あたり５００ｍｇ〜４０００ｍｇ投与することを特徴とする上記（１）乃至（２）に記載の脂肪蓄積抑制剤。
（４）脂肪蓄積抑制効果が善玉アディポカインの分泌を促進することを特徴とする上記（１）乃至（３）に記載の脂肪蓄積抑制剤。
（５）脂肪蓄積抑制効果がエネルギー代謝を亢進することを特徴とする上記（１）乃至（３）に記載の脂肪蓄積抑制剤。
（６）脂肪蓄積抑制効果が、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することを特徴とする上記（１）乃至（４）に記載の脂肪蓄積抑制剤。
（７）脂肪蓄積抑制効果が、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進することを特徴とする上記（１）乃至（３）、（５）に記載の脂肪蓄積抑制剤。
（８）脂肪蓄積抑制効果が、褐色脂肪細胞を活性化することを特徴とする上記（１）乃至（３）、（５）に記載の脂肪蓄積抑制剤。
（９）上記（１）乃至（８）のいずれかに記載の脂肪蓄積抑制剤を含むことを特徴とする脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料又は脂肪蓄積抑制用医薬品。
（１０）上記（１）乃至（８）のいずれかに記載の脂肪蓄積抑制剤を経口摂取することによる脂肪の蓄積を抑制する方法。
The inventors of the present invention have intensively studied to solve the above-mentioned problems. As a result, the butter oil promotes the production of good adipokines by promoting the differentiation of white fat precursor cells into small white fat cells. It has a remarkable effect of suppressing fat accumulation in vivo through the action of promoting differentiation of white adipose precursor cells to brown adipocytes and activating brown adipocytes to enhance energy metabolism. I found it.
That is, the present invention includes the following modes.
(1) A fat accumulation inhibitor comprising butter oil as an active ingredient.
(2) The fat accumulation inhibitor according to (1), wherein the butter oil is derived from milk.
(3) The fat accumulation inhibitor as described in (1) or (2) above, wherein the butter oil is administered at a dose of 500 mg to 4000 mg per day.
(4) The fat accumulation inhibitor according to (1) to (3) above, wherein the fat accumulation inhibitory effect promotes the secretion of good adipokine.
(5) The fat accumulation inhibitor as described in (1) to (3) above, wherein the fat accumulation inhibitory effect enhances energy metabolism.
(6) The fat accumulation inhibitor according to (1) to (4) above, wherein the fat accumulation inhibitory effect promotes differentiation from white fat precursor cells to small white fat cells.
(7) The fat accumulation inhibitor as described in (1) to (3) and (5) above, wherein the fat accumulation inhibitory effect promotes differentiation from white fat precursor cells to brown fat cells.
(8) The fat accumulation inhibitor as described in (1) to (3) and (5) above, wherein the fat accumulation inhibitory effect activates brown adipocytes.
(9) A fat accumulation-inhibiting food or drink, a fat accumulation-inhibiting nutrition composition, a fat accumulation-inhibiting feed or fat, comprising the fat accumulation-inhibiting agent according to any one of (1) to (8) above Accumulation medicine.
(10) A method for suppressing fat accumulation by orally ingesting the fat accumulation inhibitor according to any one of (1) to (8) above.
本発明の脂肪蓄積抑制剤は、白色脂肪前駆細胞から小型の白色脂肪細胞への分化を促進することにより善玉アディポカインの産生を促進する作用や、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進したり、褐色脂肪細胞を活性化することでエネルギー代謝を亢進する作用が顕著であり、脂肪の蓄積を抑制して、糖尿病や高血圧、脂質代謝異常症、動脈硬化症等の生活習慣病や高血圧、高脂血症、耐糖能障害等のリスクファクターが一個人に集積した状態であるメタボリックシンドロームの予防や治療に有用である。また、本発明の脂肪蓄積抑制剤は、哺乳類の乳を原料としているため、簡便且つ経済的に製造することができ、日常的に安全に長期間摂取することが可能である。 The fat accumulation inhibitor of the present invention promotes the production of good adipokines by promoting the differentiation of white adipose precursor cells into small white adipocytes, and promotes the differentiation of white adipose precursor cells into brown adipocytes Or by activating brown adipocytes, the effect of promoting energy metabolism is remarkable, suppressing the accumulation of fat, lifestyle-related diseases such as diabetes, hypertension, dyslipidemia, arteriosclerosis and hypertension It is useful for the prevention and treatment of metabolic syndrome, in which risk factors such as hyperlipidemia and impaired glucose tolerance are accumulated in one individual. Moreover, since the fat accumulation inhibitor of the present invention uses mammalian milk as a raw material, it can be easily and economically produced, and can be safely and regularly ingested for a long period of time.
本発明の脂肪蓄積抑制剤の有効成分であるバターオイルは、乳等省令にて定義されるものであり、公知の方法で調製されたものを使用することが可能である。例えば、生乳から分離したクリームを遠心分離等により脱水して脂肪分を９９．３重量％以上に濃縮したり、常法により製造されたバターを６０℃前後で加温融解した後に遠心分離等によりほとんどすべての水相成分を除去し、脂肪分を９９．３重量％以上に濃縮することにより、バターオイルを調製することが可能であり、必要に応じて炭酸水素ナトリウムや水酸化ナトリウム等のアルカリ製剤を用いて中和することもできる。また、上記のように調製したバターオイルは、凍結乾燥や噴霧乾燥等により乾燥することも可能である。 The butter oil, which is an active ingredient of the fat accumulation inhibitor of the present invention, is defined by a ministerial ordinance such as milk and can be prepared by a known method. For example, the cream separated from raw milk is dehydrated by centrifugation or the like to concentrate the fat to 99.3% by weight or more, or the butter produced by a conventional method is heated and melted at around 60 ° C. and then centrifuged. Butter oil can be prepared by removing almost all water phase components and concentrating the fat to 99.3% by weight or more. If necessary, alkali such as sodium bicarbonate or sodium hydroxide can be used. It can also be neutralized using a formulation. The butter oil prepared as described above can be dried by freeze drying, spray drying, or the like.
本発明のバターオイルは、ヒト、ウシ、水牛、ヤギ、ヒツジ等の哺乳類の乳から調製されるものや、市販されているバターオイル等、すべてのバターオイルを使用することが可能である。 As the butter oil of the present invention, it is possible to use all butter oils such as those prepared from milk of mammals such as humans, cows, buffalos, goats and sheep, and commercially available butter oils.
本発明のバターオイルは、そのまま脂肪蓄積抑制剤として使用してもよいが、必要に応じて、常法に従い、粉末剤、顆粒剤、錠剤、カプセル剤、ドリンク剤等に製剤化して用いることも出来る。また、凍結乾燥や噴霧乾燥等により乾燥したバターオイルについても、そのまま脂肪蓄積抑制剤として使用することも可能であり、常法に従い、製剤化して用いることもできる。
さらに、これらを製剤化した後に、これを栄養剤やヨーグルト、飲料、ウエハース等の飲食品、栄養組成物、飼料及び医薬品に配合することも可能である。
The butter oil of the present invention may be used as a fat accumulation inhibitor as it is, but if necessary, it may be formulated into a powder, granule, tablet, capsule, drink or the like according to a conventional method. I can do it. Also, butter oil dried by freeze drying, spray drying or the like can be used as it is as a fat accumulation inhibitor, and can be formulated and used according to a conventional method.
Furthermore, after formulating these, it is also possible to mix this with foods and beverages such as nutrients, yogurt, beverages, wafers, nutritional compositions, feeds and pharmaceuticals.
本発明の脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料及び脂肪蓄積抑制用医薬品とは、このバターオイルのみを含む場合の他に、安定剤や糖類、脂質、フレーバー、ビタミン、ミネラル、フラボノイド、ポリフェノール等、他の飲食品、飼料及び医薬に通常含まれる原材料等を含有することができる。また、本発明の有効成分であるバターオイルに加えて、脂肪蓄積抑制作用を示す他の成分、例えば、κ−カゼインやラクトフェリン等とともに使用することも可能である。
また、そのような脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料又は脂肪蓄積抑制用医薬品を原材料として、他の飲食品等に通常含まれる原材料等を配合して調製することも可能である。
The food and drink for fat accumulation suppression, the nutrition composition for fat accumulation suppression, the feed for fat accumulation suppression and the medicine for fat accumulation suppression of the present invention include not only the butter oil alone, but also stabilizers, saccharides, lipids, Flavors, vitamins, minerals, flavonoids, polyphenols, and other raw materials usually contained in other foods, feeds and medicines can be contained. Moreover, in addition to the butter oil which is an active ingredient of the present invention, it can be used together with other components exhibiting an action of inhibiting fat accumulation, such as κ-casein and lactoferrin.
In addition, using such a food for suppressing fat accumulation, a nutritional composition for suppressing fat accumulation, a feed for suppressing fat accumulation, or a drug for suppressing fat accumulation as a raw material, the ingredients normally contained in other food and drink are blended. It is also possible to prepare.
脂肪蓄積抑制用飲食品、脂肪蓄積抑制用栄養組成物、脂肪蓄積抑制用飼料及び脂肪蓄積抑制用医薬品におけるバターオイルの配合量については、バターオイルが乳に由来する食品であることから、特に制限はなく、多量の摂取によっても安全性に全く問題はない。但し、本発明で白色脂肪前駆細胞や褐色脂肪前駆細胞等に作用して脂肪蓄積抑制効果を発揮させるためには、成人一人一日あたり本発明のバターオイルを５００ｍｇから４０００ｍｇ、好ましくは、５００ｍｇから２０００ｍｇ経口摂取できるように、飲食品や栄養組成物、飼料及び医薬等への配合量を調整すれば良い。 Regarding the amount of butter oil in fat accumulation-inhibiting foods, fat accumulation-inhibiting nutrition compositions, fat accumulation-inhibiting feeds, and fat accumulation-inhibiting pharmaceuticals, especially because butter oil is a food derived from milk There is no problem with safety even if a large amount is consumed. However, in order to exert a fat accumulation inhibitory effect by acting on white fat precursor cells, brown fat precursor cells, etc. in the present invention, 500 mg to 4000 mg, preferably 500 mg, of the butter oil of the present invention per adult day. What is necessary is just to adjust the compounding quantity to food / beverage products, a nutritional composition, feed, a medicine, etc. so that 2000 mg can be ingested orally.
本発明の脂肪蓄積抑制剤は、上記の有効成分に適当な助剤を添加して任意の形態に製剤化して、経口投与が可能な脂肪蓄積抑制用組成物とすることができる。製剤化に際して、通常使用される充填剤、増量剤、結合剤、崩壊剤、界面活性剤、滑沢剤等の希釈剤又は賦形剤を用いることができる。賦形剤としては、例えばショ糖、乳糖、デンプン、結晶性セルロース、マンニット、軽質無水珪酸、アルミン酸マグネシウム、合成珪酸アルミニウム、メタ珪酸アルミン酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、リン酸水素カルシウム、カルボキシルメチルセルロースカルシウム等の１種又は２種以上を組み合わせて加えることができる。 The fat accumulation-suppressing agent of the present invention can be formulated into an arbitrary form by adding an appropriate auxiliary agent to the above-mentioned active ingredient to obtain a composition for inhibiting fat accumulation that can be administered orally. In the formulation, diluents or excipients such as fillers, extenders, binders, disintegrants, surfactants, lubricants and the like that are usually used can be used. Examples of excipients include sucrose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium aluminate, synthetic aluminum silicate, magnesium magnesium metasilicate, calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate. One or two or more of carboxymethylcellulose calcium and the like can be added in combination.
以下に実施例、試験例を示し、本発明について詳細に説明するが、これらは単に例示するのみであり、本発明はこれらによって何ら限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples. However, these are merely illustrative, and the present invention is not limited thereto.
（バターオイルの製造）
遠心分離機を用いて、生乳から分離したクリーム（脂肪分４７％）１０ｋｇの脂肪分を濃縮して、脂肪分８０％のクリームを調製した。次に、調製したクリームをホモゲナイザーで均質処理した後、遠心分離機と真空チャンバーを用いて脱水処理して、本発明のバターオイル（実施例品１）４．６ｋｇを得た。このようにして得られたバターオイルは、乳脂肪分が９９．８％であり、そのまま本発明の脂肪蓄積抑制剤として使用可能である。
(Manufacture of butter oil)
Using a centrifuge, 10 kg of fat (cream with a fat content of 47%) separated from raw milk was concentrated to prepare a cream with a fat content of 80%. Next, the prepared cream was homogenized with a homogenizer, and then dehydrated using a centrifuge and a vacuum chamber to obtain 4.6 kg of butter oil of the present invention (Example product 1). The butter oil thus obtained has a milk fat content of 99.8% and can be used as it is as the fat accumulation inhibitor of the present invention.
［試験例１］
白色脂肪前駆細胞である３Ｔ３−Ｌ１細胞の白色脂肪細胞への分化に対する、バターオイルの効果を調べた。
３Ｔ３-Ｌ１細胞を１２ウェルプレートに播種し、１０％ウシ胎児血清（ＦＢＳ）を含有する高グルコースダルベッコ変法基礎培地（ＤＭＥＭ）で培養した。コンフルーエントに達してから２日後に、白色脂肪細胞への分化を誘導する物質であるインスリン、イソブチルキサンチン（ＩＢＭＸ）、デキサメタゾン（ＤＥＸ）を、それぞれ１０μｇ／ｍｌ、０．５ｍＭ、０．２５μＭ含む１０％ＦＢＳ含有高グルコースＤＭＥＭに交換して２日間培養した。次に、インスリンを５μｇ／ｍｌ含む１０％ＦＢＳ含有高グルコースＤＭＥＭに交換し、さらに６日間培養した。また、白色脂肪細胞への分化誘導開始時より、上記培地に実施例品１のバターオイル（終濃度：１５０μg／ｍｌ、エタノールに溶解）を添加した。培養後、細胞を冷ホルマリン／ＰＢＳで固定し、０．５％ Ｏｉｌ ｒｅｄ Ｏ染色液を添加し脂肪分を染色した。ＰＢＳで洗浄後、白色脂肪細胞の写真を撮影して、画像解析ソフト（ＩｍａｇｅＪ、ＮＩＨ）を用いて脂肪細胞の面積を測定するとともに、イソプロパノールにより抽出した色素の５１０ｎｍにおける吸光度を測定して細胞内の脂肪蓄積量を半定量化し、白色脂肪細胞への分化の程度を確認した。また、脂肪細胞分化のマスター因子であるＰｐａｒγ２遺伝子の発現を調べるために、培養後の細胞からＴｒｉｚｏｌ試薬（ライフテクノロジー社製）を用いて全ＲＮＡを抽出した。逆転写反応はＨｉｇｈ―Ｃａｐａｃｉｔｙ ｃＤＮＡ Ｒｅｖｅｒｓｅ Ｔｒａｎｓｃｒｉｐｔｉｏｎ Ｋｉｔ（ライフテクノロジー社製）を用いた。得られたｃＤＮＡを使用して、ＳＹＢＲ Ｐｒｅｍｉｘ Ｅｘ ＴａｑＩＩ（タカラバイオ社製）でリアルタイムＰＣＲを用い、Ｐｐａｒγ２遺伝子の発現量を測定した。なお、遺伝子発現量を評価するための内部標準として、１８Ｓ遺伝子の発現量を使用し、解析には以下のプライマーを用いた。
Ｐｐａｒγ２遺伝子の発現解析に用いたプライマー
Ｐｐａｒγ２−Ｆ；ｔｇｃｔｇｔｔａｔｇｇｇｔｇａａａｃｔｃｔｇ
Ｐｐａｒγ２−Ｒ；ｃｔｇｔｇｔｃａａｃｃａｔｇｇｔａａｔｔｔｃｔｔ
その結果、表１から表３に示したように、バターオイルの添加により、脂肪蓄積量とＰｐａｒγ２遺伝子の発現量が有意に高値を示したものの、コントロールに比べ、白色脂肪細胞の平均面積が有意に減少した。したがって、本発明のバターオイルは白色脂肪前駆細胞から白色脂肪細胞への分化を促進するものの、分化した白色脂肪細胞は小型であることがわかった。
[Test Example 1]
The effect of butter oil on the differentiation of 3T3-L1 cells, which are white adipose precursor cells, into white adipocytes was examined.
3T3-L1 cells were seeded in 12-well plates and cultured in high glucose Dulbecco's modified basic medium (DMEM) containing 10% fetal bovine serum (FBS). Two days after reaching confluence, 10 μg / ml, 0.5 mM, and 0.25 μM each of insulin, isobutylxanthine (IBMX), and dexamethasone (DEX), which are substances that induce differentiation into white adipocytes, are obtained. The medium was replaced with high glucose DMEM containing% FBS and cultured for 2 days. Next, the medium was replaced with high glucose DMEM containing 10% FBS containing 5 μg / ml of insulin, and further cultured for 6 days. Also, butter oil of Example Product 1 (final concentration: 150 μg / ml, dissolved in ethanol) was added to the medium from the start of differentiation induction into white adipocytes. After culturing, the cells were fixed with cold formalin / PBS, and 0.5% Oil red O staining solution was added to stain the fat. After washing with PBS, a photograph of white adipocytes is taken, the area of adipocytes is measured using image analysis software (ImageJ, NIH), and the absorbance at 510 nm of the dye extracted with isopropanol is measured to determine the intracellular level. The amount of accumulated fat was semi-quantified, and the degree of differentiation into white adipocytes was confirmed. In addition, in order to examine the expression of the Pparγ2 gene, which is a master factor for adipocyte differentiation, total RNA was extracted from the cultured cells using Trizol reagent (Life Technologies). For the reverse transcription reaction, High-Capacity cDNA Reverse Transcription Kit (manufactured by Life Technology) was used. Using the obtained cDNA, the expression level of Pparγ2 gene was measured using real-time PCR with SYBR Premix Ex TaqII (manufactured by Takara Bio Inc.). As an internal standard for evaluating the gene expression level, the expression level of 18S gene was used, and the following primers were used for the analysis.
Primer Pparγ2-F used for expression analysis of Pparγ2 gene; tgctgttatgggggaaaactctg
Pparγ2-R; ctgtgtcaacccatggtattttctt
As a result, as shown in Tables 1 to 3, although the fat accumulation amount and the expression level of the Pparγ2 gene were significantly increased by the addition of butter oil, the average area of white adipocytes was significantly higher than that of the control. Decreased. Therefore, it was found that the butter oil of the present invention promotes differentiation from white fat precursor cells to white fat cells, but the differentiated white fat cells are small.
※は、コントロール（無添加）と比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (no addition) (p <0.05).
※は、コントロール（無添加）と比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (no addition) (p <0.05).
※は、コントロール（無添加）と比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (no addition) (p <0.05).
［試験例２］
白色脂肪前駆細胞である３Ｔ３−Ｌ１細胞の褐色脂肪細胞への分化に対する、バターオイルの効果を調べた。
３Ｔ３-Ｌ１細胞を１２ウェルプレートに播種し、１０％ＦＢＳ含有高グルコースＤＭＥＭで培養した。コンフルーエントに達してから２日後に、褐色脂肪細胞へ分化させるために、インスリン、ＩＢＭＸ、ＤＥＸ、トリヨードサイロニン（Ｔ３）をそれぞれ１０μｇ／ｍｌ、０．５ｍＭ、０．２５μＭ、５０ｎＭ含む１０％ＦＢＳ含有高グルコースＤＭＥＭに交換して２日間培養した。次に、インスリン、ＩＢＭＸ、Ｔ３、ロジグリタゾン、Ａ−８３−０１をそれぞれ５μｇ／ｍｌ、０．５ｍＭ、５０ｎＭ、１μＭ、２μＭ含む１０％ＦＢＳ含有高グルコースＤＭＥＭに交換し、さらに６日間培養した。また、褐色脂肪細胞への分化誘導開始時より上記培地に、実施例品１のバターオイル（終濃度：１５０μg／ｍｌ、エタノールに溶解）を添加した。８日間培養した細胞を、インスリンを含む１０％ＦＢＳ含有高グルコースＤＭＥＭにイソプロテノール（Ｉｓｏ）を１０μＭ添加した培地で４時間培養した後、全ＲＮＡの抽出ならびにｃＤＮＡの合成を行った。その後、リアルタイムＰＣＲを行い、褐色脂肪細胞特異的遺伝子であるＵＣＰ１遺伝子の発現量を測定した。なお、解析には以下のプライマーを用いた。
ＵＣＰ１遺伝子の発現解析に用いたプライマー
ＵＣＰ１−Ｆ；ｃｃａａａｇｔｃｃｇｃｃｔｔｃａｇａ
ＵＣＰ１−Ｒ；ｇｇｃａａｔｃｃｔｔｃｔｇｔｔｔｔｔｇｃ
その結果、表４から明らかなように、バターオイルはＵＣＰ１遺伝子の発現量を有意に増加させた。したがって、本発明のバターオイルは白色脂肪前駆細胞から褐色脂肪細胞への分化を促進することがわかった。
[Test Example 2]
The effect of butter oil on the differentiation of 3T3-L1 cells, which are white fat precursor cells, into brown adipocytes was examined.
3T3-L1 cells were seeded in a 12-well plate and cultured in high glucose DMEM containing 10% FBS. Two days after reaching confluence, 10% containing 10 μg / ml, 0.5 mM, 0.25 μM, and 50 nM of insulin, IBMX, DEX, and triiodothyronine (T3), respectively, for differentiation into brown adipocytes The culture was replaced with high glucose DMEM containing FBS and cultured for 2 days. Next, insulin, IBMX, T3, rosiglitazone, and A-83-01 were replaced with high glucose DMEM containing 10% FBS containing 5 μg / ml, 0.5 mM, 50 nM, 1 μM, and 2 μM, respectively, and cultured for 6 days. In addition, the butter oil of Example Product 1 (final concentration: 150 μg / ml, dissolved in ethanol) was added to the medium from the beginning of induction of differentiation into brown adipocytes. The cells cultured for 8 days were cultured in a medium in which 10 μM isoprotenol (Iso) was added to 10% FBS-containing high glucose DMEM containing insulin, and then total RNA was extracted and cDNA was synthesized. Thereafter, real-time PCR was performed to measure the expression level of UCP1 gene, which is a brown adipocyte-specific gene. The following primers were used for the analysis.
Primer UCP1-F used for the expression analysis of UCP1 gene; ccaagtccgccttcaga
UCP1-R; ggcaatccttctgtttttgc
As a result, as apparent from Table 4, butter oil significantly increased the expression level of the UCP1 gene. Therefore, it was found that the butter oil of the present invention promotes differentiation from white fat precursor cells to brown fat cells.
※は、コントロール（無添加）と比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (no addition) (p <0.05).
［試験例３］
褐色脂肪細胞の活性化に対する、バターオイルの効果を調べた。
褐色脂肪前駆細胞であるＨＢ２細胞を１２ウェルプレートに播種し、１０％ＦＢＳ含有高グルコースＤＭＥＭで培養した。コンフルーエントに達してから２日後に、２０ｎＭのインスリンを含む１０％ＦＢＳ含有高グルコースＤＭＥＭに、実施例品１のバターオイル（終濃度：１５０μg／ｍｌ、エタノールに溶解）を添加した培地に交換して８日間培養した後、上記培地に１０μＭのＩｓｏを添加した培地に交換し、さらに４時間培養した。その後、試験例２と同様の方法で全ＲＮＡを抽出してＵＣＰ１遺伝子の発現量をリアルタイムＰＣＲにて解析した。なお、遺伝子発現量を評価するための内部標準として、ＴＡＴＡ ｂｉｎｄｉｎｇ ｐｒｏｔｅｉｎ遺伝子の発現量を使用した。その結果、表５に示したように、バターオイルは褐色脂肪細胞のＵＣＰ１遺伝子の発現を有意に増加させた。したがって、本発明のバターオイルは褐色脂肪細胞を活性化することがわかった。
[Test Example 3]
The effect of butter oil on brown adipocyte activation was examined.
HB2 cells, which are brown fat precursor cells, were seeded in a 12-well plate and cultured in high glucose DMEM containing 10% FBS. Two days after reaching confluence, the medium was replaced with medium supplemented with 10% FBS-containing high glucose DMEM containing 20 nM insulin and butter oil of Example Product 1 (final concentration: 150 μg / ml, dissolved in ethanol). After culturing for 8 days, the medium was replaced with a medium in which 10 μM Iso was added to the medium, and further cultured for 4 hours. Thereafter, total RNA was extracted in the same manner as in Test Example 2, and the expression level of the UCP1 gene was analyzed by real-time PCR. In addition, the expression level of the TATA binding protein gene was used as an internal standard for evaluating the gene expression level. As a result, as shown in Table 5, butter oil significantly increased UCP1 gene expression in brown adipocytes. Therefore, it was found that the butter oil of the present invention activates brown adipocytes.
※は、コントロール（無添加）と比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (no addition) (p <0.05).
［試験例４］
善玉アディポカインであるアディポネクチンの分泌と褐色脂肪細胞の活性化に対する、バターオイルの効果を調べた。
６週齢の雄性Ｆｉｓｈｅｒラットを８匹ずつ、実施例品１のバターオイルをラット体重１ｋｇあたり５００ｍｇ投与する群と実施例品１のバターオイルをラット体重１ｋｇあたり１５００ｍｇ投与する群に分け、１日１回ゾンデで経口投与し、溶媒である水のみを投与する群（コントロール）とアディポネクチンの分泌と褐色脂肪細胞の活性化に対する効果を比較検証した。なお、すべてのラットには、高脂肪食を４週間自由に摂取させた。試験終了後に、血液に分泌されたアディポネクチン量をマウス／ラットアディポネクチンＥＬＩＳＡキット（大塚製薬製）を用いて測定した。また、摘出した腸管膜脂肪を用いて、試験例２と同様にＵＣＰ１遺伝子の発現量を解析した。その結果を、表６、７に示す。バターオイルを体重１ｋｇ当たり５００ｍｇ以上投与した群では、ラット血清中のアディポネクチン濃度が有意に増加した。また、腸間膜脂肪におけるＵＣＰ１遺伝子の発現量は、バターオイルを体重１ｋｇ当たり５００ｍｇ以上投与した群で、コントロールに比べ有意に増加した。したがって、バターオイルは、優れたアディポネクチン分泌促進効果を有するとともに、白色脂肪前駆細胞から褐色脂肪細胞への分化を促進することがわかった。また、その効果は、ラット体重１ｋｇあたり５００ｍｇ以上摂取した場合に認められることが明らかとなった。
[Test Example 4]
We investigated the effect of butter oil on the secretion of adiponectin, a good adipokine, and the activation of brown adipocytes.
Eight 6-week-old male Fisher rats are divided into a group in which 500 mg of butter oil of Example Product 1 is administered per kg body weight of a rat and a group in which 1500 mg of butter oil of Example Product 1 is administered per kg body weight of a rat. The group (control), which was orally administered once with a sonde and given only water as a solvent, was compared and verified for the effects on adiponectin secretion and brown adipocyte activation. All rats were given a high fat diet freely for 4 weeks. After the test, the amount of adiponectin secreted into the blood was measured using a mouse / rat adiponectin ELISA kit (manufactured by Otsuka Pharmaceutical). Further, using the extracted mesenteric fat, the expression level of the UCP1 gene was analyzed in the same manner as in Test Example 2. The results are shown in Tables 6 and 7. In the group administered with 500 mg or more of butter oil per 1 kg of body weight, the adiponectin concentration in the rat serum was significantly increased. In addition, the expression level of UCP1 gene in mesenteric fat was significantly increased in the group administered with 500 mg or more of butter oil per kg of body weight as compared with the control. Therefore, it was found that butter oil has an excellent adiponectin secretion promoting effect and promotes differentiation from white fat precursor cells to brown fat cells. Moreover, it became clear that the effect is recognized when ingesting 500 mg or more of rat body weight per kg.
※は、コントロールと比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (p <0.05).
※は、コントロールと比較して有意差があることを示す（ｐ＜０．０５）。
* Indicates that there is a significant difference compared to the control (p <0.05).
（脂肪蓄積抑制用カプセル剤の調製）
表８に示す配合で原材料を混合後、常法により造粒し、カプセルに充填して、本発明の脂肪蓄積抑制用カプセル剤を製造した。
(Preparation of capsules for inhibiting fat accumulation)
After mixing the raw materials with the formulation shown in Table 8, the mixture was granulated by a conventional method and filled into capsules to produce a capsule for inhibiting fat accumulation according to the present invention.
（脂肪蓄積抑制用液状栄養組成物の調製）
実施例品１のバターオイル５０ｇと乳化剤２０ｇを４，９３０ｇの脱イオン水に溶解し、５０℃まで加熱後、ＴＫホモミクサー（ＴＫ ＲＯＢＯ ＭＩＣＳ；特殊機化工業社製）にて、６，０００ｒｐｍで３０分間撹拌混合して５０ｇ／５ｋｇのバターオイル溶液を得た。このバターオイル溶液５．０ｋｇに、カゼイン５．０ｋｇ、大豆タンパク質５．０ｋｇ、魚油１．０ｋｇ、シソ油３．０ｋｇ、デキストリン１７．０ｋｇ、ミネラル混合物６．０ｋｇ、ビタミン混合物１．９５ｋｇ、乳化剤２．０ｋｇ、安定剤４．０ｋｇ、香料０．０５ｋｇを配合し、２００ｍｌのレトルトパウチに充填し、レトルト殺菌機 (第１種圧力容器、ＴＹＰＥ: ＲＣＳ−４ＣＲＴＧＮ、日阪製作所製)で１２１℃、２０分間殺菌して、本発明の脂肪蓄積抑制用液状栄養組成物５０ｋｇを製造した。
(Preparation of liquid nutritional composition for fat accumulation suppression)
50 g of butter oil of Example product 1 and 20 g of emulsifier were dissolved in 4,930 g of deionized water, heated to 50 ° C., and then at 6,000 rpm with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.). The mixture was stirred and mixed for 30 minutes to obtain a 50 g / 5 kg butter oil solution. 5.0 kg of this butter oil solution, 5.0 kg of casein, 5.0 kg of soy protein, 1.0 kg of fish oil, 3.0 kg of perilla oil, 17.0 kg of dextrin, 6.0 kg of mineral mixture, 1.95 kg of vitamin mixture, emulsifier 2 0.0kg, 4.0kg stabilizer, 0.05kg fragrance, filled in 200ml retort pouch, 121 ° C with retort sterilizer (first pressure vessel, TYPE: RCS-4CRTGN, manufactured by Nisaka Seisakusho) Sterilized for 20 minutes to produce 50 kg of a liquid nutrition composition for fat accumulation suppression according to the present invention.
（脂肪蓄積抑制用飲料の調製）
脱脂粉乳３００ｇを４０８ｇの脱イオン水に溶解した後、実施例品１のバターオイル１ｇと乳化剤１ｇを溶解し、５０℃まで加熱後、ウルトラディスパーサー（ＵＬＴＲＡ−ＴＵＲＲＡＸ Ｔ−２５；ＩＫＡジャパン社製）にて、９，５００ｒｐｍで３０分間撹拌混合した。マルチトール１００ｇ、酸味料２ｇ、還元水飴２０ｇ、香料２ｇ、脱イオン水１６６ｇを添加した後、１００ｍｌのガラス瓶に充填し、９５℃、１５秒間殺菌後、密栓し、本発明の脂肪蓄積抑制用飲料１０本（１００ｍｌ入り）を調製した。
(Preparation of fat accumulation suppression beverage)
After dissolving 300 g of skim milk powder in 408 g of deionized water, 1 g of butter oil and 1 g of emulsifier of Example Product 1 were dissolved, heated to 50 ° C., and then Ultradisperser (ULTRA-TURRAX T-25; manufactured by IKA Japan). The mixture was stirred and mixed at 9,500 rpm for 30 minutes. After adding 100 g maltitol, 2 g acidulant, 20 g reduced starch syrup, 2 g fragrance, and 166 g deionized water, it is filled into a 100 ml glass bottle, sterilized at 95 ° C. for 15 seconds, sealed, and the fat accumulation-inhibiting beverage of the present invention Ten pieces (100 ml) were prepared.
（イヌ用脂肪蓄積抑制用飼料の調製）
実施例品１のバターオイル２ｋｇと乳化剤１ｋｇを９７ｋｇの脱イオン水に溶解し、５０℃まで加熱後、ＴＫホモミクサー（ＭＡＲＫ ＩＩ １６０型；特殊機化工業社製）にて、３，６００ｒｐｍで４０分間撹拌混合して２ｇ／１００ｇのバターオイル溶液を得た。このバターオイル溶液１０ｋｇに大豆粕１２ｋｇ、脱脂粉乳１４ｋｇ、大豆油４ｋｇ、コーン油２ｋｇ、パーム油２３．２ｋｇ、トウモロコシ澱粉１４ｋｇ、小麦粉９ｋｇ、ふすま２ｋｇ、ビタミン混合物５ｋｇ、セルロース２．８ｋｇ、ミネラル混合物２ｋｇを配合し、１２０℃、４分間殺菌して、本発明の脂肪蓄積抑制用飼料１００ｋｇを製造した。
(Preparation of canine fat accumulation suppression feed)
2 kg of butter oil of Example Product 1 and 1 kg of emulsifier were dissolved in 97 kg of deionized water, heated to 50 ° C., and then heated at 40 ° C. at 3,600 rpm with a TK homomixer (MARK II 160 type; manufactured by Tokushu Kika Kogyo Co., Ltd.). The mixture was stirred and mixed for 2 minutes to obtain a 2 g / 100 g butter oil solution. 10 kg of this butter oil solution, 12 kg of soybean meal, 14 kg of skim milk powder, 4 kg of soybean oil, 2 kg of corn oil, 23.2 kg of palm oil, 14 kg of corn starch, 9 kg of flour, 2 kg of bran, 5 kg of vitamin mixture, 2.8 kg of cellulose, 2 kg of mineral mixture And pasteurized at 120 ° C. for 4 minutes to produce 100 kg of the fat accumulation-inhibiting feed of the present invention.
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| DIABETES, vol. 52, JPN6017045502, 2003, pages 2266 - 2273, ISSN: 0003690354 * |
| INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION, vol. Vol.64(5), JPN6017028583, August 2013 (2013-08-01), pages 575 - 586, ISSN: 0003690353 * |
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