TRPV1 activator

Abstract

To provide a new TRPV1 activator, a fragrant composition containing the activator as an active ingredient and having actions such as energy consumption promotion and heat production promotion, and a fragrant product and food or drink containing them.SOLUTION: The present invention discloses: a TRPV1 activator containing menthyl 3-hydroxy butylate as an active ingredient; an oral composition or a fragrant product containing the TRPV1 activator; and methods for producing an oral composition or a fragrant product for dieting, improved poor circulation, or improved glucose tolerance, using the TRPV1 activator as raw material.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel TRPV1 activator, an oral composition using the same, cosmetics, and the like.

Background Art

[0002] The capsaicin receptor TRPV1 is a type of protein belonging to the transient receptor potential ion channel, and is a non-selective cation channel with high calcium ion permeability. Its expression extends over a wide range from the central nervous system to peripheral tissues, and in peripheral tissues, it is expressed in sensory nerves, vagus nerves, stomach, adipose tissue, etc. (Non-Patent Document 1). In nerve cells, capsaicin, allicin, piperine, etc. promote the influx of calcium ions into the axon via TRPV1, causing depolarization and generating action potentials (Non-Patent Documents 2 to 4).

[0003] The generation of action potentials due to TRPV1 activation leads to an increase in catecholamine release from the adrenal medulla and the like, induces the expression of UCP1 (uncoupling protein 1) via the β3-adrenergic receptor (β3-AR), and induces energy consumption (Non-Patent Document 1). UCP1 is a molecular uncoupling protein specific to the mitochondria of brown adipocytes. When this is activated, fat is decomposed to produce heat and energy is consumed. That is, activation of UCP1 induces heat production in brown adipocytes.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a novel TRPV1 activator, a fragrance composition having an action such as promoting energy consumption and heat production, which contains the activator as an active ingredient, and cosmetics and oral compositions using these.

Means for Solving the Problems

[0006] The inventors of the present invention have found that menthyl 3-hydroxybutyrate has an action of activating TRPV1 by screening using Ca 2+ imaging using TRPV1 stably expressing cells, and have completed the present invention.

[0007] That is, the present invention is as follows. [1] A TRPV1 activator comprising menthyl 3-hydroxybutyrate as an active ingredient. [2] A brown adipocyte activator comprising menthyl 3-hydroxybutyrate as an active ingredient. [3] An energy consumption promoter comprising menthyl 3-hydroxybutyrate as an active ingredient. [4] A body heat production promoter comprising menthyl 3-hydroxybutyrate as an active ingredient. [5] An antihyperglycemic agent comprising menthyl 3-hydroxybutyrate as an active ingredient. [6] A fragrance composition containing any one of the agents of [1] to [5]. [7] An oral composition containing any one of the agents of [1] to [5] or the fragrance composition of [6]. [8] The oral composition of [7], which is ingested for dieting, improving cold sensitivity, or improving glucose tolerance. [9] A method for producing an oral composition for dieting, improving cold sensitivity, or improving glucose tolerance, using any one of the agents of [1] to [5] or the fragrance composition of [6] as a raw material.

[10] A cosmetic containing any one of the agents of [1] to [5] or the fragrance composition of [6].

[11] The cosmetic of

[10] , which is used for dieting, improving cold sensitivity, or improving glucose tolerance.

[12] A method for producing a cosmetic for dieting, improving cold sensitivity, or improving glucose tolerance, using any one of the agents of [1] to [5] or the fragrance composition of [6] as a raw material. [Advantages of the Invention]

[0008] The TRPV1 activator according to the present invention generates action potentials by the influx of calcium ions in various cells such as brown adipocytes. Therefore, the present invention can provide a fragrance composition, a cosmetic, and an oral composition having the effects of activating brown adipocytes, promoting energy consumption, promoting body heat production, and improving glucose tolerance induced by the activation of TRPV1. [Brief Description of the Drawings]

[0009]

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Mode for Carrying Out the Invention

[0010] Hereinafter, the present invention will be described in detail in accordance with embodiments.

[0011] The TRPV1 activator according to the present invention contains menthyl 3-hydroxybutyrate (M3HB) as an active ingredient. M3HB is an ester of menthol, which has stereoisomers, and 3-hydroxybutyric acid, and there are a plurality of stereoisomers in M3HB depending on the combination of the respective isomers. In the present invention, M3HB only needs to be an ester of menthol and 3-hydroxybutyric acid, and there is no particular limitation on the type of stereoisomer, and any stereoisomer can be used. Generally, an ester of menthol, which is a mixture of the l-form or d-form and the l-form, and optically active or racemic 3-hydroxybutyric acid can be used, and preferably an ester of l-menthol and racemic 3-hydroxybutyric acid (l-Menthyl (R,S)-3-hydroxybutyrate) can be used. M3HB can be chemically synthesized, but it is also commercially available as a reagent, etc., and can be appropriately purchased and used from Seikaido Ishida Shoten Co., Ltd., A2B Chem LLC, MuseChem, etc. As shown in the following examples, M3HB increases the influx of calcium ions in TRPV1 stably expressing cells, while having no effect on the influx of calcium ions in cells that do not express TRPV1. As shown by this experimental result, M3HB activates TRPV1 and increases the influx of calcium ions into cells.

[0012] Activation of TRPV1 activates brown adipocytes and promotes energy consumption. Therefore, by ingesting M3HB, body heat production is promoted. Furthermore, by ingesting M3HB for a long period of time, an increase in body weight is suppressed. Furthermore, since lipid metabolism is also improved by promoting energy consumption, long-term ingestion of M3HB can be expected to have effects of suppressing obesity and fatty liver. Therefore, M3HB is useful as an active ingredient of a brown adipocyte activator, an energy consumption promoter, and a body heat production promoter.

[0013] In addition, due to its energy consumption promoting effect, M3HB also has an effect of improving dietary insulin resistance and glucose tolerance. Therefore, M3HB is useful as an active ingredient of a glucose tolerance improving agent.

[0014] The TRPV1 activator, brown adipocyte activator, energy consumption promoter, body heat production promoter, and glucose tolerance improving agent containing M3HB as an active ingredient may all be directly contained in cosmetics or oral compositions, or may be a fragrance composition combined with other fragrance materials. Such other fragrance materials may be natural fragrance materials, synthetic fragrance materials, or mixtures thereof.

[0015] When the fragrance composition containing M3HB contains other components in addition to M3HB, the other components are not particularly limited as long as the effects of M3HB are not impaired. For example, other than M3HB contained in the fragrance composition, examples include fragrance raw materials (essential oils, essences, concretes, absolutes, extracts, oleoresins, resinoids, recovered flavors, carbon dioxide extracted essential oils, synthetic fragrances) described in, for example, "Patent Office Gazette, Well-Known and Conventional Technology Collection (Fragrances), Part III, Fragrances for Cosmetics" (published on June 15, 2001, Japan Patent Office), various plant extracts, etc., and each can be blended in an amount that does not impair the effects of the present invention.

[0016] As spice raw materials, specifically, eugenol, octanol, octanal, ethyl octanoate, isoamyl formate, geranyl formate, citronellyl formate, cinnamic acid, ethyl cinnamate, methyl cinnamate, ketones, geraniol, isoamyl acetate, ethyl acetate, geranyl acetate, cyclohexyl acetate, citronellyl acetate, cinnamyl acetate, terpinyl acetate, phenethyl acetate, butyl acetate, benzyl acetate, l-menthyl acetate, linalyl acetate, methyl salicylate, allyl cyclohexylpropionate, citral, citronellal, citronellol, 1,8-cineole, fatty acids, higher aliphatic alcohols, higher aliphatic aldehydes, higher aliphatic hydrocarbons, cinnamyl alcohol, cinnamaldehyde, thioethers, thiols, decanal, decanol, ethyl decanoate, terpineol, limonene, pinene,

[0017] myrcene, terpinolene, terpene hydrocarbons, γ-nonalactone, vanillin, paramethylacetophenone, hydroxycitronellal, hydroxycitronellal dimethyl acetal, piperonal, isoamyl phenylacetate, isobutyl phenylacetate, ethyl phenylacetate, phenol ethers, phenols, furfural and its derivatives, propionic acid, isoamyl propionate, ethyl propionate, benzyl propionate, hexanoic acid, allyl hexanoate, ethyl hexanoate, ethyl heptanoate, l-perilla aldehyde, benzyl alcohol, benzaldehyde, aromatic alcohols, aromatic aldehydes, d-borneol, maltol, methyl N-methylanthranilate, methyl β-naphthyl ketone, dl-menthol, l-menthol, butyric acid,

[0018] In addition to synthetic or natural-derived fragrances such as isoamyl butyrate, ethyl butyrate, cyclohexyl butyrate, butyl butyrate, lactones, linalool, etc., citrus essential oils such as orange, lemon, lime, grapefruit, etc., fruit-based essential oils or recovered flavors such as apple, banana, grape, melon, peach, pineapple, strawberry, blackcurrant, etc., milk-based extracted flavors such as milk, cream, butter, cheese, yogurt, etc., recovered flavors of favorite products such as green tea, oolong tea, black tea, coffee, cocoa, etc., mint-based essential oils such as peppermint, spearmint, etc., and spices extracts obtained from asanomi, asafetida, ajowan, anise, angelica, urukyo, turmeric, oregano, allspice, orange peel, cassia, cinnamon, chamomile, mustard greens, cardamom, curry leaf, licorice, caraway, gardenia,

[0019] cumin, cress, clove, caperberry, caper, pepper, sesame, coriander, sassafras, saffron, savory, sage, sansho, shiso, cinnamon, shallot, juniper berry, ginger, star anise, spearmint, horseradish, celery, sorrel, thyme, onion, tamarind, tarragon, chive, dill, chili pepper, nutmeg, Japanese mugwort, nigella, carrot, garlic, basil, parsley, perilla, vanilla, paprika, hyssop, fenugreek, peppermint, hoarhound, horseradish, marjoram, myoga, lavender, linden, lemon balm, rose, rosemary, laurel, wasabi, etc., and lichens such as Iceland moss, akayajio, akebi, asa, asafetida, asianum,

[0020] Ajowan, adzuki bean, Asparagus officinalis, apple mint, artichoke, anise, avocado, ama-cha, ama-cha zuzu, Amigasa lily, amaryllis, almond, Arisaema ringens, Alkanna tinctoria, Artemisia, Arnica montana, alfalfa, aloe, angostura, angora weed, anise, anise mushroom, angelica, amber, ambergris, amblet, squid, Icariopsis ventricosa, east, Japanese knotweed, strawberry, fig, ginkgo, Inonotus obliquus, ilang-ilang, Iwaki-o-gi, Imperatoria ostruthium, Inmortelle, wintergreen, watercress, Japanese spikenard, turmeric, Usuba saishin, woodruff, sea urchin, Japanese apricot, oolong tea, egoma, enoki mushroom, shrimp, Ebisu grass, Erigeron canadensis, elder, Eleutherococcus senticosus, Erechtites hieraciifolius, elemi, arrowhead,

[0021] loquat, endive, European thistle, Korean ginseng, rhubarb, okazeri, krill, oak, oak moss, okera, osmanthus, opopanax, Urtica thunbergiana, arrow arum, Dutch senna, oregano, orris, olibanum, olive, allspice, orange, orange flower, kai, Chinese flowering cabbage, cacao, oyster, kassai, cashew nut, cascara, cassia bark, castorium, arrowroot, bonito flakes, katchou, kashafistula, catechu, crab, carnation, motherwort, chamomile, kayapte, mustard, black nightshade, Caladium bicolor, guarana, calamus, galangal, carrant, carissa, carambola, cardamom, galbanum, curry, kawamidori, licorice, Gambia, kanran, kiwifruit, Kikaimyces galactinus, balloon flower, chrysanthemum,

[0022] Mushroom, Prickly Chaff Flower, Hairy Bittercress, Aloe Vera, Chinese Cinquefoil, Japanese Apricot, Japanese Banana, Sunflower, Gymnema Sylvestre, Catnip, Caraway, Calopogonium, Cucumber, Cleome, Goldenrod, Caper, Guava, Guaiacum, Cuckoo, Kudzu Vine, Japanese Horsetail, Kudzu, Mulberry, Mulberry Leaf, Gooseberry, Gardenia, Japanese Cinnamon, Quince, Loquat, Gumi, Cumin, Ground Ivy, Clarar, Clarisse, Cranberry, Chestnut, Walnut, Cream, Grain of Paradise, Cretan Dictamnus, Grapefruit, Clover, Cloves, Purple Sweet Potato, Mulberry, Mulberry Fruit, Caper, Getto, Cadet, Japanese Sophora, Germander, Centaury, Cape Jasmine, Coptis, Koji, Phellinus Linteus, Black Tea, Koho Wood, Coca, Gold Flower, Sugar, Poison, Coconut,

[0023] Goshuyu, Pepper, Costus, Costmary, Copaiba, Coffee, Kaffir Lime, Burdock, Sesame, Cola, Coriander, Coltsfoot, Goldenrod, Colombo, Consai, Conzylango, Confrey, Cypress, Fish, Cherry Blossom, Strawberry, Pomelo, Salmon Roe, Sasa, Sasakusa, Search, Sassafras, Saffron, Sapojira, Cactus, Sarashina Arrowhead, Sarsaparilla, Salsify, Monkey Fern, Japanese Apricot, Sichuan Pepper, Santa Herb, Sandarac, Sandalwood, Red Sandalwood, Shiitake Mushroom, Gene, Perilla, Cider, Citrus, Citronella, Sinus, Siberian, Simarouba, Shimeji Mushroom, Chinese Peony, Jasmine, Beardless Jasmine, Jabolanji, Shallot, Shukusha, Juniper Berry, Ginger, Soy Sauce, Soy Sauce Residue,

[0024] Ginger, Lily, Shirotamogitake, Ginseng, Cinnamon, Vinegar, Watermelon, Gladiolus, Japanese Cedar, Star Anise, Star Fruit, Storax, Pumpkin, Suppontake, Zudrabetz, Snake Root, Spikenard, Spruce, Spearmint, Japanese Butterbur, Strawberry, Celery, Cabbage, Sage, Zedoary, Senega, Geranium, Celery Root, Ginseng, Centaurea, Senggen, St. John's Wort, Senna, Sauce, Rhubarb, Soybean, Thyme, Bamboo Shoot, Octopus, Knotweed, Indian Pennywort, Egg, Tamagotake, Onion, Tamarind, Damiana, Tamogitake, Tarragon, Taranoaki, Tansy, Tangelo, Dandelion, Cherry Plum, Cherry Laurel, Wild Cherry, Chigaya, Chicory, Cheese, Chichitake, Chive, Chervil, Champaca, Tuberose, Japanese Bellflower, Chiratta, Tsukushi, Pickles, Ivy,

[0025] Camellia, Duckweed, Burdock, Tsurudokudami, Diathanium, Tisul, Dittany, Dill, Dates, Tendaiuyaku, Tenma, Chili Pepper, Torreya nucifera, Photosynthetic Plant Protein, Photosynthetic Plant Oil, Honey, Corn, Dokudami, Chinese Magnoliavine, Dog Grass, Tomato, Dragon's Blood, Durian, Truffle, Tolu Balsam, Tonka, Naginata Kojyu, Pear, Nasturtium, Nuts, Natto, Jujube, Jujube Kernel, Gypsophila, Nameko, Naratake, Niauri, Niw Sankinbaiyou Extract, Carrot, Garlic, Mouse Ear, Nettle, Nemunoki, Knot Grass, Violet, Pineapple, Hibiscus, Malt, Hacobe, Basil, Lotus, Haskap, Persimmon, Parsley, Butter, Butter Oil, Buttermilk, Birch, Honey, Patchouli,

[0026] Hacca, Back Bean, Hakkoushu, Hakkounyuu, Hakkoumiek, Passion Fruit, Hatsutake, Buffalo Berry, Job's Tears, Hanasuge, Banana, Vanilla, Hanesakuru, Papaya, Barberry, Hamagou, Hamasuge, Hamanasu, Hamaboufuu, Hamamelis, Rose, Palma Rosa, Banreishi, Hikioji, Hisa, Pistachio, Hyssop, Hickory, Peanut, Hinoki, Hiba, Pipushishiwa, Himemochi, Hyacinth, Hiratake, Loquat, Binrou, Feijoa, Fenugreek, Fennel, Fujibakama, Fujimodoki, Fsuma, Huuzeru, Puchigrain, Buchu, Grape, Grape Sakekasu, Peach, Beech, Beech Hahitake, Black Caraway, Blackberry, Plum, Bryonia, Prickly Ash, Primrose, Prunella,

[0027] Blueberry, Bred Fruit, Hay, Bay, Hazelnut, Betiba, Betel, Benibana, Pennyroyal, Peppermint, Snake, Pepino, Pepton, Bergamot, Bergamot Mint, Peru Balsam, Verbena, Veronica, Benzoin, Boadorose, Hoahound, Hou, Houkitake, Hoshou, Boufuu, Hohei, Hoonoiki, Horsemint, Horseradish, Button, Hop, Poppy, Poplar, Popo, Jojoba, Hoya, Bordeaux, Boronia, Mitake, Mugwort, Marshmallow, Marjoram, Mastic, Masoi, Matatabi, Matiko, Pine, Matsuouji, Mushroom, Matsutake, Matsubusa, Matsuhodo, Matecha, Bean, Marigold, Marva Daiou, Quince, Malayin, Marrow, Mango, Mangosteen, Tangerine, Mishima Saiko,

[0028] Natural fragrances such as those obtained from miso, mulberry, beeswax, meat, mimosa, mugwort, myoga, milk, myrtle, milfoil, myrrh, myrobalan, wheat tea, musk, purple, mesquite, meadowsweet, nettle, maple, melissa, melilot, melon, moss fern, monilia biaoyou extract, oak, peach, purslane, yakuqi, mountain peach, eucalyptus, snowdrop, yuzu, yucca, lily, iris, yoroi grass, lion's foot, lychee, life everlasting flower, lime, lilac, rakanka, rakansho, raspberry, latania, radish, lovage, lavender, langwort, lungwort, rambutan, liqueur, leek, litsea, linaroa, longan, leek chive, green tea, apple, linden, gentian, rue, lurisa, mignonette, lemon, turnip, lotus, rhubarb, rosemary, robey, laurel, longza, wasabi, watafuji azalea, wormwood, wormseed, bracken, waremokou, etc. are exemplified and appropriately selected for use.

[0029] When added to other fragrances or fragrance materials to form a fragrance composition, depending on the content of M3HB, effects such as TRPV1 activation become higher. Since a more sufficient improvement effect can be obtained, the content of the TRPV1 activator according to the present invention in the fragrance composition is preferably 1 ppm or more of the content of M3HB with respect to the total amount of the composition.

[0030] The fragrance composition according to the present invention may contain various additives in addition to M3HB and other fragrance materials. Examples of such additives include water; organic solvents such as alcohol, glycerin, and propylene glycol; excipients such as dextrin, sucrose, pectin, and chitin; fats and oils; emulsifiers; thickeners; preservatives; colorants; acidulants; seasonings, etc. These additives can be appropriately selected and used from those commonly used in fragrance compositions.

[0031] The fragrance composition can be made into various dosage forms. For example, it may be a water-soluble or oil-soluble liquid agent, a paste, a powder, a capsule, or a tablet. Various dosage forms can be manufactured by known methods.

[0032] By incorporating agents such as the TRPV1 activator according to the present invention and fragrance compositions containing them into cosmetics, oral compositions, etc., various functional mechanisms such as TRPV1 activation by M3HB can be imparted to these cosmetics and oral compositions. For example, oral compositions and cosmetics intended for ingestion for diet purposes can be manufactured using agents such as the TRPV1 activator according to the present invention and fragrance compositions containing them as raw materials. Also, oral compositions and cosmetics intended for ingestion for the purpose of improving cold sensitivity can be manufactured using agents such as the TRPV1 activator according to the present invention and fragrance compositions containing them as raw materials.

[0033] Various functional mechanisms such as TRPV1 activation by M3HB are exerted by introducing M3HB into cells expressing TRPV1 in the animal's body. M3HB can be ingested by animals not only through oral administration but also through percutaneous absorption or nasal absorption by inhalation. Therefore, agents such as the TRPV1 activator according to the present invention and fragrance compositions containing them can also impart various functional mechanisms such as TRPV1 activation by M3HB to cosmetics and oral compositions by incorporating them into cosmetics used by contacting the skin or inhaling the fragrance, as well as oral compositions used through oral administration.

[0034] That is, cosmetics, oral compositions, etc. containing the TRPV1 activator according to the present invention and fragrance compositions are not particularly limited and can be widely used in general cosmetics and oral compositions. Specific examples are as follows.

[0035] Examples of oral compositions include food and drink products, pharmaceuticals for oral ingestion, quasi-drugs, feeds, and the like. Food and drink products include, in addition to those consumed from the viewpoints of nutrition supplementation and palatability, so-called health foods that contribute to maintaining and improving health. Examples of food and drink products include beverages, confectioneries, supplements, breads, fats and oils and processed food products containing fats and oils, milk, dairy products, flavor seasonings, processed food products such as powdered beverages and powdered soups, and the like. Examples of quasi-drugs include oral hygiene agents and the like. Examples of feeds include those for various animals such as livestock animals such as cows, pigs, and chickens, pet animals such as dogs, cats, budgerigars, medakas, and goldfish, and experimental animals such as mice, rats, hamsters, guinea pigs, and rabbits, which are ingested for nutrition supplementation and the like. More specifically, the following can be mentioned.

[0036] Examples of beverages include tea beverages (green tea, black tea, oolong tea, etc.), coffee, cocoa, herbal tea, soft drinks, lactic acid bacteria beverages, milk beverages, non-juice beverages, beverages containing fruit juice, carbonated beverages, protein beverages, vinegar beverages, vegetable juices, soy milk, non-alcoholic beverages (non-alcoholic beer, non-alcoholic chu-hai, etc.), alcoholic beverages (beer, beer-taste beverages, chu-hai, etc.), beauty drinks such as beverages containing collagen, nutritional drinks, and the like. Examples of confectioneries include jelly, pudding, bavarois, mousse, cake, candy, biscuit, cookie, protein bar, chocolate, gum, ramune confectionery, tablet, ice cream, sherbet, ice candy, steamed bun, yokan, and the like. In particular, it is suitable for confectioneries such as candy, gum, ramune confectionery, and tablet that exist in the oral cavity for a relatively long time. Examples of fats and oils and processed food products containing fats and oils include edible fats and oils (animal fats and oils, vegetable fats and oils), margarine, shortening, mayonnaise, dressing, hard butter, and the like. Further, instant (fried) noodles, deep-fried tofu (abura-age, nama-age, ganmodoki), deep-fried fish cakes, tempura, fried foods, snacks (potato chips, arare, karinto, donuts), cooked frozen foods (frozen croquettes, shrimp fry, etc.), and the like. Examples of milk and dairy products include raw milk, cow's milk, processed milk, etc. as milk, and cream, butter, butter oil, condensed whey, cheese, ice creams, yogurt, sweetened condensed milk, powdered milk, condensed milk, etc. as dairy products. Examples of processed foods include soups, rice porridge, risottos, plant-based meats, etc.

[0037] Examples of oral hygiene agents include toothpastes, mouthwashes, gargles, oral fresheners, bad breath preventives, etc.

[0038] Examples of fragrances include fragrance raw materials (essential oils, essences, concretes, absolutes, extracts, oleoresins, resinoids, recovered flavors, carbon dioxide-extracted essential oils, synthetic fragrances) and fragrance compositions containing them.

[0039] The scope of cosmetics includes quasi-drugs, pharmaceuticals, and quasi-pharmaceuticals under the Pharmaceutical Affairs Law. Specific examples include fragrance products (perfumes, eau de parfums, body colognes, etc.), skin care cosmetics (toners, lotions, creams, lipsticks, foundations, facial cleansers, soaps, body shampoos, body care products, bath salts, antiperspirant deodorants, etc.), hair care cosmetics (shampoos, rinses, conditioners, hair treatments, hair tonics, hair growth stimulants, hair coloring agents, hair styling agents, permanent waving agents, etc.), laundry detergents for clothes, fabric softeners for clothes, finishing agents for clothes, fabric mists, various detergents (for fibers, leather, hard surfaces, living quarters, households, toilets, bathrooms, etc.), aromatic deodorants, incense sticks, aroma diffusers, scented toilet papers, household products such as wax agents.

[0040] The TRPV1 activator and the like according to the present invention can be appropriately added during the manufacturing process of fragrance compositions, cosmetics, oral compositions, and the like. The amount of the agent containing M3HB and the fragrance composition to be contained in various products is not particularly limited as long as it can exhibit effects such as promoting energy consumption of M3HB when the product is used. For example, when contained in cosmetics, it can be added so that the content of M3HB in the whole product is 1 ppb to 99.9% by mass. Further, when contained in oral compositions such as food and drink products and oral hygiene agents, it can be added so that the content of M3HB in the whole product is 1 ppb to 5% by mass.

Examples

[0041] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto. Also, unless otherwise specified, “%” means “% by mass”.

[0042] [Rearing of mice] In the following experiments, unless otherwise specified, the mice used in the experiments were reared under breeding conditions of a temperature of 23 ± 1°C, a humidity of 50 to 60%, and a 12-hour light-dark cycle (light period: 7:00 to 19:00). During the rearing period, tap water and chips were replaced once a week. As the diet, usually MF (mouse multi-feeder: manufactured by Oriental Yeast Co., Ltd.) was used. As wild-type (WT) mice, C57BL / 6 mice (supplied from Shimizu Experimental Materials) were used.

[0043] [Example 1] A fragrance substance acting as a TRPV1 agonist was selected by calcium imaging. As candidate compounds for the TRPV1 agonist, 34 types of fragrance substances were used for measurement.

[0044] Calcium imaging is a method for measuring intracellular calcium ions by changes in fluorescence intensity. Ca 2+Fluo-4AM used as a fluorescent probe (excitation wavelength: 495 nm, fluorescence wavelength: 518 nm, Ca complex dissociation constant (Kd): 345 nmol / L) becomes Fluo-4 when the acetoxymethyl group is hydrolyzed by intracellular esterase after being taken up into the cell. Fluo-4 is highly water-soluble and becomes less permeable to the cell membrane, remaining inside the cell. As a result, when calcium ions flow into the cell, Fluo-4 inside the cell forms a complex with calcium ions and emits fluorescence.

[0045] For the experiment, rTRPV1-HEK cells with forced stable expression of TRPV1 and HEK293A cells, which are TRPV1-non-expressing HEK cells, were used. rTRPV1-HEK cells are cells obtained by transfecting HEK293 cells (Human Embryonic Kidney Cell 293), which are cultured cells derived from human fetal kidneys, with a mammalian expression vector, pcDNA3, into which the rat TRPV1 gene has been introduced.

[0046] rTRPV1-HEK cells were seeded at 4×10 5 cells / dish in a 35-mm dish with a coverslip adhered for cell culture and incubated for 1 day. The next day, Fluo-4 AM was added to each dish to a final concentration of 2.5 μM and cultured for approximately 1 hour. Then, a recording buffer containing each aroma substance at 100 or 300 μM and capsaicin at 500 nM was sequentially flowed for 30 seconds each, and then a recording buffer containing ionomycin at 5 μM was flowed for 10 seconds. During the series of treatments, changes in the fluorescence intensity of each cell were measured over time using a confocal laser microscope. Capsaicin is a TRPV1 agonist, and ionomycin is a general-purpose intracellular calcium ion introduction agent widely used in calcium imaging.

[0047] In all 34 cases, an increase in fluorescence intensity was confirmed during capsaicin treatment and ionomycin treatment, indicating that TRPV1 functions normally in all cells. Among these 34 compounds, M3HB was selected as a compound in which an increase in fluorescence intensity was observed at both 100 μM and 300 μM, and the fluorescence intensity at 300 μM was clearly greater than that at 100 μM. Figure 1(A) shows the change in fluorescence intensity over time of rTRPV1-HEK cells to which M3HB was added.

[0048] The change in fluorescence intensity observed by calcium imaging in rTRPV1-HEK cells may be due not only to the influx of calcium ions into the cell via TRPV1, but also to the influx via transporters other than TRPV1 and the release from the endoplasmic reticulum. Therefore, calcium imaging was similarly performed using HEK293A cells that do not express TRPV1 to examine whether the influx of calcium ions into the cell is promoted in a TRPV1-dependent manner. Figure 1(B) shows the change in fluorescence intensity over time of HEK293A cells to which M3HB was added. As shown in Figure 1(B), the intracellular fluorescence intensity did not increase during M3HB addition and capsaicin addition, and an increase in fluorescence intensity was confirmed only during ionomycin treatment. From these results, it was found that M3HB is a TRPV1 agonist having a TRPV1 activation effect.

[0049] [Example 2] It has been shown that single administration of capsaicin or capsinoid to mice enhances heat production in a TRPV1-dependent manner, and the temperature of brown adipose tissue (BAT) and body surface temperature increase (Non-Patent Documents 5 and 6). Therefore, M3HB was orally administered to mice once, and the change in rectal temperature was measured as an index of deep body temperature under warming conditions to examine whether M3HB contributes to heat production and enhanced energy metabolism.

[0050] WT mice (5 - 7 weeks old, male) or TRPV1 knockout (TRPV1 KO) mice (5 - 8 weeks old, male) were orally administered with an M3HB solution (100 mg / kg body weight as M3HB, solvent: physiological saline containing 10% Tween80) or a Vehicle solution (physiological saline containing 10% Tween80, 5 mL / kg body weight) under isoflurane anesthesia, and the rectal temperature was measured. A thermocouple temperature sensor (Physitemp RT - 3) was used for the measurement.

[0051] Specifically, on the day of administration, the mice were fasted from 10:00. From 14:00, the mice were placed in an anesthesia chamber and anesthetized with isoflurane. Then, while applying isoflurane anesthesia (air pressure: 0.5 L / min, 20 °C, isoflurane concentration: 1.5% (concentration in air)) on a heat block (38.0 °C), after inserting the temperature probe into the anus, a buffer sheet and a cloth were further placed over the mice for heat preservation. After confirming that the body temperature before administration showed a constant value for more than 5 minutes on the heat block, the M3HB solution or the Vehicle solution was orally administered. From immediately after administration to 60 minutes after oral administration, the rectal temperature (deep body temperature) was measured with a temperature probe, and the values every 1 minute were recorded.

[0052] The measurement results of WT mice are shown in Fig. 2(A), and those of TRPV1 KO mice are shown in Fig. 2(B). In WT mice, in the M3HB - administered group, a significant temperature increase was continuously confirmed compared with the Vehicle - administered group after 20 minutes from the time of oral administration (Fig. 2(A)). On the other hand, in TRPV1 KO mice, no significant body temperature change was observed between the M3HB - administered group and the Vehicle - administered group (Fig. 2(B)). From these results, it was found that M3HB causes an increase in rectal temperature in a TRPV1 - dependent manner. Thus, since heat production is induced by M3HB ingestion, M3HB is useful as an additive for oral compositions and cosmetics for improving cold sensitivity.

[0053] [Example 3] In Example 2, a single administration of M3HB resulted in an increase in deep body temperature. If this was due to enhanced heat production by UCP1 activation, it was considered that energy metabolism was enhanced. Therefore, we investigated whether energy metabolism would be enhanced by TRPV1 activation and diet-induced obesity (DIO) would be suppressed when M3HB was administered long-term.

[0054] <Long-term administration of M3HB and body weight measurement> After 1 week of acclimation, 3-week-old male wild-type (WT) mice were divided into a normal diet (ND) group (MF, manufactured by Oriental Yeast Co., Ltd.) or a high-fat diet (HFD) group (60 kcal% High fat diet, manufactured by RESEARCH DIETS). Each group was further divided into a Vehicle administration group (physiological saline containing 10% Tween80, 5 mL / kg body weight) and an M3HB administration group (100 mg / kg body weight as M3HB, solvent: physiological saline containing 10% Tween80). Every day, each administration solution was orally administered and body weight was measured (n = 8 for each group). At 16 weeks from the start of administration, dissection was performed and various tissue weights were measured.

[0055] Figure 3 shows the results of measuring the changes in body weight over time for each group (NV: normal diet Vehicle administration group, NM: normal diet M3HB administration group, HV: high-fat diet Vehicle administration group, HM: high-fat diet M3HB administration group). As shown in Figure 3, a significant difference in weight gain was confirmed between the high-fat diet Vehicle administration group and the high-fat diet M3HB administration group from the 5th week of long-term administration. From these results, it was suggested that M3HB has the ability to suppress weight gain, and that a flavor composition containing M3HB is useful as an additive for oral compositions and cosmetics for dieting purposes.

[0056] <Tissue weight, daily energy intake, and feed conversion efficiency after long-term administration of M3HB> Table 1 shows the measurement results of body weight at the time of dissection, the weight of each tissue, the daily energy intake (feed intake) over 16 weeks, and the feed conversion efficiency representing the weight gain rate per calorie intake. In the table, the numerical values represent the mean ± SEM of the mice in each group (n = 8). "*" represents p < 0.05, and "**" represents p < 0.01 (both HV vs HM).

[0057]

Table 1

[0058] In addition to energy consumption, food intake and excretion are also involved in suppressing weight gain. As a result of measuring food intake for 16 weeks, the high-fat diet M3HB administration group had significantly less food intake than the high-fat diet Vehicle administration group (Table 1). From this, it was considered that the decrease in food intake also partly contributed to the suppression of weight gain in the high-fat diet M3HB administration group. On the other hand, the feed conversion efficiency representing the weight gain rate per calorie intake was also significantly lower in the high-fat diet M3HB administration group than in the high-fat diet Vehicle administration group (Table 1). This suggested that energy consumption was enhanced by M3HB administration. Moreover, there was no difference in food intake and feed conversion efficiency between the normal diet Vehicle administration group and the normal diet M3HB administration group. Since it is known that a high-fat diet can cause damage to the feeding center and lead to overeating, it was also considered possible that the feeding regulation was maintained normally by the action of M3HB in the high-fat diet M3HB administration group. From these results, it was shown that long-term administration of M3HB enhances energy metabolism through TRPV1 activation and suppresses diet-induced obesity (DIO). It was found that food and drink products containing M3HB and cosmetics containing M3HB are suitable as oral compositions and cosmetics for continuous use for the purpose of dieting.

[0059] <Lipid Metabolism in BAT and iWAT> From the microscopic images of tissue sections, it was confirmed that in the high-fat diet M3HB administration group, the lipid droplets in BAT and iWAT were smaller compared to the high-fat diet Vehicle administration group. The expressions of Atgl and Hsl, which are enzymes involved in lipid metabolism, were significantly increased in the high-fat diet M3HB administration group compared to the high-fat diet Vehicle administration group in both BAT and iWAT. From these results, it was considered that lipid accumulation was suppressed by the enhancement of such enzyme expression in the high-fat diet M3HB administration group.

[0060] Proteins were extracted from BAT collected from the mice in each group, and the expression level of UCP1 was examined by Western blot. Protein extraction from each tissue was performed as follows. First, the tissue was minced in a protein extraction sample buffer (0.078 M Tris-HCl (pH 6.8), 6.25% (mass / volume) sucrose, 1× protease inhibitor), and then disrupted with a homogenizer. Next, sodium lauryl sulfate was added to the obtained suspension and mixed by inversion, and then left standing at room temperature for 30 minutes. Thereafter, the cells in the suspension were disrupted with a BioRuptor (30 seconds ON → 30 seconds OFF × 2). This disrupted product was centrifuged (25°C, 15,000 rpm, 30 minutes), and the middle layer (the transparent liquid part) was collected as a protein extract into a new 1.5 mL tube. The recovered protein extract was subjected to SDS-PAGE to separate the proteins, and then Western blot was performed using an anti-UCP1 antibody and an anti-β-actin antibody, and the relative amount of UCP1 ([UCP1 amount] / [β-actin amount]) corrected by the amount of β-actin in each sample (taking the [UCP1 amount] / [β-actin amount] of the NV group as 100%) was examined. The results are shown in Figure 4. As shown in Figure 4, in the high-fat diet M3HB administration group, a tendency for an increase in the expression level of UCP1 protein in BAT was observed compared to the high-fat diet Vehicle administration group. From this, it was suggested that the enhancement of UCP1 activity in BAT contributed to a part of the DIO suppression in the high-fat diet M3HB administration group.

[0061] <Total lipid mass and triglyceride (TG) amount in the liver> The total lipid mass and TG amount in the livers of mice in each group were measured. For the measurement, Triglyceride E Test Wako (manufactured by Wako) was used. Specifically, first, approximately 50 mg of liver samples thawed on ice were collected into a crushing tube containing 1.5 mL of lipid extraction solution (hexane: 2-propanol = 3:2 (volume ratio)) and stainless steel beads (5 mm). After crushing the liver tissue with stainless steel beads in the crushing tube (3200 rpm, 30 seconds × 5 times), it was shaken at room temperature for about 30 minutes, and then the crushing tube was centrifuged (4 °C, 10000 × g, 20 minutes), and 1.2 mL of the supernatant was aliquoted into a 1.5 mL tube whose tare weight had been measured. The supernatant aliquoted into the 1.5 mL tube was subjected to centrifugal evaporation at 50 °C for about 1 hour. To the residue in the crushing tube, 0.6 mL of the lipid extraction solution was added, suspended once with a crusher (3200 rpm, 30 seconds × 5 times), shaken at room temperature for about 1 hour, and then centrifuged (4 °C, 10000 × g, 10 minutes), and 0.55 mL of the supernatant was put into the 1.5 mL tube and mixed with the suspension prepared inside, and centrifugal evaporation was performed at 50 °C for about 1 hour. To the obtained residue, 1 mL of lipid dissolution solution (2-propanol containing 10% TritonX-100) was added, suspended by vortexing, sonicated with a BioRuptor (High power, 30 seconds × 5 times), and further suspended by vortexing to obtain a liver extraction sample. The TG amount in the liver extraction sample of each group was measured by adding TG chromogenic solution, shaking at 37 °C for 20 minutes, and then measuring the absorbance at 595 nm with a microplate reader. Based on the calibration curve prepared from this absorbance value and the absorbance values measured in the same manner for TG solutions with known concentrations, the TG amount of each liver extraction sample was measured. Furthermore, the total lipid mass was calculated from the tare weight and the weight after evaporation.

[0062] The measurement results of the total lipid mass of each group are shown in Fig. 5(A), and the measurement results of the TG amount are shown in Fig. 5(B). As shown in Fig. 5, fatty liver was confirmed in the high-fat diet Vehicle-administered group due to long-term high-fat diet loading, whereas in the high-fat diet M3HB-administered group, suppression of the onset of fatty liver, reduction of lipids in the liver, and a tendency for reduction of the TG amount were confirmed. From these results, it was confirmed that M3HB promotes lipid metabolism, and by ingesting M3HB for a long period, the onset of DIO can be suppressed, and the onset of fatty liver and hyperlipidemia can also be suppressed.

[0063] <Measurement of oxygen consumption> Furthermore, regarding whether energy metabolism is enhanced by M3HB administration, it was examined using oxygen consumption as an index. Specifically, for the mice in each group, after acclimation in the measurement chamber for 1 week at 15 to 16 weeks after administration, the oxygen consumption and carbon dioxide emission amount were measured for each individual for 2 days using a flow-through open-type calorimeter (“OxyMax equal flow system”, Bio Research Center). The %O2 value and %CO2 value in the test chamber were periodically measured using the OxyMax equal flow system, and the O2 consumption (VO2), carbon dioxide emission amount (VCO2), respiratory quotient, and calorie consumption were calculated.

[0064] The measurement results of the average oxygen consumption of each group during the light period (7:00 to 19:00), dark period (19:00 to 7:00), and entire period (46 hours) are shown in Fig. 6. In the figure, the values are mean ± SEM (n = 8). Also, “*” represents p < 0.05, and “**” represents p < 0.01 (both HV vs HM). As shown in Fig. 6, no difference in oxygen consumption was observed between the normal diet Vehicle-administered group and the normal diet M3HB-administered group, but among the high-fat diet-administered groups, the high-fat diet M3HB-administered group had a higher oxygen consumption throughout the whole compared to the high-fat diet Vehicle-administered group, and the oxygen consumption increased significantly due to long-term ingestion of M3HB. Also, on average during the light period and the entire period, in the high-fat diet M3HB-administered group, a significant tendency for an increase in oxygen consumption was observed compared to the high-fat diet Vehicle-administered group, and also during the dark period, a tendency for the high-fat diet M3HB-administered group to have a higher oxygen consumption than the high-fat diet Vehicle-administered group was observed.

[0065] <Measurement of Spontaneous Locomotor Activity> In addition to the enhancement of heat production, changes in locomotor activity also affect the change in oxygen consumption. Therefore, by measuring locomotor activity, it was determined whether the previously observed change in oxygen consumption was due to a change in locomotor activity or a change in heat production ability.

[0066] Specifically, for the mice in each group, during the 9th to 11th weeks after administration, locomotor activity was measured for each individual for 2 days using a locomotor activity measurement device (“Actimo-100S”, manufactured by Shin Factory). “Actimo-100S” adopts an infrared beam sensor method and is a device that enables comparison between individuals and highly accurate measurement. Infrared sensors at 20 mm intervals count the movement of animals, and two consecutive light ring shields are counted as one. The measurement range is 30 cm × 20 cm, and the measurement was carried out using a transparent cage. The data output utilizes a non-voltage contact signal and was measured using countable software. Simultaneous measurement of 8 animals is possible, and the data acquisition device used “Actimo-DATA”.

[0067] The measurement results of the average locomotor activity of each group during the light period (7:00~19:00), dark period (19:00~7:00), and the entire period (46 hours) are shown in Fig. 7. In the figure, the values are mean ± SEM (n = 8). Also, “*” represents p < 0.05, and “**” represents p < 0.01 (both HV vs HM). As shown in Fig. 7, no consistent change in locomotor activity due to long-term intake of M3HB was confirmed in either the normal diet group or the high-fat diet group. From these results, it was suggested that the change in oxygen consumption due to long-term administration of M3HB is not due to a change in locomotor activity but due to a change in heat production, and the DIO suppression and decrease in feed conversion efficiency observed in the high-fat diet M3HB administration group are likely due to an enhancement of heat production.

[0068] <Evaluation of Insulin Resistance (OGTT and ITT)> Insulin resistance is induced by DIO. Therefore, whether insulin resistance is induced in the high-fat diet Vehicle administration group and whether improvement of insulin resistance is observed by administration of M3HB were examined by an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). In the OGTT, glucose tolerance was examined by measuring plasma glucose concentration before and after glucose administration, and insulin sensitivity was examined by measuring insulin concentration.

[0069] (OGTT) At 13 weeks after administration, mice were fasted for 6 hours (9:00 to 15:00), and then blood was collected from the tail vein using a heparinized capillary. This blood collection time point was defined as the 0-minute time point, and immediately thereafter, a glucose solution (150 mg / mL) was orally administered so that the glucose dose was 1.5 g / kg body weight. At 15, 30, 60, 90, and 120 minutes after the first blood collection, blood was collected from the tail vein using a heparinized capillary. The collected blood samples were centrifuged at 4°C and 10,000×g for 5 minutes to recover plasma. The glucose concentration in the plasma was measured using a commercially available glucose measurement kit ("Glucose Test CII-Test Wako", manufactured by FUJIFILM Wako). In addition, for the plasma collected at 0, 15, 30, and 60 minutes after administration, the insulin concentration was measured using a commercially available insulin measurement kit ("Ultra-Sensitive Mouse Insulin Measurement Kit", manufactured by Morinaga Institute of Biological Science).

[0070] HOMA-IR (homeostasis model assessment insulin resistance) was calculated as an index of insulin resistance, and HOMA-β (homeostatic model assessment beta cell function) was calculated as an index of insulin secretory capacity. The calculation formulas are shown below. The unit of insulin was converted to the same as that of humans, 26 U / ng.

[0071] [HOMA-IR] = [fasting insulin value (μU / mL)] × [fasting blood glucose value (mg / dL)] / 22.5 [HOME-β] = (20 × [Fasting insulin value (μU / mL)] / ([Fasting blood glucose value] (mg / dL) - 3.5)

[0072] The time-course changes in plasma glucose concentration of mice in each group are shown in Fig. 8(A), and the time-course changes in plasma insulin concentration are shown in Fig. 8(B), respectively. The plasma glucose concentration increased significantly after glucose administration in the high-fat diet Vehicle-administered group and remained high thereafter. In contrast, in the high-fat diet M3HB-administered group, the blood glucose level decreased to the baseline after the increase. At this time, since the plasma insulin concentration was very high in the high-fat diet Vehicle-administered group, it was considered that insulin resistance was induced by the high-fat diet, and the insulin concentration was high because the effect of decreasing blood glucose level was weak.

[0073] Based on the fasting blood glucose value and insulin concentration at this time, the values of HOMA-IR, an index of insulin resistance, and HOMA-β, an index of insulin secretory capacity, were calculated. The measurement results of HOMA-IR for each group are shown in Fig. 9(A), and the measurement results of HOMA-β are shown in Fig. 9(B), respectively. As shown in the figure, a significant difference was confirmed between the high-fat diet Vehicle-administered group and the high-fat diet M3HB-administered group in terms of HOMA-IR. Also, a tendency towards a significant difference was observed between the high-fat diet Vehicle-administered group and the high-fat diet M3HB-administered group in terms of HOMA-β. From the value of HOMA-IR, it was considered that the insulin resistance induced by DIO was improved by the administration of M3HB. Also, from HOMA-β, it was considered that there was a tendency towards improvement in insulin secretory capacity by the administration of M3HB.

[0074] (ITT) In ITT, insulin sensitivity was examined by measuring the blood glucose value before and after intraperitoneal administration of insulin. After fasting the mice at the 14th week after administration for 6 hours (9:00 - 15:00), blood glucose levels were measured from the tail vein using a blood glucose meter ("One Touch Ultra", manufactured by LifeScan). The time point of the first blood glucose measurement was set as the 0-minute mark, and immediately an insulin solution was intraperitoneally administered at a dose of 0.75 U / kg body weight. Blood glucose levels were measured from the tail vein using "One Touch Ultra" at 0, 15, 30, 60, and 120 minutes after administration.

[0075] The measurement results of the blood glucose levels of the mice in each group are shown in Figure 10. It was confirmed that in the high-fat diet M3HB administration group, the decrease in blood glucose levels was improved to the same extent as in the normal diet Vehicle administration group. Similar to the results of the OGTT, the results of the ITT also suggested that insulin resistance was induced in the HV group and was improved by M3HB administration.

[0076] [Formulation Example 1] (Beer-flavored beverage) M3HB was added to a beer flavor fragrance (manufactured by Ogawa Flavor & Fragrance Co., Ltd.) so that the M3HB content was 2% by mass. The obtained beer flavor fragrance was added at 0.1% to a commercially available beer-flavored beverage (0% carbohydrate, 0% purine body) to prepare a beer-flavored beverage.

[0077] [Formulation Example 2] (Fruit juice beverage) The following compositions were mixed to produce a fruit juice beverage. M3HB was added to a grapefruit fragrance (manufactured by Ogawa Flavor & Fragrance Co., Ltd.) so that the M3HB content was 2% by mass, and the obtained grapefruit fragrance was used.

[0078]

Table 2

[0079] [Formulation Example 3] (Black tea beverage) For 400 mL of hot water at 80°C, 7 g of black tea leaves (manufactured by Mitsui Norin Co., Ltd.), sodium L-ascorbate 0.2 g of thorium was added and extraction was carried out for 5 minutes. After solid-liquid separation was performed on the obtained black tea extract, water was added to make it 1,000 g, and the pH was adjusted to 5.5 using sodium hydrogen carbonate. M3HB was added to the black tea flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass. The obtained black tea flavor was added to the black tea extract after pH adjustment at 0.1% by mass to prepare a black tea beverage.

[0080] [Formulation Example 4] (Coffee Beverage) 60 g of roasted coffee beans were ground with a commercially available coffee mill, and the obtained ground coffee beans were extracted by dripping with hot water at 90 to 95 °C and then cooled to room temperature to obtain 480 g of a coffee extract. 0.6 g of baking soda and ion-exchanged water were added to the extract to make it 1,000 g. M3HB was added to the coffee flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass. The obtained coffee flavor was added to the adjusted coffee extract at 0.1% by mass to prepare a coffee beverage.

[0081] [Formulation Example 5] (Vegetable Juice) The following compositions were mixed to produce a vegetable juice. M3HB was added to the apple flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained apple flavor was used.

[0082]

Table 3

[0083] [Formulation Example 6] (Soy Milk) The following compositions were mixed to produce soy milk. M3HB was added to the grapefruit flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained grapefruit flavor was used.

[0084]

Table 4

[0085] [Formulation Example 7] (Protein Beverage) The following compositions were mixed to produce a protein beverage. M3HB was added to a cocoa flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained cocoa flavor was used.

[0086]

Table 5

[0087] [Formulation Example 8] (Beauty Drink) The following compositions were mixed to produce a beauty drink. M3HB was added to a lemon flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained lemon flavor was used.

[0088]

Table 6

[0089] [Formulation Example 9] (Near Water Drink) The following compositions were mixed to produce a near water drink. M3HB was added to a grapefruit flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained grapefruit flavor was used.

[0090]

Table 7

[0091] [Formulation Example 10] (Non-alcoholic Chu-hi) The following compositions were mixed to produce a non-alcoholic chu-hi. M3HB was added to an apple flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained apple flavor was used.

[0092]

Table 8

[0093] [Formulation Example 11] (Vinegar Drink) The following compositions were mixed to produce vinegar beverages. M3HB was added to an apple flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained apple flavor was used.

[0094]

Table 9

[0095] [Formulation Example 12] (Sports Drink) The following compositions were mixed to produce sports drinks. M3HB was added to a grapefruit flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained grapefruit flavor was used.

[0096]

Table 10

[0097] [Formulation Example 13] (Lactic Acid Bacteria Drink) The following compositions were mixed to produce lactic acid bacteria drinks. M3HB was added to a yogurt flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained yogurt flavor was used.

[0098]

Table 11

[0099] [Formulation Example 14] (Jelly Drink) The following compositions were mixed to produce jelly drinks. M3HB was added to an apple flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained apple flavor was used.

[0100]

Table 12

[0101] [Formulation Example 15] (Protein Bar) The following raw materials were molded and fired to produce protein bars. M3HB was added to a chocolate flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content was 5% by mass, and the obtained chocolate flavor was used.

[0102]

Table 13

[0103] [Formulation Example 16] (Gum) The following raw materials were kneaded uniformly, molded, and gum was produced. M3HB was added to a mint flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content was 10% by mass, and the obtained mint flavor was used.

[0104]

Table 14

[0105] [Formulation Example 17] (Tablet) The following raw materials were mixed, molded, and tablets were produced. M3HB was added to a mint flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content was 10% by mass, and the obtained mint flavor was used.

[0106]

Table 15

[0107] [Formulation Example 18] (Soup) The following raw materials were mixed, and soup was produced. M3HB was added to a chicken flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content was 2% by mass, and the obtained chicken flavor was used.

[0108]

Table 16

[0109] [Formulation Example 19] (Vegetarian Meat Hamburger) The following raw materials were mixed to produce a plant-based meat hamburger. M3HB was added to the beef flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 2% by mass, and the obtained beef flavor was used.

[0110]

Table 17

[0111] [Formulation Example 20] (Hard Candy) The following raw materials were mixed and molded to produce hard candy. M3HB was added to the mint flavor (manufactured by Ogawa Flavor Co., Ltd.) so that the M3HB content became 10% by mass, and the obtained mint flavor was used.

[0112]

Table 18

[0113] [Formulation Example 21] (Perfume) According to the formulation in Table 19, the perfume was produced by mixing the fragrance and ethanol.

[0114]

Table 19

[0115] [Formulation Example 22] (Liquid Aromatic Agent) According to the formulation in Table 20, methyl paraben, fragrance, POE hydrogenated castor oil, ethanol, and water were mixed in order to produce an aromatic spray.

[0116]

Table 20

[0117] [Formulation Example 23] (Lotion) According to the formulation in Table 21, the lotion was manufactured. First, 1,3-butylene glycol, glycerin, and methyl paraben were dissolved in ethanol and mixed with water to prepare a lotion base. Then, PEG-20 sorbitan cocoate and fragrance, which had been uniformly mixed in advance, were added to the lotion base to manufacture the lotion.

[0118]

Table 21

[0119] [Formulation Example 24] (Shampoo) According to the formulation in Table 22, the shampoo was manufactured. First, the components of the aqueous base were measured into a beaker and uniformly mixed while heating at 85°C. To the prepared aqueous base, an activator such as sodium cocoamphoacetate was added while stirring and uniformly dissolved, and further 1% citric acid water and water were added and uniformly mixed. Finally, fragrance was added to the obtained mixture to manufacture the shampoo.

[0120]

Table 22

[0121] [Formulation Example 25] (Fabric Softener) According to the formulation in Table 23, the fabric softener was manufactured. First, the components of Phase A were measured into a beaker and uniformly mixed while heating at 80°C. To the obtained Phase A, Phase B, which had been uniformly mixed at 80°C, was added and stirred with a homomixer. Finally, fragrance was added to the obtained mixture to manufacture the fabric softener.

[0122]

Table 23

[0123] [Formulation Example 26] (Incense Stick) Incense sticks were manufactured according to the recipe in Table 24. First, the raw material for incense sticks, which is mainly composed of powdered Machilus thunbergii, was mixed with the fragrance, and 100g of water was added and kneaded thoroughly. The kneaded mixture was formed into a rod shape with a diameter of about 2mm and a length of 10cm, which was then dried at room temperature for one week to produce incense sticks.

[0124] [Table 24]

[0125] [Prescription Example 27] (Aroma Diffuser) An aroma diffuser was manufactured by mixing the fragrance and ethanol according to the recipe in Table 25. The obtained aroma diffuser was filled into a container or diffuser device with a stick for absorbing aroma, to manufacture an aroma diffuser product.

[0126] [Table 25]

[0127] [Prescription Example 28] (Fabric Mist) According to the formulation in Table 26, the ingredients of phase A were weighed out into a beaker and mixed uniformly, and then water was added and mixed uniformly to produce a fabric mist.

[0128] [Table 26]

[0129] [Formulation Example 29] (Powdered bath additive) According to the recipe in Table 27, the ingredients other than the fragrance were mixed, and then the fragrance was added to produce a powdered bath additive.

[0130] [Table 27]

[0131] [Formulation Example 30] (Bath oil) According to the formulation in Table 28, liquid paraffin, cetyl ethylhexanoate, octyldodecanol, sorbeth-30 tetraoleate, and fragrance were mixed in order to produce bath oil.

[0132]

Table 28

Claims

1. A TRPV1 activator comprising menthyl 3-hydroxybutyrate as an active ingredient.

2. A brown adipose cell activator comprising menthyl 3-hydroxybutyrate as an active ingredient.

3. An energy consumption promoter comprising menthyl 3-hydroxybutyrate as an active ingredient.

4. A body heat production promoter comprising menthyl 3-hydroxybutyrate as an active ingredient.

5. A glucose tolerance improver comprising menthyl 3-hydroxybutyrate as an active ingredient.

6. A fragrance composition for diet, improvement of cold sensitivity, or improvement of glucose tolerance, containing the agent according to any one of Claims 1 to 5.

7. An oral composition for diet, improvement of cold sensitivity, or improvement of glucose tolerance, containing the agent according to any one of Claims 1 to 5 or the fragrance composition according to Claim 6.

8. A method for producing an oral composition for diet, improvement of cold sensitivity, or improvement of glucose tolerance, using the agent according to any one of Claims 1 to 5 or the fragrance composition according to Claim 6 as a raw material.

9. A cosmetic containing the agent according to any one of Claims 1 to 5 or the fragrance composition according to Claim 6 for diet, improvement of cold sensitivity, or improvement of glucose tolerance.

10. A method for producing a cosmetic for diet, improvement of cold sensitivity, or improvement of glucose tolerance, using the agent according to any one of Claims 1 to 5 or the fragrance composition according to Claim 6 as a raw material.

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