WO2021205852A1 - 生体機能調整剤、表皮代謝促進剤、脂肪蓄積抑制剤、脂肪分解促進剤、アディポネクチン産生促進剤、機能性食品、化粧料および生体機能調整剤の製造方法 - Google Patents
生体機能調整剤、表皮代謝促進剤、脂肪蓄積抑制剤、脂肪分解促進剤、アディポネクチン産生促進剤、機能性食品、化粧料および生体機能調整剤の製造方法 Download PDFInfo
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Definitions
- the present invention relates to a method for producing a biological function regulator, an epidermal metabolism promoter, a fat accumulation inhibitor, a lipolysis promoter, an adiponectin production promoter, a functional food, a cosmetic and a biological function regulator.
- Patent Document 1 Woo et al.'S paper
- Non-Patent Document 2 Kobayashi et al.'S publication
- Patent Document 2 discloses that collagen peptide was obtained by fermenting collagen with lactic acid bacteria.
- Patent Document 2 does not disclose that collagen peptide is obtained by fermenting any of collagen, gelatin and gelatin decomposition product with koji. Further, the collagen peptide reported to have an anti-obesity effect in Patent Document 1, Non-Patent Document 1 and Non-Patent Document 2 is obtained by fermenting any of collagen, gelatin and gelatin decomposition product with koji. It is not a collagen peptide (hereinafter, also referred to as "fermented collagen peptide"). That is, the action and effect of the fermented collagen peptide on the living body has not yet been elucidated.
- the present invention provides a fermented collagen peptide having at least one action selected from the group consisting of an epidermal metabolism promoting action, an adipose accumulation suppressing action, a lipolysis promoting action and an adipocytokine amount adjusting action in vivo. It is an object of the present invention to provide a method for producing a biological function regulator, a skin metabolism promoter, an adipose accumulation inhibitor, a lipolytic promoter, an adiponectin production promoter, a functional food, a cosmetic and a biological function regulator.
- the obtained fermented collagen peptide has at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an in vivo adipocytogenic amount adjusting action.
- the biological function adjusting agent according to the present invention contains a fermented collagen peptide, and the fermented collagen peptide has an effect of promoting epidermal metabolism, an effect of suppressing fat accumulation, an effect of promoting lipolysis, and an effect of adjusting the amount of adipocytokine in the living body. It has at least one action selected from the group.
- the fermented collagen peptide preferably contains the collagen peptide and at least one first compound selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional.
- the fermented collagen peptide preferably contains the collagen peptide and at least three first compounds selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional.
- the epidermal metabolism promoter according to the present invention includes the above-mentioned biological function regulator.
- the fat accumulation inhibitor according to the present invention includes the above-mentioned biological function adjusting agent.
- the adiponectin production promoter according to the present invention includes the above-mentioned biological function regulator.
- the lipolysis accelerator according to the present invention includes the above-mentioned biological function adjusting agent.
- the functional food according to the present invention contains the above-mentioned biological function adjusting agent.
- the cosmetic according to the present invention contains the above-mentioned biological function adjusting agent.
- the method for producing a biological function adjusting agent according to the present invention is a method for producing a biological function adjusting agent containing a fermented collagen peptide, which comprises a step of preparing a gelatin containing aspergillus and a collagen raw material, and the above collagen raw material.
- the step of obtaining a biological function modifier containing the fermented collagen peptide by fermenting with the above-mentioned gelatin is included, and the above-mentioned bacterial species of the aspergillus is a bacterial species belonging to the genus Aspergillus, and the above-mentioned collagen raw material is the following first. At least one selected from the group consisting of the group to the sixth group, collagen extracted from at least one selected from the above group, gelatin obtained by treating the above collagen, and obtained by hydrolyzing the above gelatin. At least one of the gelatin degradation products to be obtained.
- Group 1 Group consisting of cow skin, skin, bone, cartilage and tendon
- Group 2 Group consisting of pig skin, skin, bone, cartilage and tendon
- Group 3 Sheep skin, skin, bone, cartilage and Group consisting of tendons
- Group 4 Group consisting of chicken skin, skin, bones, cartilage and tendons
- Group 5 Group consisting of ostrich skin, skin, bones, cartilage and tendons
- Group 6 Fish bones, skins and scales
- the biological function modifier according to the present invention contains a fermented collagen peptide produced by fermenting a collagen raw material with koji.
- biological function regulation including fermented collagen peptide having at least one action selected from the group consisting of epidermal metabolism promoting action, fat accumulation suppressing action, lipolysis promoting action and adipocytokine amount adjusting action in the living body. It is possible to provide a method for producing an agent, an epidermal metabolism promoter, a fat accumulation inhibitor, a lipolysis promoter, an adiponectin production promoter, a functional food, a cosmetic and a biological function regulator.
- FIG. 1 is a graph showing changes in body weight of mice in each group in the first test.
- FIG. 2 is a graph showing the amount of intestinal membrane fat in each group of mice in the first test.
- FIG. 3 is a graph showing the perikidney fat mass of the mice in each group in the first test.
- FIG. 4 is a graph showing the peritesticular fat mass of the mice in each group in the first test.
- FIG. 5 is a graph showing the total visceral fat mass of the mice in each group in the first test.
- FIG. 6 is a graph showing the serum leptin concentration of the mice of each group in the first test.
- FIG. 7 is a graph showing the serum adiponectin concentration of the mice of each group in the first test.
- FIG. 8 is a graph showing the intensity of FAS activity in the liver of the mice of each group in the first test.
- FIG. 9 is a graph showing the intensity of CPT activity in the liver of the mice of each group in the first test.
- FIG. 10 is a graph showing the serum leptin concentration of the mice of each group in the second test.
- FIG. 11 is a graph showing the serum adiponectin concentration of the mice of each group in the second test.
- FIG. 12 is a graph showing changes in body weight of mice in each group in the seventh study.
- FIG. 13 is a graph showing the body weight of the mice in each group in the eighth test.
- FIG. 14 is a graph showing the amount of intestinal membrane fat in each group of mice in the eighth test.
- FIG. 15 is a graph showing the perikidney fat mass of the mice in each group in the eighth test.
- FIG. 16 is a graph showing the peritesticular fat mass of the mice in each group in the eighth test.
- FIG. 17 is a graph showing the total visceral fat mass of the mice in each group in the eighth test.
- FIG. 18 is a graph showing the serum blood glucose level of the mice of each group in the eighth test.
- FIG. 19 is a graph showing the amount of insulin in the serum of the mice of each group in the eighth test.
- FIG. 20 is a graph showing the serum leptin concentration of the mice of each group in the eighth test.
- FIG. 21 is a graph showing the intensity of FAS activity in the liver of the mice of each group in the eighth test.
- FIG. 22 is a graph showing the intensity of CPT activity in the liver of the mice of each group in the eighth test.
- the present embodiment will be described in more detail.
- the notation in the form of "A to B” means the upper and lower limits of the range (that is, A or more and B or less), and there is no description of the unit in A and the unit is described only in B.
- the unit of A and the unit of B are the same.
- biological function regulator in the powder state. It may be a solid such as, and it may be a liquid such as an aqueous solution dissolved in water.
- the "fermented collagen peptide” means a peptide mixture obtained by fermenting a collagen raw material described later with koji.
- the term “fermentation” means the entire process in which beneficial organic substances are produced from a raw material by the activity of aspergillus contained in Jiuqu, and "non-beneficial organic substances are produced from the raw material by the activity of microorganisms”. Distinguished from “corruption”.
- gelatin may be used when referring to a substance name, gelatin gel and gelatin solution, respectively.
- collagen peptide may also be used when referring to a substance name and a collagen peptide solution, as in the case of gelatin.
- the "collagen raw material” is at least one “itself” selected from the following groups 1 to 6, and at least one selected from the following groups 1 to 6.
- “Collagen” extracted from, “gelatin” obtained by treating the above collagen using a known method such as hot water extraction, and “gelatin decomposition product” obtained by hydrolyzing the above gelatin are summarized. It may be used in such cases.
- the “hydrolysis” of gelatin includes all of hydrolysis using acid, hydrolysis using base, hydrolysis using enzyme and hydrolysis using heating.
- Group 1 Group consisting of cow skin, skin, bone, cartilage and tendon
- Group 2 Group consisting of pig skin, skin, bone, cartilage and tendon
- Group 3 Sheep skin, skin, bone, cartilage and Group consisting of tendons
- Group 4 Group consisting of chicken skin, skin, bones, cartilage and tendons
- Group 5 Group consisting of ostrich skin, skin, bones, cartilage and tendons
- Group 6 Fish bones, skins and scales A group consisting of.
- the biological function modifier according to the present embodiment contains a fermented collagen peptide.
- the fermented collagen peptide has at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an adipocytokine amount adjusting action in a living body.
- the biological function regulator having such characteristics is at least one selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an in vivo adipocytokine amount adjusting action on the living body. It can exert an action (hereinafter, also referred to as "biological function adjusting action").
- the biological function modifier according to the present embodiment contains a fermented collagen peptide as described above.
- the fermented collagen peptide preferably contains collagen peptide and at least one first compound selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional.
- the fermented collagen peptide more preferably contains the collagen peptide and at least three first compounds selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional.
- the biological function adjusting agent according to the present embodiment is produced by fermenting a collagen raw material with jiuqu. That is, the biological function adjusting agent according to the present embodiment is a biological function adjusting agent containing a fermented collagen peptide.
- the odor that the conventional collagen peptide has is suppressed by the first compound. Therefore, the above-mentioned biological function adjusting agent can be used, for example, an epidermal metabolism promoter, a fat accumulation inhibitor, a lipolysis promoter, an adiponectin production promoter, and functionality, which will be described later, without simplifying the deodorizing treatment or performing the deodorizing treatment. It can be used in foods and cosmetics.
- the fermented collagen peptide preferably contains the collagen peptide as described above.
- This collagen peptide is apparently the same as a conventionally known collagen peptide. That is, the collagen peptide contained in the fermented collagen peptide contains various peptides such as dipeptides, tripeptides, oligopeptides and polypeptides obtained by subjecting collagen or gelatin to a conventionally known treatment as an apparent peptide mixture. obtain.
- the fermented collagen peptide is obtained by fermenting the collagen raw material with koji as described above. Therefore, the collagen peptide contained in the fermented collagen peptide is obtained by fermenting the collagen raw material with koji, and is produced together with the first compound described later.
- the collagen peptide contained in the fermented collagen peptide preferably has a weight average molecular weight of 20000 or less.
- the biological function regulator is used for epidermal metabolism promoters, fat accumulation inhibitors, lipolysis promoters, adiponectin production promoters, functional foods and cosmetics.
- the collagen peptide has a weight average molecular weight of 10000 or less, more preferably 6000 or less.
- the lower limit of the weight average molecular weight of the collagen peptide is 76.
- the biological function regulator is used as a skin metabolism promoter, a fat accumulation inhibitor, a lipolysis promoter, an adiponectin production promoter, a functional food or a cosmetic.
- the above-mentioned action can be sufficiently exerted on the living body.
- the weight average molecular weight of the collagen peptide contained in the biological function adjusting agent can be determined by performing size exclusion chromatography (SEC) under the following measurement conditions.
- SEC size exclusion chromatography
- the fermented collagen peptide preferably contains at least one first compound selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional as described above, and more preferably at least three kinds. Contains the above first compound.
- the first compound is considered to be produced together with the collagen peptide by fermenting the collagen raw material with koji.
- the first compound can function as a marker indicating that the fermented collagen peptide is obtained by fermenting a collagen raw material with koji.
- the fermented collagen peptide may contain the first compound of any one of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional as the first compound.
- the fermented collagen peptide may contain isobarrel aldehyde and 1-octen-3-ol as the first compound, may contain isobarrel aldehyde and phenylacetaldehyde, may contain isobarrel aldehyde and methional, 1 - May contain octene-3-ol and phenylacetaldehyde, may contain 1-octen-3-ol and methional, and may contain phenylacetaldehyde and methional.
- the fermented collagen peptide may contain isobarrel aldehyde, 1-octen-3-ol and phenylacetaldehyde as the first compound, may contain isobarrel aldehyde, 1-octen-3-ol and methional, and may contain isobarrel. It may contain aldehydes, phenylacetaldehyde and methional, and may contain 1-octen-3-ol, phenylacetaldehyde and methional.
- the fermented collagen peptide may also contain the first compound of four types (isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional).
- the biological function regulator exerts at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an in vivo adipocytokine amount adjusting action on the living body. , Can be played more sufficiently.
- Isovaleraldehyde is a compound also called isovaleraldehyde, 3-methylbutanal or 3-methylbutyraldehyde, and is a compound conventionally used as a flavor (food additive) or the like.
- (1-Octen-3-all) 1-octen-3-ol is a kind of unsaturated alcohol and is a compound conventionally known to be a component that contributes to the scent of matsutake mushrooms.
- Phenylacetaldehyde is a kind of aromatic aldehyde, and is a compound that has been conventionally used as a raw material for blending fragrances and flavors.
- Methional is a kind of organic sulfur compound and is also called 3-methylthio-1-propanol. Methional is a compound conventionally known to be contained in soy sauce. In addition, methional is known to have the effect of reducing the fishy odor of meat and fish.
- the first compound is contained in the above-mentioned biological function adjusting agent in an amount of 0.05 ppm or more as a total amount (total of at least one kind or more). That is, the biological function adjusting agent preferably contains 0.05 ppm or more of the first compound. Further, it is more preferable that the first compound is contained in the biological function adjusting agent in an amount of 0.4 ppm or more as a total amount. That is, it is more preferable that the biological function adjusting agent contains 0.4 ppm or more of the first compound.
- the lower limit of the content of the first compound in the above-mentioned biological function adjusting agent is not particularly limited, but it is preferable that the total amount of the first compound is 0.01 ppm or more.
- the upper limit of the content of the first compound is not particularly limited, but the total amount of the first compound is preferably 5 ppm or less.
- the qualitative analysis and quantification of the first compound contained in the biological function adjusting agent can be obtained by the following procedure.
- a dry powder of the biological function adjusting agent is obtained by the production method described later. Further, 0.5 g of the above dry powder is dissolved in 4.5 mL of RO water to obtain a measurement sample.
- the above-mentioned measurement sample was put into a gas chromatograph mass spectrometer (trade name: "7890A GC system", Agilent Technologies, Inc., and product name: "JMS-Q1050GC", manufactured by JEOL Ltd.). Is vaporized and then moved to a column provided in the analyzer using ultra-high purity helium as a carrier gas to separate the components contained in the measurement sample for each compound.
- the qualification of the first compound is performed by detecting the compound with a detector provided in the analyzer and comparing the data (spectral data) obtained from the detector with the standard data. Can be done. At the same time, the first compound can be quantified based on the spectral data (peak area) obtained from the detector.
- the epidermal metabolism promoter includes the above-mentioned biological function regulator.
- the epidermis metabolism-promoting agent may promote the discharge of melanin granules on the skin surface (in the epidermis) from the skin surface as stains, freckles, etc. without stagnation by the epidermis metabolism-promoting action of the biological function regulator.
- the epidermal metabolism promoter can enhance the expression level of at least one gene selected from the group consisting of transglutaminase 1 (TGM1), involucrin (Ivl) and keratin 10 (KRT10).
- genes are known to contribute to the maturation and differentiation of each layer (stratum corneum, stratum granulosum, stratum spinosum and basal layer) that compose the epidermis, and thus metabolism in the epidermis (so-called turnover) due to the increased expression of the above-mentioned genes. ) Is considered to be promoted. Further, based on the promotion of metabolism in the epidermis, there is a possibility that a skin moisturizing effect, a skin wrinkle prevention effect and / or a wrinkle improving effect and the like can be obtained.
- the concentration of the biological function regulator in the epidermal metabolism promoter may be 0.01 to 100% by mass.
- the concentration of the biological function adjusting agent in the epidermal metabolism promoting agent means the concentration of collagen peptide in the biological function adjusting agent because the content of the first compound is very small. Therefore, the concentration of the biological function regulator in the epidermal metabolism promoter can be determined by a conventionally known method for measuring the concentration of collagen peptide. For example, the concentration of the biological function regulator in the epidermal metabolism promoter can be determined by measuring the mass percentage of hydroxyproline in the collagen peptide by the chloramine-T method. It can also be determined by measuring the mass percent of hydroxyproline in collagen peptide using an amino acid analyzer.
- the fat accumulation inhibitor according to the present embodiment includes the above-mentioned biological function adjusting agent.
- the fat accumulation inhibitor can obtain an effect of suppressing the accumulation of fat (so-called visceral fat) in the liver, intestine, kidney, testis, etc. by the fat accumulation inhibitory action of the biological function regulator.
- the fat accumulation inhibitor has an inverse correlation with the blood concentration reducing action of leptin known as an appetite hormone and the visceral fat mass in the body based on the adipocytokine level regulating action of the biological function regulator. Through the action of increasing the blood concentration of adiponectin, which is known to be active, the effect of suppressing fat accumulation can be obtained.
- the leptin and adiponectin are known as proteins classified into adipocytokines secreted from adipocytes. That is, the adiponectin production promoter according to the present embodiment includes the above-mentioned biological function adjusting agent.
- the concentration of the biological function adjusting agent in the fat accumulation inhibitor may be 0.01 to 100% by mass.
- the concentration of the biological function modifier in the adiponectin production promoter can also be 0.01 to 100% by mass.
- the concentration of the biological function adjusting agent in the fat accumulation inhibitor and the adiponectin production promoter means the concentration of collagen peptide in the biological function adjusting agent because the content of the first compound is very small. .. Therefore, the concentration of the biological function regulator in the fat accumulation inhibitor and the adiponectin production promoter can be the same as the concentration measuring method of the biological function regulator in the epidermal metabolism promoter described above.
- the lipolysis accelerator according to the present embodiment includes the above-mentioned biological function adjusting agent.
- the lipolysis-promoting agent can obtain a lipolysis-promoting effect of fat (so-called visceral fat) in the liver, intestine, kidney, testis, etc. by the lipolysis-promoting action of the biological function adjusting agent.
- the concentration of the biological function adjusting agent in the lipolysis accelerator may be 0.01 to 100% by mass.
- the concentration of the biological function adjusting agent in the lipolysis accelerator means the concentration of collagen peptide in the biological function adjusting agent because the content of the first compound is very small. Therefore, the concentration of the biological function regulator in the lipolysis promoter can be the same as the method for measuring the concentration of the biological function regulator in the epidermal metabolism promoter described above.
- the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter described above are administered in various forms orally or parenterally as supplements, pharmaceuticals or quasi-drugs. be able to.
- the form can be, for example, a dosage form such as a tablet, a granule, a capsule, a powder, a liquid, a suspension, an emulsified product, or a paste. Further, the above-mentioned dosage form can be mixed with the functional food described later.
- epidermal metabolism promoter fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter are administered parenterally, for example, an injection into the body, an injection, a transdermal agent (coating agent, patch and patch) Dosage forms such as aerosols), suppositories, nasal drops and inhalants.
- dosage forms of the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter include tablets, granules, capsules, powders, liquids and transdermal agents.
- the doses of the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter differ depending on the age, sex, body weight, sensitivity difference, administration method, administration interval, type of preparation, etc. of the subject.
- the respective doses are preferably 0.0001 to 2500 mg / kg per day for adults, for example. , 0.0001 to 500 mg / kg, more preferably.
- the epidermal metabolism promoter, lipolysis inhibitor, lipolysis promoter and adiponectin production promoter are 0.001 to 80% by mass per tablet when the dosage form is, for example, tablets. Tablets containing inhibitors, lipolysis promoters or adiponectin production promoters, for example in the case of powders, 0.001 to 100% by mass of epidermal metabolism promoters, lipolysis inhibitors, lipolysis promoters or adiponectin production promoters It can be a powder containing the agent.
- the doses of the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter can be appropriately determined with reference to the doses when administered parenterally or orally. ..
- the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter and adiponectin production promoter can be administered once to several times a day, or once a day to several days. ..
- the epidermal metabolism promoter, fat accumulation inhibitor, lipolysis promoter, and adiponectin production promoter may appropriately contain other active ingredients, carriers for preparation, etc. as long as they do not adversely affect the effects of the present invention.
- Other active ingredients include, for example, phosphoric acid ( ⁇ ) - ⁇ -tocopherol disodium salt, heparin analog, allantin, glycyrrhizinic acid, glycyrrhetin, D-amino acid, aminosilane compound, tiliroside, extract of yuzu, ⁇ -glucosyl hesperidine, Mulberry leaf extract, mangostin peel extract, ⁇ -mangostin, ⁇ -mangostin, cacao seed extract, cacao hull extract, ginseng extract, lychee polyphenol, legume family Psophocarpus extract, button bow fu (long-lived grass) ) Extracts, lactic acid bacteria, glabridin, eyebright extract, dried kudzu flower extract
- diluents binders (syrup, gum arabic, gelatin, sorbitol, tragacant, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch) , Potassium phosphate, sorbitol, glycine), lubricants (magnesium stearate, talc, polyethylene glycol, silica), disintegrants (potassium starch) and wetting agents (sodium lauryl sulfate) and the like.
- the functional food according to the present embodiment contains the above-mentioned biological function adjusting agent.
- the functional food include foods for specified health use and foods with functional claims.
- the functional food comprises, for example, a food for specified health use or a food with a functional claim, which has an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an adipocytokine amount adjusting action in the living body. It can exert at least one action selected from the group.
- the concentration of the biological function adjusting agent in the food for specified health use or the food with functional claims can be 0.01 to 100% by mass.
- the concentration of the biological function adjusting agent in the functional food means the concentration of collagen peptide in the biological function adjusting agent because the content of the first compound is very small. Therefore, the concentration of the biological function adjusting agent in the functional food can be the same as the method for measuring the concentration of the biological function adjusting agent in the epidermal metabolism promoting agent described above.
- the cosmetic according to this embodiment contains the above-mentioned biological function adjusting agent.
- the cosmetic can be provided as a cosmetic having a whitening effect, a moisturizing effect, a wrinkle prevention effect and / or a wrinkle improving effect, for example, based on the epidermal metabolism promoting effect of the biological function adjusting agent.
- the concentration of the biological function adjusting agent in the above cosmetics may be 0.01 to 100% by mass.
- the concentration of the biological function adjusting agent in the cosmetics means the concentration of collagen peptide in the biological function adjusting agent because the content of the first compound is very small. Therefore, the concentration of the biological function adjusting agent in the cosmetic can be the same as the method for measuring the concentration of the biological function adjusting agent in the epidermal metabolism promoting agent described above.
- the method for producing a biological function adjusting agent is a method for producing a biological function adjusting agent containing a fermented collagen peptide.
- the method for producing the biological function adjusting agent includes a step of preparing a koji containing aspergillus and a collagen raw material (first step) and a step of fermenting the collagen raw material with the koji to adjust the biological function containing the fermented collagen peptide. It includes a step of obtaining an agent (second step).
- the bacterial species of Aspergillus is a bacterial species belonging to the genus Aspergillus.
- the collagen raw material is at least one selected from the group consisting of the following groups 1 to 6, collagen extracted from at least one selected from the above group, gelatin obtained by treating the above collagen, and It is at least one of the gelatin decomposition products obtained by hydrolyzing the above gelatin.
- Group 1 Group consisting of cow skin, skin, bone, cartilage and tendon
- Group 2 Group consisting of pig skin, skin, bone, cartilage and tendon
- Group 3 Sheep skin, skin, bone, cartilage and Group consisting of tendons
- Group 4 Group consisting of chicken skin, skin, bones, cartilage and tendons
- Group 5 Group consisting of ostrich skin, skin, bones, cartilage and tendons
- Group 6 Fish bones, skins and scales A group consisting of.
- a method for producing a biological function adjusting agent having such characteristics is at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an in vivo adipocytokine amount adjusting action. It is possible to produce a biological function adjusting agent containing a fermented collagen peptide having.
- the biological function regulator produced by the above production method has at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an in vivo adipocytokine amount adjusting action.
- the reason why it can be done is thought to be due to the following mechanism, although the details are not clear. That is, the above-mentioned production method includes a step (second step) of obtaining a biological function modifier containing a fermented collagen peptide by fermenting a collagen raw material with koji.
- Jiuqu contains a wide variety of enzymes produced by the propagation of Jiuqu. Therefore, in the second step, the polypeptide in the collagen raw material, the sugar in the koji, and the like may be decomposed or redoxed by the action of these various enzymes.
- the fermented collagen peptide is produced by the action of the above-mentioned various enzymes, the above-mentioned epidermal metabolism promoting action, fat accumulation suppressing action, and lipolysis promoting action are performed in the fermented collagen peptide. It is presumed that a collagen peptide containing a dipeptide, a tripeptide, an oligopeptide or a polypeptide having at least one of the physiological activities of adjusting the amount of adipocytokine in the living body is contained.
- the fermented collagen peptide when a fermented collagen peptide is produced by the action of a wide variety of the above-mentioned enzymes, the fermented collagen peptide may contain a compound (non-peptide) having at least one of the above-mentioned actions. Presumed. Therefore, according to the above production method, a biological function containing a fermented collagen peptide having at least one action selected from the group consisting of an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action and an adipocytokine amount adjusting action in the living body. It is believed that a regulator can be obtained.
- each step in the method for producing a biological function adjusting agent according to the present embodiment will be described.
- the first step is a step of preparing the jiuqu containing the aspergillus and the collagen raw material.
- the first step is carried out for the purpose of preparing each necessary material (jiuqu containing aspergillus and collagen raw material) for producing the above-mentioned biological function adjusting agent.
- the collagen raw material is extracted from at least one "itself” selected from the following groups 1 to 6 and at least one selected from the following groups 1 to 6. At least one of the above-mentioned “collagen”, “gelatin” obtained by treating the above-mentioned collagen using a known method such as hot water extraction, and “gelatin decomposition product” obtained by hydrolyzing the above-mentioned gelatin. May be.
- Group 1 Group consisting of cow skin, skin, bone, cartilage and tendon
- Group 2 Group consisting of pig skin, skin, bone, cartilage and tendon
- Group 3 Sheep skin, skin, bone, cartilage and Group consisting of tendons
- Group 4 Group consisting of chicken skin, skin, bones, cartilage and tendons
- Group 5 Group consisting of ostrich skin, skin, bones, cartilage and tendons
- Group 6 Fish bones, skins and scales A group consisting of.
- the first step at least one selected from the group consisting of the first group to the sixth group and at least one selected from the group consisting of the collagen, the gelatin and the gelatin decomposition product are prepared as the collagen raw material. Is preferable.
- one type of collagen raw material selected from these may be prepared, or two or more types of collagen raw materials may be combined and prepared.
- the group consisting of the first group to the sixth group, the collagen, the gelatin, and the gelatin decomposition product can all be prepared by a conventionally known method.
- the gelatin is subjected to pretreatment by acid treatment or alkali treatment, hot water extraction, purification treatment and sterilization treatment on collagen extracted from at least one selected from the group consisting of the first group to the sixth group. It is more preferable to obtain by executing in this order.
- gelatin having high safety for the human body and the like can be prepared, and the biological function adjusting agent to be produced in the present embodiment can be used as the above-mentioned epidermal metabolism promoting agent, fat accumulation inhibitor, and lipolysis promoting agent.
- Adiponectin production promoter, functional foods and cosmetics can be applied to each application.
- Such gelatin is also excellent in economy.
- the above-mentioned pretreatment by acid treatment or alkali treatment, hot water extraction, purification treatment and sterilization treatment can all be carried out by conventionally known methods.
- the gelatin decomposition product can be obtained by subjecting the gelatin to any of conventionally known hydrolysis using an acid, hydrolysis using a base, hydrolysis using an enzyme, and hydrolysis using heating.
- the weight average molecular weight of the gelatin decomposition product should not be particularly limited, but is preferably, for example, 20,000 or less, and more preferably 10,000 or less.
- the lower limit of the weight average molecular weight of the gelatin decomposition product is 76.
- the weight average molecular weight of the gelatin decomposition product can be determined by the same measuring method as the weight average molecular weight of the collagen peptide described above.
- Jiuqu containing aspergillus can be prepared by a conventionally known method as long as the koji that can obtain the effect of the present embodiment is selected by carrying out the second step described later. That is, it can be obtained by inoculating the millet porridge such as rice, barley, wheat or soybean as the seed koji, and then propagating in the rice, barley, wheat or millet porridge.
- the aspergillus is preferably inoculated in an amount of 0.01 to 1% by mass with respect to the rice, barley, wheat or milletmeal.
- “milletmeal” includes not only the above-mentioned soybeans but also bran, bran, okara and defatted soybeans.
- Jiuqu containing Jiuqu it is preferable to provide an environment in which Jiuqu can easily grow by providing a Jiuqu chamber to prevent contamination with other bacteria, and to perform the necessary work in the Jiuqu chamber.
- the bacterial species of Aspergillus is preferably a bacterial species belonging to the genus Aspergillus. It is more preferable that the strain of Aspergillus oryzae is at least one selected from the group consisting of Aspergillus sawyer, Aspergillus oryzae and Aspergillus luciensis. Since it has been confirmed that these bacterial species are safe for the human body and the like, the biological function regulator produced in the present embodiment can be easily used as the above-mentioned epidermal metabolism promoter, fat accumulation inhibitor, and lipolysis. It can be applied to each use of a promoter, an adiponectin production promoter, a functional food and a cosmetic. In the first step, a jiuqu containing one species selected from the group of these bacterial species may be prepared, or a jiuqu containing two or more species selected from the group of the above bacterial species may be prepared.
- the second step is a step of obtaining a biological function modifier containing the fermented collagen peptide by fermenting the collagen raw material with the koji.
- the second step is carried out for the purpose of obtaining the fermented collagen peptide contained in the biological function adjusting agent.
- the collagen raw material and the koji are put into warm water, and these are cultured in warm water for a predetermined time to ferment the collagen raw material with the koji, thereby adjusting the biological function containing the fermented collagen peptide.
- the agent can be obtained.
- the pH value at the time of culturing is preferably 2 to 10, and more preferably 5 to 8. If the pH value at the time of culturing is less than 2 or exceeds 10, there is a risk that the reduction of the molecular weight of the collagen raw material and the reduction of the collagen odor will be insufficient.
- the dispersion After preparing a dispersion having a mass of 100% by mass and adjusting the pH to 2 to 10, the dispersion can be cultured for 1 to 24 hours while maintaining the temperature of the dispersion at 10 to 65 ° C. preferable. Thereby, a fermented product containing fermented collagen peptide can be first obtained.
- a dispersion having a total of 100% by mass of the above-mentioned koji and 60 to 99.9% by mass of water having a dry mass (dry weight) of 0.1 to 40% by mass was prepared, and the dispersion liquid was prepared.
- the mixture is cultured for 1 to 24 hours while maintaining the temperature at 10 to 65 ° C., and roughly filtered through a nylon mesh and filtered through diatomaceous earth and cellulose to obtain a koji extract.
- a dispersion having a total of 100% by mass was prepared, and further dispersed.
- the dispersion is cultured for 1 to 24 hours while maintaining the temperature of the dispersion at 10 to 65 ° C.
- a fermented product containing a fermented collagen peptide can also be obtained by this method.
- a biological function modifier containing a fermented collagen peptide can be obtained without performing a separation treatment step described later on the fermented product.
- the temperature of the hot water during culturing is preferably 15 to 60 ° C, more preferably 20 to 50 ° C. If the temperature of the warm water during culturing is lower than 10 ° C or higher than 65 ° C, the efficiency of fermentation by the koji may decrease and the fermented collagen peptide may not be sufficiently obtained.
- the culture time is preferably 2 to 18 hours, more preferably 4 to 8 hours. If the culture time exceeds 24 hours, it may be economically inefficient. If the culture time is less than 1 hour, fermentation with Jiuqu may be insufficient.
- the content of the collagen raw material in warm water at the time of culturing is preferably 10 to 45% by mass, more preferably 20 to 40% by mass. If the content of the collagen raw material in warm water during culturing is less than 0.1% by mass, it may be economically inefficient. If the content of the collagen raw material in warm water during culturing exceeds 75% by mass, the work may become inefficient.
- the content of the jiuqu in the dispersion liquid consisting of the jiuqu, the collagen raw material and water is preferably 1 to 15% by mass and more preferably 5 to 10% by mass as a dry mass (dry weight). If the content of Jiuqu in warm water at the time of culturing is less than 0.1% by mass as a dry mass (dry weight), fermentation by Jiuqu may be insufficient. If the content of Jiuqu in warm water during culturing exceeds 20% by mass as a dry mass (dry weight), it may be economically inefficient.
- the content of Jiuqu in the Jiuqu extract is preferably 2 to 25% by mass, more preferably 8 to 16% by mass.
- the dry mass (dry weight) in the Jiuqu extract is less than 0.1% by mass, fermentation with Jiuqu may be insufficient. If the content of Jiuqu in the Jiuqu extract exceeds 40% by mass as the dry mass (dry weight), it may be economically inefficient.
- the action (activity) of the aspergillus is inactivated by setting the temperature to 75 ° C. or higher depending on the purpose, and thus fermentation with the collagen raw material aspergillus. Can be stopped. Specifically, the weight average molecular weight of the collagen peptide in the fermented product is measured to confirm that the molecular weight is lower than that of the collagen raw material, or when the culture time elapses for a predetermined time, for example, 24 hours. By setting the temperature of the fermented product to 75 ° C. or higher, the progress of fermentation by the collagen raw material koji may be stopped.
- the weight average molecular weight of the collagen peptide in the fermented product can be, for example, the same as the method for measuring the weight average molecular weight of the collagen peptide described above.
- the second step preferably includes a separation treatment step in order to separate and obtain a biological function modifier containing a fermented collagen peptide from the fermented product.
- Conventionally known separation treatment can be applied to this separation treatment step.
- the fermented collagen peptide can be separated from the fermented product by a separation treatment such as coarse filtration using a nylon mesh, centrifugation, or filter paper filtration using a commercially available filter paper.
- This preferably comprises a collagen peptide and a fermented collagen peptide containing at least one selected from the group consisting of isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional, and more preferably three first compounds.
- a biofunction adjusting agent containing the above can be obtained. Since the fermented product contains a fermented collagen peptide, the fermented product itself can be regarded as a biological function regulator.
- the second step preferably includes a step (purification step) of purifying the biological function adjusting agent or the fermented product obtained by applying the above-mentioned separation treatment step for the purpose of increasing the transparency thereof.
- a conventionally known purification treatment can be applied, for example, a purification treatment using diatomaceous earth, a purification treatment by microfiltration, or the like can be performed.
- a deodorizing treatment can be performed by using activated carbon or the like.
- the biological function modifier obtained as described above can be stored as it is in a solution state.
- a dry powder of the biological function adjusting agent can be obtained by using a conventionally known method such as spraying or drum drying with respect to the biological function adjusting agent in a solution state, and the dried powder can be stored in that state.
- a conventionally known formulation technique for the dry powder of the biological function adjusting agent it is possible to obtain various dosage forms as described above.
- the method for producing a biological function adjusting agent according to the present embodiment contains a fermented collagen peptide, and based on the fermented collagen peptide, has an epidermal metabolism promoting action, a fat accumulation suppressing action, a lipolysis promoting action, and an adipocytokine in the living body. It is possible to obtain a biological function adjusting agent having at least one biological function adjusting action selected from the group consisting of an amount adjusting action.
- Samples 1 to 5 and Samples 41 to 49 are biological function modifiers of Examples
- Samples 101 to 104 are collagen peptides or gelatin of Comparative Examples.
- gelatin derived from pig skin (trade name: "BCN-HL", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: about 65,000) was prepared.
- a fermented product containing fermented collagen peptide was obtained by fermenting the collagen raw material with the above-mentioned koji by the following procedure. First, a dispersion consisting of 5 g of the collagen raw material, 1 g of the barley bran koji (dry weight) and 50 mL of RO water was prepared, and cultured for 5 hours while maintaining the temperature of the dispersion at 40 ° C. Then, the temperature of the dispersion is set to 75 ° C., and the dispersion is maintained at a temperature of about 75 ° C. for 10 minutes to inactivate the aspergillus in the barley bran koji, thereby obtaining a fermented product containing fermented collagen peptide. rice field.
- the biological function adjusting agent of Sample 1 was an aqueous solution, and when the weight average molecular weight thereof was measured, it was confirmed that the molecular weight was lower than that of the collagen raw material. Further, it was confirmed that the biological function adjusting agent of Sample 1 contained isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional as the first compound from the analysis using the above-mentioned gas chromatograph mass spectrometer.
- a dispersion consisting of 1 kg of the collagen raw material, 200 g of the barley bran koji (dry weight) and 1500 mL of RO water was prepared, and cultured for 6 hours while maintaining the temperature of the dispersion at 40 ° C. Then, the temperature of the dispersion is set to 70 ° C., and the dispersion is maintained at a temperature of about 70 ° C. for 1 hour to inactivate the aspergillus in the barley bran koji, thereby obtaining a fermented product containing fermented collagen peptide. rice field. Further, the above fermented product was subjected to ADVANTEC FILTER PAPER No. It was purified by filtering using No. 5 (manufactured by Toyo Filter Paper Co., Ltd.) and further performing diatomaceous earth filtration. Other than that, the biological function modifier of Sample 2 was obtained by the same method as that of Sample 1.
- the biological function modifier of Sample 2 was made into a dry powder by using a spray dryer (manufactured by Okawara Seisakusho Co., Ltd.).
- the biological function modifier of Sample 2 was a dry powder, and when the weight average molecular weight thereof was measured, it was confirmed that the molecular weight was lower than that of the collagen raw material. Further, it was confirmed that the biological function adjusting agent of Sample 2 contained isovaleraldehyde, phenylacetaldehyde and methional as the first compound from the analysis using the above-mentioned gas chromatograph mass spectrometer.
- gelatin derived from pig skin (trade name: "BCN-HL", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: about 65,000) was prepared.
- a fermented product containing fermented collagen peptide was obtained by fermenting the collagen raw material with the above-mentioned koji by the following procedure. First, a dispersion consisting of 13% by mass (dry weight) of barley bran koji and 87% by mass of RO water was prepared, and the mixture was stirred for 1 hour while maintaining the temperature of the dispersion at 40 ° C. Then, a koji extract was obtained by rough filtration with a nylon mesh and filtration with diatomaceous earth and cellulose. Next, a dispersion consisting of 40% by mass of the collagen raw material and 60% by mass of the koji extract was prepared and cultured for 6 hours while maintaining the temperature of the dispersion at 40 ° C.
- the temperature of the dispersion liquid was set to 80 ° C.
- the above dispersion liquid was maintained at a temperature of about 80 ° C. for 60 minutes for low temperature sterilization, and a spray dryer (manufactured by Okawara Seisakusho Co., Ltd.) was used to obtain a dry powder. Therefore, the biological function adjusting agent of Sample 3 was obtained.
- the biological function modifier of Sample 3 was a dry powder, and when the weight average molecular weight thereof was measured, it was confirmed that the molecular weight was lower than that of the collagen raw material. Further, it was confirmed that the biological function adjusting agent of Sample 3 contained isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional as the first compound from the analysis using the above-mentioned gas chromatograph mass spectrometer.
- Example 4 A dispersion consisting of 40% by mass of the collagen raw material and 60% by mass of the koji extract was prepared and cultured for 6 hours while maintaining the temperature of the dispersion at 40 ° C., and then the temperature of the dispersion was 60 ° C. and 60 ° C.
- a biological function adjusting agent for Sample 4 was obtained by the same method as for obtaining Sample 3, except that the dispersion was kept at a nearby temperature for 60 minutes for low temperature sterilization.
- the biological function modifier of Sample 4 was a dry powder, and when the weight average molecular weight thereof was measured, it was confirmed that the molecular weight was lower than that of the collagen raw material. Further, it was confirmed that the biological function adjusting agent of Sample 4 contained isovaleraldehyde, 1-octen-3-ol, phenylacetaldehyde and methional as the first compound from the analysis using the above-mentioned gas chromatograph mass spectrometer.
- a fermented product containing fermented collagen peptide was obtained by fermenting the collagen raw material with the above-mentioned koji by the following procedure. First, a dispersion consisting of 10% by mass of the collagen raw material, 2% by mass (dry weight) of the barley bran koji, and 88% by mass of RO water was prepared, and cultured for 6 hours while maintaining the temperature of the dispersion at 40 ° C. Then, the temperature of the dispersion is set to 75 ° C., and the dispersion is maintained at a temperature of about 75 ° C. for 60 minutes to inactivate the aspergillus in the barley bran koji, thereby obtaining a fermented product containing fermented collagen peptide. rice field.
- the fermented product was centrifuged at a centrifugal acceleration of 1610 G for 30 minutes, and the supernatant was obtained to obtain a biological function adjusting agent for Sample 5.
- the biological function adjusting agent of Sample 5 was an aqueous solution, and when the weight average molecular weight thereof was measured, it was confirmed that the molecular weight was lower than the weight average molecular weight of the collagen raw material. Further, it was confirmed from the analysis using the above-mentioned gas chromatograph mass spectrometer that the biological function adjusting agent of Sample 5 contained isovaleraldehyde, 1-octen-3-ol and phenylacetaldehyde as the first compound.
- sample 101 A dry powder of collagen peptide (trade name: "Korapep PU", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: 630) was prepared as a sample 101. It was confirmed that the sample 101 did not contain the first compound from the analysis using the gas chromatograph mass spectrometer described above.
- sample 102 A dry powder of gelatin derived from pig skin (trade name: "BCN-HL", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: about 65,000) was prepared as a sample 102. It was confirmed that the sample 102 did not contain collagen peptide and did not contain the first compound from the analysis using the gas chromatograph mass spectrometer described above.
- sample 103 A dry powder of collagen peptide (trade name: "CP prototype", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: 500 to 1000) was prepared as sample 103. It was confirmed that the sample 103 did not contain the first compound from the analysis using the gas chromatograph mass spectrometer described above.
- CP prototype manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: 500 to 1000
- sample 104 A dry powder of collagen peptide (trade name: "SCP-5200", manufactured by Nitta Gelatin Co., Ltd., weight average molecular weight: 3000 to 6000) was prepared as a sample 104. It was confirmed that the sample 104 did not contain the first compound from the analysis using the gas chromatograph mass spectrometer described above.
- mice Thirty 5-week-old male C57BL / 6J mice were prepared by purchasing from Japan Marie Co., Ltd.
- the mice are referred to as a low-fat diet intake group (hereinafter, also referred to as “L group”), a high-fat diet intake group (hereinafter, also referred to as “H group”), and a high-fat diet and sample 2 (5% by mass) intake group (hereinafter, also referred to as “H group”).
- L group low-fat diet intake group
- H group high-fat diet intake group
- H group high-fat diet and sample 2 (5% by mass) intake group
- breeding pH feeding breeding
- the liver was treated as follows. First, 0.5 g of the liver was homogenized with 2.5 mL of a 1.15 mass% potassium chloride (KCl) solution and placed in an ice-cooled test tube. Further, the test tube was centrifuged (gravitational acceleration 9830 G, 10 minutes, 4 ° C.), and the supernatant was used as a crude enzyme solution. Then, 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA were added to the crude enzyme solution based on the methods described by Nepokuroeff et al.
- KCl potassium chloride
- the strength of fatty acid synthase (FAS) activity was determined by measuring the enzyme activity (wavelength 340 nm) from the rate of decrease of NAPDH in the presence of 25 ⁇ M acetyl-CoA. Further, the crude enzyme solution was subjected to dithionitrobenzoic acid (DTNB) in the presence of 2 mM palmitoyl CoA and 125 mM L-carnitine based on the method described by Markwell et al. (J Biol. Chem, 248: 3426-3432, 1973). The strength of the fatty acid degrading enzyme (carnitine palmitoyl transferase: CPT) activity was determined by measuring the enzyme activity (wavelength 412 nm) from the reaction rate of. The results are shown in FIGS. 1 to 9. Regarding the significant difference between each group (L group, H group and FCP group) in FIGS. 1 to 9, Bonferrioni multiple comparison test was performed, and P ⁇ 0.05 was determined to be statistically significant.
- FIG. 1 is a graph showing changes in body weight of mice in each group in the first test. According to FIG. 1, it is understood that the weight gain of the FCP group is significantly suppressed as compared with the H group.
- FIG. 2 is a graph showing the amount of intestinal fat in the mice of each group in the first test.
- FIG. 3 is a graph showing the perikidney fat mass of the mice in each group in the first test.
- FIG. 4 is a graph showing the peritesticular fat mass of the mice in each group in the first test.
- FIG. 5 is a graph showing the total visceral fat mass of the mice in each group in the first test. According to FIGS. 2 to 5, it is evaluated that the fat accumulation in each organ of the FCP group is significantly suppressed as compared with that of the H group. Therefore, it is suggested that the effect of suppressing fat accumulation can be obtained in the FCP group.
- FIG. 6 is a graph showing the serum leptin concentration of the mice of each group in the first test.
- FIG. 7 is a graph showing the serum adiponectin concentration of the mice of each group in the first test.
- the blood concentration of leptin in the FCP group was significantly decreased as compared with that in the H group, and the blood concentration of adiponectin in the FCP group was significantly increased as compared with that in the H group. It is evaluated that it is doing. Therefore, in the FCP group, it is suggested that the effect of suppressing fat accumulation can be obtained through the action of adjusting the amount of adipocytokine in the living body.
- FIG. 8 is a graph showing the intensity of FAS activity in the liver of the mice of each group in the first test.
- FIG. 9 is a graph showing the intensity of CPT activity in the liver of the mice of each group in the first test.
- mice Forty 5-week-old male C57BL / 6J mice were prepared by purchasing from Japan Marie Co., Ltd.
- the mice were grouped into L group, H group, FCP group, high fat diet and sample 101 (5% by mass) intake group (hereinafter, also referred to as "CP group”) and high fat diet and sample 102 (5% by mass) intake group (hereinafter, also referred to as "CP group”).
- CP group high fat diet and sample 101 (5% by mass) intake group
- CP group high fat diet and sample 102 (5% by mass) intake group
- the feed intake and body weight of the mice were measured daily at predetermined times.
- the composition of the feed given to the mice in each of the above groups is as shown in Table 1 above.
- FIG. 10 is a graph showing the serum leptin concentration of the mice of each group in the second test.
- FIG. 11 is a graph showing the serum adiponectin concentration of the mice of each group in the second test.
- the blood concentration of leptin in the FCP group decreased with respect to that of the H group, and the blood concentration of adiponectin in the FCP group increased with respect to that of the H group. Be evaluated. Furthermore, it is evaluated that the blood concentration of leptin in the FCP group is lower than that in the CP group and the GL group, and the blood concentration of adiponectin in the FCP group is higher than that in the CP group and the GL group.
- NS Therefore, it is suggested that in the FCP group, a fat accumulation inhibitory effect can be obtained based on the effect of adjusting the amount of adipocytokine in the living body.
- ⁇ Test method> The above mouse-derived preadipocytes (Research Resource Bank, resource number JCRB9014, Lot. No. 01282009) were used as a culture medium (DMEM / F12 medium (subculture medium, catalog number: "11330-032", Gibco, 10 mass). Precultured with% FBS (containing penicillin and streptomycin). Then, from the precultured medium and the cells, a cell suspension in which the cells were 3 ⁇ 10 4 cells / mL was prepared. Further, the cell suspension was prepared. the 60mm dishes (catalog number: Corning, Cat.No.430166) by 5mL each dish were seeded (1.5 ⁇ 10 5 cell / dish), 2 days under the conditions of 37 ° C.
- DMEM / F12 medium subculture medium, catalog number: "11330-032", Gibco, 10 mass.
- FBS containing penicillin and streptomycin
- the medium in each dish was then cultivated with isobutylmethylxanthin (IBMX) and dexamethasone attached to the adipogenesis assay kit (catalog number: "ECM950", manufactured by Millipore) at a final concentration of 0.5 mM, respectively.
- the cells were replaced with the differentiation-inducing medium added so as to be 1 ⁇ M, and cultured under the condition of 37 ° C. (5% by volume CO 2 ) for another 2 days.
- the insulin attached to ECM950 manufactured by Millipore
- the differentiation medium was replaced with the subculture medium.
- the final concentration was 0.1% by mass based on the adipocytes in the subculture medium.
- Sample 1 sample 2, sample 101, sample 103, velverin chloride solution and RO water were added to each of the three dishes. After that, the subculture medium was replaced with a new subculture medium and the final concentration was adjusted. Sample 1, sample 2, sample 101, and sample 103 were re-added so as to be 0.1% by mass, and a penicillin chloride solution was added so that the final concentration was 2 ⁇ g / mL. Was re-added and RO water was re-added to each corresponding dish.
- the Oil Red O solution attached to the above-mentioned kit was added to each dish at room temperature. That is, the adipocytes in each medium to which sample 1, sample 2, sample 101, sample 103, velverin chloride solution and RO water were added were washed twice with PBS (phosphate buffered saline), and then to each dish 36. 1.25 mL of the above Oil Red O solution having a mass% concentration was added.
- Fat accumulation rate (%) [(measured value of OD520 nm of each sample) / (measured value of Blank OD520 nm) ⁇ 100].
- Table 3 shows the average value (Ave) and standard deviation of the fat accumulation rates of the three samples in each sample and the like. Further, in Table 3, by performing statistical processing on each measured value, a significant difference regarding whether or not fat accumulation was suppressed was also determined. Analysis processing software (trade name: "STAT Mate V", manufactured by Atoms Co., Ltd.) was used for the above statistical processing. The above significant difference was determined by performing one-way analysis of variance (One-way ANOVA) with a confidence interval of 95% and Tukey's test as post-tests. In Table 3, p ⁇ 0.001 is represented by ***, p ⁇ 0.01 is represented by **, and p ⁇ 0.05 is represented by *.
- the biological function adjusting agents of Samples 41 to 49 are prepared by the same method as for obtaining the biological function adjusting agent of Sample 2, except that the conditions for fermenting the collagen raw material with the above-mentioned koji are as shown in Table 4. Made.
- the conditions for fermenting the collagen raw material with the above-mentioned Jiuqu were the same as in Sample 2.
- Table 4 also shows the weight average molecular weight of the collagen peptide contained in each sample.
- the medium in the petri dish was replaced with a test medium (trade name: "HuMedia KB2", manufactured by Kurabo Industries Ltd.). Further, the biological function adjusting agents of Sample 1 and Sample 2, Sample 104 and RO water were added to each well of each plate so that the final concentration was 0.1% by mass, and 37 ° C. (5% by volume CO). It was cultured under the conditions of 2).
- the cells in the plate for measuring the gene expression level of keratin 10 (KRT10) described later are cultured for 24 hours, and the gene expression levels of involucrin (Ivr) and transglutaminase (TGM1) described later are measured.
- the cells in the above plate were cultured for 48 hours.
- CDNA was obtained by reverse transcription of the above total RNA using High Capacity RNA to cDNA Kit (catalog number: "4387406", manufactured by Life Technologies), and the cDNA was subjected to real-time RT-PCR.
- KRT10 (primer: Hs01043114_gl, manufactured by Thermo Fisher Scientific)
- TGM1 primary: Hs01070310_ml, manufactured by Thermo Fisher Scientific
- Ivr primary: Hs00846307_sl, Thermo Fisher
- FAM dye was used as a primer and a probe.
- Real-time RT-PCR is performed by an apparatus (trade name: "Step One Plus”, manufactured by Applied Biosystems), and a reagent kit (trade name: “TaqMan (registered trademark) fast advanced master mix", catalog number: “4444556", (Manufactured by Applied Biosystems) was used.
- the PCR conditions were as follows: initial denaturation (95 ° C., 20 seconds, 1 cycle), annealing (95 ° C., 1 second) and polymerization (60 ° C., 20 seconds) for 40 cycles.
- the total RNA (cDNA) obtained from the well to which RO water is added becomes Blank. The results are shown in Tables 6-8.
- Table 6 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of KRT10 in Samples 1 and 2, and Sample 104 with respect to Blank.
- Table 7 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of TGM1 in Sample 2 and Sample 104 with respect to Blank.
- Table 8 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of Ivr in Samples 1 and 2, and Sample 104 with respect to Blank.
- Tables 6 to 8 also show significant differences regarding whether or not the expression of each gene determined by performing statistical processing on each measured value is enhanced.
- Table 9 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of KRT10 in Samples 41 to 49 with respect to Blank.
- Table 10 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of TGM1 in Samples 41 to 49 with respect to Blank.
- Table 11 shows the relative values (average value (Ave) and standard deviation of each of the three samples) of the gene expression level of Ivr in Samples 41 to 49 with respect to Blank.
- FIG. 12 is a graph showing changes in body weight of mice in each group in the seventh study. According to FIG. 12, it is understood that the weight gain of the FCP group is significantly suppressed as compared with the H group.
- Negative control group (Group B) ingesting and, FCP ingesting a diet in which 6% by mass of 20% by mass of casein contained in a normal diet is replaced with a biological function regulator of sample 3 and 15% by mass of fructose water.
- Group -3 (Group C)
- FCP-4 group (Group C) ingesting a diet in which 6% by mass of 20% by mass of casein contained in a normal diet was replaced with the biological function modifier of Sample 4 and 15% by mass of fructose water.
- Group D Korapep PU group (Group E) ingesting a diet in which 6% by mass of casein contained in the normal diet was replaced with sample 101 and 15% by mass of fructose water, and the normal diet.
- mice in each group were bred (pair feeding) by feeding the corresponding diet and water for 35 days.
- feed intake and body weight in each mouse were measured daily at predetermined times.
- Table 12 shows a list of diet (unit: mass%) and water content given to the mice in each of the above groups.
- “water / 15% by mass fructose water” in Table 12 “W” indicates that water was given, and “F” indicates that fructose water was given.
- the composition of the ordinary diet is 20% by mass of casein, 26.75% by mass of corn starch, 10% by mass of sucrose, 20% by mass of corn oil, 13.2% by mass of ⁇ corn starch, and 5% by mass of cellulose.
- AIN-93G purified feed is 20% by mass of casein, 26.75% by mass of corn starch, 10% by mass of sucrose, 20% by mass of corn oil, 13.2% by mass of ⁇ corn starch, and 5% by mass of cellulose.
- AIN-93 a diet
- AIN-93G 1% by
- the liver was treated as follows. First, 0.5 g of the liver was homogenized with 2.5 mL of a 1.15 mass% potassium chloride (KCl) solution and placed in an ice-cooled test tube. Further, the test tube was centrifuged (gravitational acceleration 9830 G, 10 minutes, 4 ° C.), and the supernatant was used as a crude enzyme solution. Then, 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA and 100 ⁇ M malonyl-CoA were added to the crude enzyme solution based on the methods described by Nepokuroeff et al.
- KCl potassium chloride
- the strength of fatty acid synthase (FAS) activity was determined by measuring the enzyme activity (wavelength 340 nm) from the rate of decrease of NAPDH in the presence of 25 ⁇ M acetyl-CoA. Further, the crude enzyme solution was subjected to dithionitrobenzoic acid (DTNB) in the presence of 2 mM palmitoyl CoA and 125 mM L-carnitine based on the method described by Markwell et al. (J Biol. Chem, 248: 3426-3432, 1973). The strength of the fatty acid degrading enzyme (carnitine palmitoyl transferase: CPT) activity was determined by measuring the enzyme activity (wavelength 412 nm) from the reaction rate of. The results are shown in FIGS. 13 to 22. Regarding the significant difference between each group (Group A to Group F) in FIGS. 13 to 22, Tukey's HSD multiple comparison test was performed, and P ⁇ 0.05 was determined to be statistically significant.
- FIG. 13 is a graph showing the body weight of the mice in each group in the eighth test. According to FIG. 13, the weight gain of the B group, the E group and the F group could not be suppressed with respect to the A group, but the weight gain of the C group and the D group was significantly suppressed with respect to the A group. It is understood that it has been done.
- FIG. 14 is a graph showing the amount of intestinal fat in the mice of each group in the eighth test.
- FIG. 15 is a graph showing the perikidney fat mass of the mice in each group in the eighth test.
- FIG. 16 is a graph showing the peritesticular fat mass of the mice in each group in the eighth test.
- FIG. 17 is a graph showing the total visceral fat mass of the mice in each group in the eighth test. According to FIGS. 14 to 17, it is evaluated that the fat accumulation in each organ of the C group and the D group is significantly suppressed or tends to be suppressed as compared with that of the B group, the E group and the F group. Therefore, it is suggested that the C group and the D group have an effect of suppressing the accumulation of visceral fat under fructose loading.
- FIG. 18 is a graph showing the blood glucose level in the serum of the mice of each group in the eighth test.
- FIG. 19 is a graph showing the amount of insulin in the serum of the mice of each group in the eighth test.
- FIG. 18 suggests that the blood glucose levels of the C group and the D group are significantly lower than those of the B group.
- FIG. 19 suggests that the insulin levels in the C and D groups are significantly lower than those in the B, E and F groups.
- FIG. 20 is a graph showing the serum leptin concentration of the mice of each group in the eighth test. According to FIG. 20, it is suggested that in groups C and D, the amount of leptin produced in the living body is reduced, so that the effect of suppressing the accumulation of visceral fat can be obtained even when fructose is loaded.
- FIG. 21 is a graph showing the intensity of FAS activity in the liver of the mice of each group in the eighth test. According to FIG. 21, it is evaluated that the synthesis of fatty acids in the C group and the D group is significantly suppressed as compared with that of the B group, the E group and the F group. Therefore, it is suggested that the C group and the D group have an effect of suppressing the accumulation of visceral fat under fructose loading by suppressing the synthesis of fatty acids. Further, FIG. 22 is a graph showing the intensity of CPT activity in the liver of the mice of each group in the eighth test. According to FIG.
- ⁇ Test method> Fifteen 7-week-old female Hos: HR-1 mice were prepared by purchasing from Hoshino Test Animal Breeding Co., Ltd., and the above-mentioned mice were bred until 8 weeks of age. After that, 5 of the above mice were ingested as a normal diet with lab MR stock feed (manufactured by Nosan Corporation) and water, group X, refined feed for HR-AD and water were ingested, and a sample. The whole body was divided into 3 groups (n 5) of the Z group to ingest the purified feed for HR-AD to which 5% by mass of the biological function adjusting agent of 3 was added and water.
- mice in each group were bred by feeding the corresponding feed and water for 8 weeks (56 days). During the breeding, the feed intake and body weight of each mouse were measured and photographed once a week. Furthermore, mice to be euthanized before the start of breeding and at the end of breeding were selected from the mice in each group, and the skins on the back and abdomen (lumbar) of the euthanized mice were collected. Furthermore, regarding the above skin, H. E. A stained specimen was prepared, and histopathological observation was performed including measuring the thickness of the stratum corneum of the skin. Table 13 shows the thickness of the stratum corneum of the skin measured at each part of the back (back of the neck and the center of the back) and the abdomen (lumbar) of the mouse.
- the purified feed for HR-AD is a feed that can evaluate atopic dermatitis because deficiency of polyunsaturated fatty acids (n-6 PUFAs) causes atopic dermatitis (AD) -like symptoms. ..
- Its composition is as amino acids: arginine 0.75% by mass, histidine 0.60% by mass, isoleucine 1.03% by mass, leucine 2.02% by mass, lysine 1.69% by mass, methionine 0.69% by mass, tyrosine.
- Vitamin E 160 mg Vitamin K 5 mg, Choline 868.2 mg, Folic acid 0.09 mg, Niacin 320 mg, Biotin 0.8 mg, Vitamin B1 13 mg, Vitamin B2 16.3 mg, Vitamin B6 52.7 mg, Vitamin B12 0.08 mg, It contains 129.6 mg of vitamin C and 29.7 mg of pantothenic acid, and contains 0.9% by mass of calcium, 0.33% by mass of chlorine, 0.02% by mass of magnesium, 0.77% by mass of phosphorus, and 0.42 of potassium as minerals.
- Mass% sodium 0.2 mass%, selenium 0.00 mass%, iodine 0.22 mg / kg, iron 276.78 mg / kg, cobalt 0.002 mass%, manganese 79.28 mg / kg, zinc 122.52 mg / kg It contains kg and 21.50 mg / kg of copper.
- “Mean” means the median and "SD” means the standard deviation.
- mice in group Y were established as an atopic dermatitis-like model with dry skin and thickened epidermis.
- the thickness of the stratum corneum on the back of the neck was significantly lower, and the above-mentioned biological function modifier It was considered that the thickening of the epidermis was suppressed based on the skin metabolism promoting action.
- Test 10 By ingesting the biological function adjusting agent of Sample 4 to healthy men and women aged 20 to 70 years or younger, it was tested whether or not the biological function adjusting agent has a fat accumulation inhibitory effect on humans. Specifically, the tenth test was carried out according to the following procedure.
- the selection criteria are i) men and women between the ages of 20 and 70, ii) healthy people who have no abnormalities in the health examination within one year from the start of the test, iii) initial stage. Those with a visceral fat area of 80 cm 2 or more, iv) Those who can maintain an intake rate of 80% or more over the next 6 months.
- Exclusion criteria are A) those who have a history of serious illness, B) those who show abnormalities in liver function and renal function test values in health examination, C) those who show impaired cardiopulmonary function, D) food and drug allergies.
- test food As the test food, sample 101 (CP group) and sample 4 (FCP group) were used.
- sample 101 CP group
- sample 4 FCP group
- PL group placebo group
- maltodextrin trade name: "Paindex # 2", manufactured by Matsutani Chemical Industry Co., Ltd.
- the visceral fat area was measured using Dualscan HDS-2000 (manufactured by OMRON Corporation, medical device approval number: 22300BZX00104000).
- the Dualscan HDS-2000 is a visceral fat measuring device that can easily and safely calculate the visceral fat area by the dual impedance method, and distinguishes visceral fat and abdominal subcutaneous fat by passing current from two paths. It is possible to measure the visceral fat area non-invasively without the risk of exposure.
- the skin quality was measured only for the subjects who consented to take a facial photograph. The subjects were measured after washing the face only for men and after cleansing and washing the face for women and acclimatizing at room temperature for 20 minutes or more. The above measurement was carried out with a RoboSkin analyzer (manufactured by Shibuya Kogyo Co., Ltd.). Specifically, frontal, right-facing, and left-facing photographs of the face were taken and pigmentation was assessed by the RoboSkin Analyzer algorithm.
- ⁇ Discussion> According to Table 14, no significant difference was confirmed in the visceral fat area between the CP group and the PL group and 0time. However, in the FCP group, a significant difference from 0 time was confirmed. Furthermore, in the group of men of 110 cm 2 or more by rank, the visceral fat area was significantly reduced in the FCP group as compared with the PL group. In terms of skin quality (evaluation of increase / decrease in pigmentation), the area and number of the FCP group were significantly reduced as compared with the PL group. At the same time, ⁇ (3 months-0 time) also decreased significantly as compared with the PL group. Further, according to Table 15, in the skin quality (evaluation of increase / decrease in pigmentation), the CP group significantly decreased in ⁇ (3 months-0 time) as compared with the PL group.
- the significant difference in the subjects with a visceral fat area of 110 cm 2 or more was that the amount of visceral fat was larger than that of the subjects with a visceral fat area of less than 110 cm 2 , so that the visceral fat was easily burned by ingestion of the above-mentioned biological function adjusting agent, and the visceral fat was easily burned in 3 months. It is speculated that it was easy to make a difference. Therefore, it is considered that even a person having a visceral fat area of less than 110 cm 2 may obtain the same effect by continuing to take the above-mentioned biological function adjusting agent. In addition, it was suggested that the intake of the above-mentioned biological function modifier not only suppresses the visceral fat area but also the pigmentation of the skin at the same time.
- Test method The eleventh test was carried out by the same method as the third test except that the sample added to the adipocytes was replaced with the sample 5. The results are shown in Table 16.
- Samples 1 to 5 and Samples 41 to 49 have a fat accumulation inhibitory action and an epidermal metabolism promoting action. Furthermore, it is also suggested that Samples 1 to 5 and Samples 41 to 49 have an action of adjusting the amount of adipocytokine in the living body.
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Abstract
Description
〔1〕 本発明に係る生体機能調整剤は、発酵コラーゲンペプチドを含み、上記発酵コラーゲンペプチドは、表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の作用を有する。
〔2〕 上記発酵コラーゲンペプチドは、コラーゲンペプチドと、イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも1種の第1化合物とを含むことが好ましい。
〔3〕 上記発酵コラーゲンペプチドは、コラーゲンペプチドと、イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも3種の第1化合物とを含むことが好ましい。
〔4〕 本発明に係る表皮代謝促進剤は、上記生体機能調整剤を含む。
〔5〕 本発明に係る脂肪蓄積抑制剤は、上記生体機能調整剤を含む。
〔6〕 本発明に係るアディポネクチン産生促進剤は、上記生体機能調整剤を含む。
〔7〕 本発明に係る脂肪分解促進剤は、上記生体機能調整剤を含む。
〔8〕 本発明に係る機能性食品は、上記生体機能調整剤を含む。
〔9〕 本発明に係る化粧料は、上記生体機能調整剤を含む。
〔10〕 本発明に係る生体機能調整剤の製造方法は、発酵コラーゲンペプチドを含む生体機能調整剤の製造方法であって、麹菌を含む麹とコラーゲン原料とを準備する工程と、上記コラーゲン原料を上記麹で発酵させることにより、上記発酵コラーゲンペプチドを含む生体機能調整剤を得る工程とを含み、上記麹菌の菌種は、アスペルギルス属に属する菌種であり、上記コラーゲン原料は、以下の第1群~第6群からなる群より選ばれる少なくとも1種、上記群より選ばれる少なくとも1種から抽出されたコラーゲン、上記コラーゲンを処理することにより得られるゼラチン、および上記ゼラチンを加水分解することにより得られるゼラチン分解物の少なくともいずれかである。
第1群:牛の皮、皮膚、骨、軟骨および腱からなる群
第2群:豚の皮、皮膚、骨、軟骨および腱からなる群
第3群:羊の皮、皮膚、骨、軟骨および腱からなる群
第4群:鶏の皮、皮膚、骨、軟骨および腱からなる群
第5群:ダチョウの皮、皮膚、骨、軟骨および腱からなる群
第6群:魚の骨、皮および鱗からなる群
〔11〕 本発明に係る生体機能調整剤は、コラーゲン原料を麹で発酵させることにより製造された発酵コラーゲンペプチドを含む。
第1群:牛の皮、皮膚、骨、軟骨および腱からなる群
第2群:豚の皮、皮膚、骨、軟骨および腱からなる群
第3群:羊の皮、皮膚、骨、軟骨および腱からなる群
第4群:鶏の皮、皮膚、骨、軟骨および腱からなる群
第5群:ダチョウの皮、皮膚、骨、軟骨および腱からなる群
第6群:魚の骨、皮および鱗からなる群。
本実施形態に係る生体機能調整剤は、発酵コラーゲンペプチドを含む。上記発酵コラーゲンペプチドは、表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の作用を有する。このような特徴を備える生体機能調整剤は、生体に対して表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の作用(以下、「生体機能調整作用」ともいう)を奏することができる。
本実施形態に係る生体機能調整剤は、上述のように発酵コラーゲンペプチドを含む。上記発酵コラーゲンペプチドは、コラーゲンペプチドと、イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも1種の第1化合物とを含むことが好ましい。上記発酵コラーゲンペプチドは、コラーゲンペプチドと、イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも3種の第1化合物とを含むことがより好ましい。これにより、生体に対して表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の生体機能調整作用を、より十分に奏することができる。また後述するように本実施形態に係る生体機能調整剤は、コラーゲン原料を麹で発酵させることにより製造される。すなわち本実施形態に係る生体機能調整剤は、発酵コラーゲンペプチドを含む生体機能調整剤である。
発酵コラーゲンペプチドは、上述のようにコラーゲンペプチドを含むことが好ましい。このコラーゲンペプチドは、見かけ上、従来公知のコラーゲンペプチドと同じである。すなわち発酵コラーゲンペプチドに含まれるコラーゲンペプチドは、見かけ上ペプチド混合物として、コラーゲンまたはゼラチンに対して従来公知の処理を行うことにより得られるジペプチド、トリペプチド、オリゴペプチドおよびポリペプチドなどの各種のペプチドを含み得る。ただし発酵コラーゲンペプチドは、上述のとおりコラーゲン原料を麹で発酵させることによって得られる。このため上記発酵コラーゲンペプチドに含まれるコラーゲンペプチドは、コラーゲン原料を麹で発酵させることにより得られ、後述する第1化合物と共に産生される。
発酵コラーゲンペプチドに含まれるコラーゲンペプチドは、重量平均分子量が20000以下であることが好ましい。上記コラーゲンペプチドの重量平均分子量が20000以下である場合、生体機能調整剤は、表皮代謝促進剤、脂肪蓄積抑制剤、脂肪分解促進剤、アディポネクチン産生促進剤、機能性食品および化粧料の各用途に対し、追加的な処理を行うことなく簡便に適用することができる。上記コラーゲンペプチドは、重量平均分子量が10000以下であることがより好ましく、6000以下であることがさらに好ましい。上記コラーゲンペプチドの重量平均分子量の下限値は、76である。上記コラーゲンペプチドの重量平均分子量が上述の範囲である場合、生体機能調整剤は、表皮代謝促進剤、脂肪蓄積抑制剤、脂肪分解促進剤、アディポネクチン産生促進剤、機能性食品または化粧料の各用途において、生体に対し上述した作用を十分に奏することが可能となる。
機器 :高速液体クロマトグラフィー(HPLC)(東ソー株式会社製)
カラム:TSKGel(登録商標)G2000SWXL
カラム温度:40℃
溶離液:45質量%アセトニトリル(0.1質量%TFAを含む)
流速 :1.0mL/min
注入量:10μL
検出 :UV214nm
分子量マーカー:以下の5種を使用
Cytochrom C Mw:12000
Aprotinin Mw:6500
Bacitracin Mw:1450
Gly-Gly-Tyr-Arg Mw:451
Gly-Gly-Gly Mw:189。
発酵コラーゲンペプチドは、上述のように好ましくはイソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも1種の第1化合物を含み、より好ましくは少なくとも3種の上記第1化合物を含む。上記発酵コラーゲンペプチドにおいて第1化合物は、コラーゲン原料を麹で発酵させることにより、コラーゲンペプチドとともに産生されると考えられる。第1化合物は、上記発酵コラーゲンペプチドが、コラーゲン原料を麹で発酵させることにより得られたものであることを示すマーカーとして機能することができる。
イソバレルアルデヒドは、イソ吉草酸アルデヒド、3-メチルブタナールまたは3-メチルブチルアルデヒドとも称される化合物であり、従来から香料(食品添加物)などとして利用されている化合物である。
1-オクテン-3-オールは、不飽和アルコールの一種であって、従来からマツタケの香りに寄与する成分であることが知られる化合物である。
フェニルアセトアルデヒドは、芳香族アルデヒドの一種であって、従来からフレグランスおよびフレーバーの調合原料等として利用されている化合物である。
メチオナールは、有機硫黄化合物の一種であって、3-メチルチオ-1-プロパノールとも称される化合物である。メチオナールは、従来から醤油に含まれることが知られている化合物である。さらにメチオナールは、肉および魚の生臭さを弱める作用があることも知られている。
第1化合物は、その総量(少なくとも1種またはそれ以上の合計)として上記生体機能調整剤中に0.05ppm以上含まれることが好ましい。すなわち上記生体機能調整剤は、上記第1化合物を0.05ppm以上含むことが好ましい。さらに第1化合物は、その総量として上記生体機能調整剤中に0.4ppm以上含まれることがより好ましい。すなわち上記生体機能調整剤は、上記第1化合物を0.4ppm以上含むことがより好ましい。上記生体機能調整剤における第1化合物の含有量の下限値は、特に限定されないが、第1化合物の総量として0.01ppm以上含むことが好ましい。第1化合物の含有量の上限値についても特に制限されないが、第1化合物の総量として5ppm以下であることが好ましい。
本実施形態に係る表皮代謝促進剤は、上記生体機能調整剤を含む。上記表皮代謝促進剤は、上記生体機能調整剤が有する表皮代謝促進作用により、たとえば皮膚表面(表皮中)のメラニン顆粒をシミ、そばかす等として停滞させずに皮膚表面から排出することを促すことができる。具体的には、上記表皮代謝促進剤は、トランスグルタミナーゼ1(TGM1)、インボルクリン(Ivl)およびケラチン10(KRT10)からなる群より選ばれる少なくとも1種の遺伝子の発現量を亢進させることができる。これらの遺伝子は、表皮を構成する各層(角質層、顆粒層、有棘層および基底層)の成熟分化に寄与することが知られ、もって上述した遺伝子の発現亢進によって表皮における代謝(所謂ターンオーバー)が促進されるものと考えられる。さらに表皮における代謝が促進されることに基づき、皮膚の保湿効果、皮膚のしわ予防および/またはしわ改善効果等が得られる可能性がある。
本実施形態に係る脂肪蓄積抑制剤は、上記生体機能調整剤を含む。上記脂肪蓄積抑制剤は、上記生体機能調整剤が有する脂肪蓄積抑制作用により肝臓、腸管、腎臓、精巣等における脂肪(所謂内臓脂肪)の蓄積抑制効果を得ることができる。また上記脂肪蓄積抑制剤は、上記生体機能調整剤が有する生体内のアディポサイトカイン量の調整作用に基づいて、食欲ホルモンとして知られるレプチンの血中濃度減少作用、および体内の内臓脂肪量と逆相関することが知られるアディポネクチンの血中濃度増加作用を通じ、脂肪蓄積抑制効果を得ることができる。上記レプチンおよびアディポネクチンは、脂肪細胞から分泌されるアディポサイトカインに分類されるタンパク質として公知である。すなわち本実施形態に係るアディポネクチン産生促進剤は、上記生体機能調整剤を含む。
本実施形態に係る脂肪分解促進剤は、上記生体機能調整剤を含む。上記脂肪分解促進剤は、上記生体機能調整剤が有する脂肪分解促進作用により肝臓、腸管、腎臓、精巣等における脂肪(所謂内臓脂肪)の分解促進効果を得ることができる。上記脂肪分解促進剤における生体機能調整剤の濃度は、0.01~100質量%である場合がある。上記脂肪分解促進剤における生体機能調整剤の濃度は、第1化合物の含有量がごく僅かであることから、上記生体機能調整剤中のコラーゲンペプチドの濃度を意味するものとする。このため上記脂肪分解促進剤における生体機能調整剤の濃度は、上述した上記表皮代謝促進剤における生体機能調整剤の濃度測定方法と同じとすることができる。
ここで上述した表皮代謝促進剤、脂肪蓄積抑制剤、脂肪分解促進剤およびアディポネクチン産生促進剤は、サプリメント、医薬品または医薬部外品などとして、経口的にまたは非経口的に種々の形態で投与することができる。その形態としては、経口的に投与する場合、たとえば錠剤、顆粒剤、カプセル剤、粉剤、液剤、懸濁製剤、乳化製剤、ペースト剤などの剤型とすることができる。さらに上述した剤型を、後述する機能性食品に混合することもできる。
本実施形態に係る機能性食品は、上記生体機能調整剤を含む。上記機能性食品としては、たとえば特定保健用食品および機能性表示食品を例示することができる。上記機能性食品は、たとえば特定保健用食品または機能性表示食品として上記生体機能調整剤が有する表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の作用を奏することができる。上記機能性食品は、たとえば上記特定保健用食品または機能性表示食品における生体機能調整剤の濃度を0.01~100質量%とすることができる。上記機能性食品における生体機能調整剤の濃度は、第1化合物の含有量がごく僅かであることから、上記生体機能調整剤中のコラーゲンペプチドの濃度を意味するものとする。このため上記機能性食品における生体機能調整剤の濃度は、上述した上記表皮代謝促進剤における生体機能調整剤の濃度測定方法と同じとすることができる。
本実施形態に係る化粧料は、上記生体機能調整剤を含む。上記化粧料は、たとえば上記生体機能調整剤が有する表皮代謝促進作用に基づいて、美白効果、保湿効果、しわ予防および/またはしわ改善効果などを有する化粧料として提供することができる。上記化粧料における生体機能調整剤の濃度は、0.01~100質量%である場合がある。上記化粧料における生体機能調整剤の濃度は、第1化合物の含有量がごく僅かであることから、上記生体機能調整剤中のコラーゲンペプチドの濃度を意味するものとする。このため上記化粧料における生体機能調整剤の濃度は、上述した上記表皮代謝促進剤における生体機能調整剤の濃度測定方法と同じとすることができる。
本実施形態に係る生体機能調整剤の製造方法は、発酵コラーゲンペプチドを含む生体機能調整剤の製造方法である。上記生体機能調整剤の製造方法は、麹菌を含む麹とコラーゲン原料とを準備する工程(第1工程)と、上記コラーゲン原料を上記麹で発酵させることにより、上記発酵コラーゲンペプチドを含む生体機能調整剤を得る工程(第2工程)とを含む。
第1群:牛の皮、皮膚、骨、軟骨および腱からなる群
第2群:豚の皮、皮膚、骨、軟骨および腱からなる群
第3群:羊の皮、皮膚、骨、軟骨および腱からなる群
第4群:鶏の皮、皮膚、骨、軟骨および腱からなる群
第5群:ダチョウの皮、皮膚、骨、軟骨および腱からなる群
第6群:魚の骨、皮および鱗からなる群。
第1工程は、麹菌を含む麹とコラーゲン原料とを準備する工程である。第1工程は、上記生体機能調整剤を製造するため、必要となる各材料(麹菌を含む麹およびコラーゲン原料)を準備することを目的として実行される。
コラーゲン原料は、上述したように以下の第1群~第6群からなる群より選ばれる少なくとも1種「そのもの」、以下の第1群~第6群からなる群より選ばれる少なくとも1種から抽出された「コラーゲン」、上記コラーゲンを熱水抽出などの公知の方法を用いて処理することにより得られる「ゼラチン」、および上記ゼラチンを加水分解することにより得られる「ゼラチン分解物」の少なくともいずれかである場合がある。
第1群:牛の皮、皮膚、骨、軟骨および腱からなる群
第2群:豚の皮、皮膚、骨、軟骨および腱からなる群
第3群:羊の皮、皮膚、骨、軟骨および腱からなる群
第4群:鶏の皮、皮膚、骨、軟骨および腱からなる群
第5群:ダチョウの皮、皮膚、骨、軟骨および腱からなる群
第6群:魚の骨、皮および鱗からなる群。
麹菌を含む麹は、後述する第2工程を実行することによって本実施形態の効果が得られる麹を選択する限り、従来公知の方法により準備することができる。すなわち種麹となる麹菌を米、大麦、小麦または大豆などの雑穀に植菌し、次いで上記米、大麦、小麦または雑穀中で繁殖させることによって得ることができる。上記麹菌は、上記米、大麦、小麦または雑穀に対し0.01~1質量%となる量を植菌することが好ましい。本明細書において「雑穀」には、上述した大豆のほか、糠、ふすま、おからおよび脱脂大豆がいずれも含まれる。麹菌を含む麹の準備においては、他の細菌の混入を防ぐための麹室を設けることにより麹菌が繁殖しやすい環境を整え、上記麹室で必要な作業を行うことが好ましい。
第2工程は、上記コラーゲン原料を上記麹で発酵させることにより、上記発酵コラーゲンペプチドを含む生体機能調整剤を得る工程である。第2工程は、生体機能調整剤に含まれる発酵コラーゲンペプチドを得る目的で実行される。第2工程では、たとえば上記コラーゲン原料および上記麹を温水に投入し、かつこれらを温水中で所定時間培養することによって上記コラーゲン原料を上記麹で発酵させ、もって上記発酵コラーゲンペプチドを含む生体機能調整剤を得ることができる。培養時のpHの値は、2~10であることが好ましく、5~8であることがより好ましい。培養時のpHの値が2未満であるか、または10を超過する場合、コラーゲン原料の低分子化、コラーゲン臭の低減化などが不十分となる恐れがある。
第2工程は、上記発酵物から発酵コラーゲンペプチドを含む生体機能調整剤を分離して得るために分離処理工程を含むことが好ましい。この分離処理工程は、従来公知の分離処理を適用することができる。たとえばナイロン製メッシュを用いた粗濾過、遠心分離、市販の濾紙を用いた濾紙濾過等の分離処理により、上記発酵物から発酵コラーゲンペプチドを分離することができる。これにより好ましくはコラーゲンペプチドと、イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも1種、より好ましくは3種の第1化合物とを含む発酵コラーゲンペプチドを含む生体機能調整剤を得ることができる。なお上記発酵物は、発酵コラーゲンペプチドを含むことから上記発酵物自体を生体機能調整剤とみなすこともできる。
以上から、本実施形態に係る生体機能調整剤の製造方法は、発酵コラーゲンペプチドを含み、上記発酵コラーゲンペプチドに基づいて表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の生体機能調整作用を有する生体機能調整剤を得ることができる。
<試料1>
(第1工程)
次の手順により、麹菌を含む麹とコラーゲン原料とを準備した。
麹菌を含む麹として、アスペルギルス・ソーヤを植菌した大麦ふすま麹(株式会社樋口松之助商店製)を準備した。
コラーゲン原料として、豚皮を由来とするゼラチン(商品名:「BCN-HL」、新田ゼラチン株式会社製、重量平均分子量:約65000)を準備した。
次の手順により、上記コラーゲン原料を上記麹で発酵させることにより発酵コラーゲンペプチドを含む発酵物を得た。まず上記コラーゲン原料5g、上記大麦ふすま麹1g(乾燥重量)およびRO水50mLからなる分散液を調製し、上記分散液の温度を40℃で維持しながら5時間培養した。その後、上記分散液の温度を75℃とし、75℃付近の温度で上記分散液を10分間維持することにより上記大麦ふすま麹中の麹菌を失活させ、もって発酵コラーゲンペプチドを含む発酵物を得た。
第2工程において上記コラーゲン原料1kg、上記大麦ふすま麹200g(乾燥重量)およびRO水1500mLからなる分散液を調製し、上記分散液の温度を40℃で維持しながら6時間培養した。その後、上記分散液の温度を70℃とし、70℃付近の温度で上記分散液を1時間維持することにより上記大麦ふすま麹中の麹菌を失活させ、もって発酵コラーゲンペプチドを含む発酵物を得た。さらに、上記発酵物をADVANTEC FILTER PAPER No.5(東洋濾紙株式会社製)を用いて濾過し、さらに珪藻土濾過を行うことによって精製した。それ以外については、試料1を得るのと同じ方法により試料2の生体機能調整剤を得た。
(第1工程)
次の手順により、麹菌を含む麹とコラーゲン原料とを準備した。
麹菌を含む麹として、アスペルギルス・ソーヤを植菌した大麦ふすま麹(株式会社樋口松之助商店製)を準備した。
コラーゲン原料として、豚皮を由来とするゼラチン(商品名:「BCN-HL」、新田ゼラチン株式会社製、重量平均分子量:約65000)を準備した。
次の手順により、上記コラーゲン原料を上記麹で発酵させることにより発酵コラーゲンペプチドを含む発酵物を得た。まず上記大麦ふすま麹13質量%(乾燥重量)、RO水87質量%からなる分散液を調製し、上記分散液の温度を40℃で維持しながら1時間撹拌した。その後、ナイロン製メッシュによる粗濾過、珪藻土およびセルロースによる濾過を行うことにより麹抽出液を得た。次いで、上記コラーゲン原料40質量%、上記麹抽出液60質量%からなる分散液を調製し、分散液の温度を40℃で維持しながら6時間培養した。その後、分散液の温度を80℃とし、80℃付近の温度で上記分散液を60分間維持することにより低温殺菌を行い、かつ噴霧乾燥機(株式会社大川原製作所製)を用いることによって乾燥粉末とし、もって試料3の生体機能調整剤を得た。
上記コラーゲン原料40質量%、上記麹抽出液60質量%からなる分散液を調製し、分散液の温度を40℃で維持しながら6時間培養した後、分散液の温度を60℃とし、60℃付近の温度で上記分散液を60分間維持することにより低温殺菌を行ったこと以外、試料3を得るのと同じ方法により試料4の生体機能調整剤を得た。
(第1工程)
次の手順により、麹菌を含む麹とコラーゲン原料とを準備した。
麹菌を含む麹として、アスペルギルス・ソーヤを植菌した大麦ふすま麹(株式会社樋口松之助商店製)を準備した。
コラーゲン原料として、ティラピアの鱗を由来とするゼラチン(新田ゼラチン株式会社製、重量平均分子量:約150000)を準備した。
次の手順により、上記コラーゲン原料を上記麹で発酵させることにより発酵コラーゲンペプチドを含む発酵物を得た。まず上記コラーゲン原料10質量%、上記大麦ふすま麹2質量%(乾燥重量)およびRO水88質量%からなる分散液を調製し、上記分散液の温度を40℃で維持しながら6時間培養した。その後、上記分散液の温度を75℃とし、75℃付近の温度で上記分散液を60分間維持することにより上記大麦ふすま麹中の麹菌を失活させ、もって発酵コラーゲンペプチドを含む発酵物を得た。
コラーゲンペプチド(商品名:「コラペプPU」、新田ゼラチン株式会社製、重量平均分子量:630)の乾燥粉末を試料101として準備した。試料101は、上述したガスクロマトグラフ質量分析計を用いた分析から、第1化合物を含まないことを確認した。
豚皮を由来とするゼラチン(商品名:「BCN-HL」、新田ゼラチン株式会社製、重量平均分子量:約65000)の乾燥粉末を試料102として準備した。試料102は、コラーゲンペプチドを含まず、かつ上述したガスクロマトグラフ質量分析計を用いた分析から、第1化合物を含まないことを確認した。
コラーゲンペプチド(商品名:「CPプロトタイプ」、新田ゼラチン株式会社製、重量平均分子量:500~1000)の乾燥粉末を試料103として準備した。試料103は、上述したガスクロマトグラフ質量分析計を用いた分析から、第1化合物を含まないことを確認した。
コラーゲンペプチド(商品名:「SCP-5200」、新田ゼラチン株式会社製、重量平均分子量:3000~6000)の乾燥粉末を試料104として準備した。試料104は、上述したガスクロマトグラフ質量分析計を用いた分析から、第1化合物を含まないことを確認した。
試料2の生体機能調整剤をマウスに投与することにより、上記生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第1試験を実行した。
5週齢の雄性C57BL/6Jマウス30匹を日本クレア株式会社から購入することにより準備した。上記マウスを低脂肪食摂取群(以下、「L群」とも記す)、高脂肪食摂取群(以下、「H群」とも記す)、ならびに高脂肪食および試料2(5質量%)摂取群(以下、「FCP群」とも記す)の3群(n=10)に分け、各群に対応する飼料をそれぞれ与えることによって30日間の飼育(ペアフィーディング飼育)を行った。飼育中は、マウスの飼料摂取量および体重を毎日、所定の時間に測定した。上記の各群のマウスに与えた飼料の組成(単位は、質量%)を表1に示す。なお表1では後述する第2試験で用いる飼料の組成についても明示した。
図1は、第1試験における各群のマウスの体重の変化を示すグラフである。図1によれば、H群に対し、FCP群の体重増加が有意に抑制されていることが理解される。
試料2の生体機能調整剤をマウスに投与することにより、上記生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第2試験を実行した。
5週齢の雄性C57BL/6Jマウス40匹を日本クレア株式会社から購入することにより準備した。上記マウスをL群、H群、FCP群、高脂肪食および試料101(5質量%)摂取群(以下、「CP群」とも記す)および高脂肪食および試料102(5質量%)摂取群(以下、「GL群」とも記す)の5群(n=8)に分け、各群に対応する飼料をそれぞれ与えることによって30日間の飼育(ペアフィーディング飼育)を行った。飼育中は、マウスの飼料摂取量および体重を毎日、所定の時間に測定した。上記の各群のマウスに与えた飼料の組成は上記表1のとおりである。
表2によれば、FCP群の各臓器における脂肪蓄積が、H群のそれに対して抑制されていると評価される。さらにFCP群の各臓器における脂肪蓄積は、CP群およびGL群のそれに対しても抑制されていると評価される。もってFCP群において、脂肪蓄積抑制効果が得られるものと示唆される。
試料1および試料2の生体機能調整剤、ならびに試料101および試料103をマウス由来前駆脂肪細胞(3T3-L1、継代数:5Passage、9PDL)から分化させた脂肪細胞へ添加することにより、試料1および試料2の生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第3試験を実行した。
上記マウス由来前駆脂肪細胞(研究資源バンク製、資源番号JCRB9014、Lot.No.01282009)を培養培地(DMEM/F12培地(継代培地、カタログ番号:「11330-032」、Gibco社製、10質量%FBS、ペニシリンおよびストレプトマイシン含有)により前培養した。次いで当該前培養した培地および上記細胞から、上記細胞が3×104cell/mLとなる細胞懸濁液を調製した。さらに当該細胞懸濁液を60mmディッシュ(カタログ番号:Corning、Cat.No.430166)の各ディッシュに5mLずつ播種(1.5×105cell/ディッシュ)し、37℃(5体積%CO2)の条件下で2日間培養した。次に各ディッシュ中の上記培地を、アディポジェネシスアッセイキット(カタログ番号:「ECM950」、ミリポア社製)に付属されたイソブチルメチルキサンチン(IBMX)およびデキサメタゾンを終濃度がそれぞれ0.5mMおよび1μMとなるように添加した分化誘導培地へ置換え、37℃(5体積%CO2)の条件下でさらに2日間培養した。その後、さらに上記分化誘導培地を、アディポジェネシスアッセイキット(カタログ番号:「ECM950」、ミリポア社製)に付属されたインシュリンを終濃度が10μg/mLとなるように添加した分化培地に置換え、37℃(5体積%CO2)の条件下で2日培養した。各ディッシュ中の上記細胞が脂肪細胞に分化していることを確認した上で、上記分化培地を上記継代培地に置換えた。この継代培地中の脂肪細胞に対し、終濃度が0.1質量%となるように試料1および試料2の生体機能調整剤、ならびに試料101および試料103を添加し、終濃度が2μg/mLとなるように塩化ベルベリン溶液(カタログ番号:「027-11781」、富士フイルム和光純薬株式会社製)を添加し、かつ残余の上記継代培地中の脂肪細胞に対してはRO水を添加し、37℃(5体積%CO2)の条件下で2日間培養した。なお試料1、試料2、試料101、試料103、塩化ベルベリン溶液およびRO水については、それぞれ3枚のディッシュに添加した。その後、上記継代培地を新しい継代培地に交換するとともに、終濃度が0.1質量%となるように試料1、試料2、試料101、試料103を再添加し、終濃度が2μg/mLとなるように塩化ベルベリン溶液を再添加し、かつRO水を対応する各ディッシュへ再添加した。
脂肪蓄積率(%)=[(各試料のOD520nmの測定値)/(BlankのOD520nmの測定値)×100]。
表3によれば、試料1および試料2の生体機能調整剤は、脂肪細胞における脂肪蓄積が、試料101および試料103に比して抑制されていると評価される。
後述する試料41~試料49の生体機能調整剤をマウス由来前駆脂肪細胞(3T3-L1、継代数:7Passage、13PDL)から分化させた脂肪細胞へ添加することにより、試料41~試料49の生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第4試験を実行した。
(試料41~試料49の作製)
第2工程においてコラーゲン原料を上記麹で発酵させる条件を、表4に示すとおりとすること以外、試料2の生体機能調整剤を得るのと同じ方法により試料41~試料49の生体機能調整剤を作製した。なお試料43は、コラーゲン原料を上記麹で発酵させる条件が試料2と同じであった。表4には、各試料に含まれるコラーゲンペプチドの重量平均分子量も示した。
マウス由来前駆脂肪細胞(3T3-L1)の継代数を「7Passage、13PDL」とし、かつ上記ディッシュ中の脂肪細胞に対して添加する試料41~試料49の終濃度を0.2質量%とすること以外、上記第3試験と同じ方法により第4試験を実行した。結果を表5に示す。
表5によれば、試料41~試料49の生体機能調整剤は、脂肪細胞における脂肪蓄積が、いずれもBlankに対して抑制されていると評価される。なお第4試験では、脂肪蓄積の抑制に関する有意差の有無については判定しなかった。
試料1および試料2の生体機能調整剤、ならびに試料104をヒト正常表皮角化細胞NHEK(NB)(カタログ番号:「KK4009」、Lot.05298、倉敷紡績株式会社製)へ添加することにより、試料1および試料2の生体機能調整剤が表皮代謝促進作用を有するか否かについて試験した。具体的には、以下の手順に従って第5試験を実行した。
ヒト正常表皮角化細胞NHEK(NB)(倉敷紡績株式会社製)を培養培地(商品名:「HuMedia KG2」、倉敷紡績株式会社製)により前培養した。次いで当該前培養した培地および上記細胞から、上記細胞が1.5×104cell/mLとなる細胞懸濁液を調製し、上記細胞懸濁液を6穴プレート(カタログ番号:「353046」、ファルコン社製)の各ウエルに3×104cellずつ播種することにより、4日間培養した。次に上記細胞が上記プレート内で90面積%のサブコンフルエントになっていることを確認後、シャーレ内の培地を試験培地(商品名:「HuMedia KB2」、倉敷紡績株式会社製)に置換えた。さらに各プレート毎の各ウエルに試料1および試料2の生体機能調整剤、試料104ならびにRO水を、終濃度が0.1質量%濃度となるように添加するとともに、37℃(5体積%CO2)の条件下で培養した。ここで後述するケラチン10(KRT10)の遺伝子発現量を測定するための上記プレート内の細胞に対しては24時間培養し、後述するインボルクリン(Ivl)およびトランスグルタミナーゼ(TGM1)の遺伝子発現量を測定するための上記プレート内の細胞に対しては48時間培養した。
表6~表8によれば、試料1および試料2の生体機能調整剤は、ヒトの表皮細胞においてKRT10、TGM1およびIvlの遺伝子の発現量を亢進させることができる。もって上述した遺伝子の発現亢進によって表皮における代謝が促進されることが示唆される。
上述した試料41~試料49の生体機能調整剤を用いて上述した第5試験を行うことにより、試料41~試料49の生体機能調整剤が表皮代謝促進作用を有するか否かについて試験した。結果を表9~表11に示す。
表9~表11によれば、試料41~試料49の生体機能調整剤は、ヒトの表皮細胞においてKRT10、TGM1およびIvlの遺伝子の発現量を亢進させることができる。もって上述した遺伝子の発現亢進によって表皮における代謝が促進されることが示唆される。
上記第1試験と同じ要領により、試料2の生体機能調整剤をマウスに投与し、上記生体機能調整剤が脂肪蓄積抑制作用を有するか否かに関し、マウスの体重の変化を指標として試験した。ただしFCP群については、摂取させる試料2の濃度を上記第1試験の半量(2.5質量%含有飼料)とした。
図12は、第7試験における各群のマウスの体重の変化を示すグラフである。図12によれば、H群に対し、FCP群の体重増加が有意に抑制されていることが理解される。
試料3および試料4の生体機能調整剤を、糖負荷によって肥満としたマウスに投与することにより、上記生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第8試験を実行した。
5週齢の雄性C57BL/6Jマウス48匹を日本クレア株式会社から購入することにより準備した。上記マウスに対し、普通食(AIN-93G精製飼料)と、15質量%フルクトース(富士フイルム和光純薬工業株式会社製)を含む水(以下、「15質量%フルクトース水」とも記す)とを42日間摂取させることにより、上記マウスの体重を意図的に増加させた。次に、体重が増加した上記マウス48匹を、各群間で体重が一定となるようにして上記普通食と水とを摂取させるノーマル群(A群)、上記普通食と15質量%フルクトース水とを摂取させるネガティブコントロール群(B群)、普通食に含まれる20質量%のカゼインのうち6質量%を試料3の生体機能調整剤に置換した食餌と15質量%フルクトース水とを摂取させるFCP-3群(C群)、普通食に含まれる20質量%のカゼインのうち6質量%を試料4の生体機能調整剤に置換した食餌と15質量%フルクトース水とを摂取させるFCP-4群(D群)、普通食に含まれる20質量%のカゼインのうち6質量%を試料101に置換した食餌と15質量%フルクトース水とを摂取させるコラぺプPU群(E群)、ならびに普通食に含まれる20質量%のカゼインのうち6質量%を試料104に置換した食餌と15質量%フルクトース水とを摂取させるSCP-5200群(F群)の6群(n=8)に振り分けた。
図13は、第8試験における各群のマウスの体重を示すグラフである。図13によれば、A群に対してB群、E群およびF群は体重増加を抑制することができていないが、A群に対してC群およびD群は、体重増加が有意に抑制されていることが理解される。
試料3の生体機能調整剤を、皮膚における変化を観察するのに適したHos:HR-1マウスに投与することにより、上記生体機能調整剤が皮膚代謝促進作用を有するか否かについて試験した。具体的には、以下の手順に従って第9試験を実行した。
7週齢の雌性Hos:HR-1マウス15匹を株式会社星野試験動物飼育所から購入することにより準備するとともに、上記マウスを8週齢になるまで飼育した。その後、上記マウスを5匹ずつ、普通食としてラボMRストック飼料(日本農産工業株式会社製)と水とを摂取させるX群、HR-AD用精製飼料と水とを摂取させるY群、および試料3の生体機能調整剤を5質量%添加したHR-AD用精製飼料と水とを摂取させるZ群の3群(n=5)に振り分けた。その後、各群のマウスに対して8週間(56日間)、対応する飼料および水を与えることによって上記マウスを飼育した。飼育中は週に一度、各マウスにおける飼料摂取量および体重を測定するとともに写真撮影を行った。さらに各群のマウスの中から飼育開始前および飼育終了時に安楽死させるマウスをそれぞれ選択し、当該安楽死させたマウスの背部および腹部(腰部)の皮膚を採取した。さらに上記皮膚に関してH.E.染色標本を作製し、上記皮膚の角質層の厚さを測定すること等を含めて病理組織学的観察を行った。上記マウスの背部(頸背部および背部中央)ならびに腹部(腰部)の各部において測定された皮膚の角質層の厚さを、表13に示す。HR-AD用精製飼料とは、多価不飽和脂肪酸(n-6 PUFAs)の欠乏によってアトピー性皮膚炎(AD)様症状が引き起こされるため、アトピー性皮膚炎を評価することができる飼料である。その組成は、アミノ酸として、アルギニン0.75質量%、ヒスチジン0.60質量%、イソロイシン1.03質量%、ロイシン2.02質量%、リジン1.69質量%、メチオニン0.69質量%、チロシン1.17質量%、アラニン0.62質量%、プロリン2.32質量%、フェニルアラニン1.03質量%、トリプトファン0.07質量%、バリン1.27質量%、シスチン0.08質量%、グリシン0.39質量%、トレオニン0.87質量%、セリン1.18質量%、アスパラギン酸1.47質量%、グルタミン酸4.74質量%を含有しており、ビタミンとして1kg中、ビタミンA 32157IU、ビタミンD3 4799IU、ビタミンE 160mg、ビタミンK 5mg、コリン 868.2mg、葉酸 0.09mg、ナイアシン 320mg、ビオチン 0.8mg、ビタミンB1 13mg、ビタミンB2 16.3mg、ビタミンB6 52.7mg、ビタミンB12 0.08mg、ビタミンC 129.6mg、パントテン酸 29.7mg含有しており、ミネラルとしてカルシウム0.9質量%、塩素0.33質量%、マグネシウム0.02質量%、リン0.77質量%、カリウム0.42質量%、ナトリウム0.2質量%、セレン0.00質量%、ヨウ素0.22mg/kg、鉄276.78mg/kg、コバルト0.002質量%、マンガン79.28mg/kg、亜鉛122.52mg/kg、銅21.50mg/kg含有している。表13中、「Mean」は、中央値を意味し、「S.D.」は、標準偏差を意味する。
まずY群においては、背部(頸背部および背部中央)ならびに腹部(腰部)の皮膚に落屑がみられ、かつ角質層の厚みの有意な増加が認められた。これによりY群のマウスは、皮膚の乾燥および表皮の肥厚を伴うアトピー性皮膚炎様モデルとして成立したことが確認された。一方、Z群においては、Y群と比べ皮膚の乾燥状態に変化はないものの、表13に示すように、頸背部の角質層の厚さが有意に低値であり、上記生体機能調整剤の皮膚代謝促進作用に基づいて表皮の肥厚が抑制されたものと考えられた。
試料4の生体機能調整剤を、20~70歳以下の健康な男女に摂取させることにより、ヒトに対して上記生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第10試験を実行した。
本試験は、「ヘルシンキ宣言(2004年東京注釈追加版)」および「疫学研究に関する倫理指針(2004年文部科学省・厚生労働省告示1号)」に配慮し、本試験実施計画書を遵守して実施された。本試験のプロトコルは、倫理審査委員会によって承認(承認番号:RCB2020-001-02)され、UMIN登録(UMIN000040736)された。また本試験では、書面により被験者の同意を得た後、ランダム化二重盲検プラセボ対照並行群間試験を実施した。本試験ではスクリーニング割付時点、摂取前(0time)時点、ならびに上記摂取前時点から被験食品を絶乾量として5.0g/日ずつ3か月間摂取した時点の計3回の測定を行い、1回の測定期間は1週間の調整期間を設けた。以下、具体的な試験内容について説明する。
上記プロトコルに従って、選択基準をi)20歳以上70歳以下の男女、ii)試験開始から遡って1年以内の健康診断において異常がみられない健康な人、iii)初期内臓脂肪面積が80cm2以上の人、iv)今後6か月に渡って80%以上の摂取率を維持できる者とした。また除外基準をA)重篤な疾患既往歴がある者、B)健康診断において肝機能および腎機能検査値において異常を示す者、C)心肺機能に障害を示す者、D)食物および薬剤アレルギーのある者、E)消化管の手術を受けたことがある者、F)医師が慢性あるいは急性の感染症を発症していると判断する者、G)本試験開始時に他の臨床研究に参加中の者、H)激しいスポーツをする者およびダイエット中の者、I)妊婦、J)その他試験責任者もしくは試験担当者が不適当と判断した者とした。
本試験に参加同意した109名の内、選定基準に従って55名を本試験に組み入れた。試験責任医師が、スクリーニング時の内臓脂肪面積が群間で不均衡にならないように配慮しつつ乱数を用いて層化ランダム割付表を作成し、封緘した。上記割付表は、試験食品管理担当者のみに提供された。上記の55名の試験参加者に後述する試験食品を配布した。盲検化の対象は、主催者、試験責任医師、試験分担者、試験食品管理担当者を含むすべての試験実施機関のスタッフ、倫理審査委員会の構成メンバーであった。上記割付表の開封は、試験終了後に統計解析担当者が行った。
試験食品としては、試料101(CP群)と試料4(FCP群)とを用いた。対照食品(PL群(プラセボ群))としては、マルトデキストリン(商品名:「パインデックス♯2」、松谷化学工業社製)を用いた。
上記試験食品および対照食品をアルミパウチに入れ、中身が分からないように配布した。各食品(5.0g/日)を試験参加者(被験者)の好きなタイミングで、3か月摂取させた。摂取を忘れた際は、1日1包(5.0g)を限度とし、その日のうちに飲むように指示した。
5-1) 試験スケジュール
各種の測定を、摂取前(0time)および摂取3か月時(3months)に実施し、各時点の実測値および0timeからの変化量をアウトカムに用いた。
内臓脂肪面積については、Dualscan HDS-2000(オムロン株式会社製、医療機器承認番号:22300BZX00104000)を用いて測定した。上記Dualscan HDS-2000は、デュアルインピーダンス法により、簡単かつ安全に内臓脂肪面積を算出することができる内臓脂肪測定装置であり、2つの経路から電流を流すことによって内臓脂肪および腹部皮下脂肪を識別し、被曝のリスクが無く、非侵襲で内臓脂肪面積を測定することが可能である。
肌質の測定は、顔写真を撮ることに同意を得た被験者のみに対して実施した。被験者は、男性は洗顔のみ、女性はクレンジングおよび洗顔後、20分以上室温にて馴化したのちに測定した。上記測定は、ロボスキンアナライザー(渋谷工業株式会社製)にて実施した。詳細には、顔の正面、右向き、左向きの写真を撮影し、ロボスキンアナライザーのアルゴリズムによって色素沈着を評価した。
統計解析については、Windows(登録商標)用のSTATMATEV(株式会社アトムス社製)を用いて行った。すべての統計解析は両側検定で行うものとし、信頼区間95%にて有意差水準5%に設定した。摂取前後の群内比較についてはWilcoxon Signed Ranks Testを行った。FCP群とPL群、およびCP群とPL群の2群間比較についてはMann-Whitney U Testを行った。FCP群とPL群およびCP群との3群間比較については、One-way Anova検定を行い、さらに事後検定としてTukey検定の両側検定を行うことにより有意差を計算した。内臓脂肪面積の変化を表14に示し、肌質(色素沈着の増減評価)の結果を表15に示す。
表14によれば、内臓脂肪面積において、CP群はPL群および0timeとの有意差が確認されなかった。しかしながらFCP群は、0timeとの有意差が確認された。さらに、階層別の男性の110cm2以上の群においてFCP群は、PL群と比較して内臓脂肪面積が有意に減少した。肌質(色素沈着の増減評価)においても、FCP群は、面積および数ともにPL群と比較して有意に減少した。同時にΔ(3months-0time)においてもPL群と比較して有意に減少した。また表15によれば、肌質(色素沈着の増減評価)においてCP群は、Δ(3month-0time)においてPL群と比較して有意に減少した。
試料5の生体機能調整剤をマウス由来前駆脂肪細胞(3T3-L1、継代数:7Passage、13PDL)から分化させた脂肪細胞へ添加することにより、試料5の生体機能調整剤が脂肪蓄積抑制作用を有するか否かについて試験した。具体的には、以下の手順に従って第11試験を実行した。
上記脂肪細胞に対して添加する試料を試料5に代えたこと以外、上記第3試験と同じ方法により第11試験を実行した。結果を表16に示す。
本試験および第3試験の結果によれば、試料5は、試料1および試料2と同様に脂肪蓄積抑制効果が確認された。このことから、原料が異なっても同様な効果が得られることが確認された。
以上によれば、試料1~試料5および試料41~49の生体機能調整剤は、脂肪蓄積抑制作用および表皮代謝促進作用を有することが理解される。さらに試料1~試料5および試料41~49については、生体内のアディポサイトカイン量の調整作用を有することも示唆される。
Claims (11)
- 発酵コラーゲンペプチドを含み、
前記発酵コラーゲンペプチドは、表皮代謝促進作用、脂肪蓄積抑制作用、脂肪分解促進作用および生体内のアディポサイトカイン量の調整作用からなる群より選ばれる少なくとも1種の作用を有する、生体機能調整剤。 - 前記発酵コラーゲンペプチドは、コラーゲンペプチドと、
イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも1種の第1化合物とを含む、請求項1に記載の生体機能調整剤。 - 前記発酵コラーゲンペプチドは、コラーゲンペプチドと、
イソバレルアルデヒド、1-オクテン-3-オール、フェニルアセトアルデヒドおよびメチオナールからなる群より選ばれる少なくとも3種の第1化合物とを含む、請求項1に記載の生体機能調整剤。 - 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、表皮代謝促進剤。
- 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、脂肪蓄積抑制剤。
- 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、アディポネクチン産生促進剤。
- 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、脂肪分解促進剤。
- 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、機能性食品。
- 請求項1から請求項3のいずれか1項に記載の生体機能調整剤を含む、化粧料。
- 発酵コラーゲンペプチドを含む生体機能調整剤の製造方法であって、
麹菌を含む麹とコラーゲン原料とを準備する工程と、
前記コラーゲン原料を前記麹で発酵させることにより、前記発酵コラーゲンペプチドを含む生体機能調整剤を得る工程とを含み、
前記麹菌の菌種は、アスペルギルス属に属する菌種であり、
前記コラーゲン原料は、以下の第1群~第6群からなる群より選ばれる少なくとも1種、前記群より選ばれる少なくとも1種から抽出されたコラーゲン、前記コラーゲンを処理することにより得られるゼラチン、および前記ゼラチンを加水分解することにより得られるゼラチン分解物の少なくともいずれかである、生体機能調整剤の製造方法。
第1群:牛の皮、皮膚、骨、軟骨および腱からなる群
第2群:豚の皮、皮膚、骨、軟骨および腱からなる群
第3群:羊の皮、皮膚、骨、軟骨および腱からなる群
第4群:鶏の皮、皮膚、骨、軟骨および腱からなる群
第5群:ダチョウの皮、皮膚、骨、軟骨および腱からなる群
第6群:魚の骨、皮および鱗からなる群 - コラーゲン原料を麹で発酵させることにより製造された発酵コラーゲンペプチドを含む、生体機能調整剤。
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