Fat metabolism promoter

Abstract

[Problem] To provide a novel technology by which fat metabolism can be promoted. [Solution] A fat metabolism promoter which comprises, as an active ingredient, a compound represented by general formula (1) (in the formula, R1 and R2 independently represent an alkyl group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms), wherein the compound represented by general formula (1) has an octanol / water partition coefficient represented by log Pow of 1.9-3.8 inclusive.

Description

[Technical field]

[0001] The present invention relates to a fat metabolism promoter and the like, which contains a compound represented by the following general formula (1). [ka] (In the formula, R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms.) [Background technology]

[0002] With the worldwide spread of Western lifestyles, the number of people consuming high-calorie and / or high-fat meals is increasing. At the same time, physical activity is also on the rise, and calories consumed are on the decline. As a result, the number of people suffering from obesity is steadily increasing.

[0003] Obesity refers to a state in which fat accumulates excessively, and is one of the causes of lifestyle-related diseases such as diabetes, hypertension, dyslipidemia, etc. To prevent and improve obesity, the adjustment of calorie intake through dietary restrictions and the adjustment of calorie consumption through exercise are generally carried out.

[0004] In recent years, the development of technology for preventing or improving obesity by promoting fat metabolism has been promoted.For example, Patent Document 1 describes a composition containing arginine, alanine and phenylalanine as active ingredients, and describes that lipid metabolism in obese people can be promoted by increasing the content of arginine, alanine and phenylalanine in the composition to a predetermined amount or more. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2019-099498 A Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel technique capable of promoting fat metabolism. [Means for solving the problem]

[0007] The present inventors have discovered that fat metabolism can be promoted by ingesting a compound represented by the following general formula (1) having an octanol / water partition coefficient (logPow) in the range of 1.9 to 3.8, and have completed the present invention. [ka] (In the formula, R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms.)

[0008] The gist of the present invention is as follows. [1] General formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms), wherein the compound represented by general formula (1) has a logPow, which represents an octanol / water partition coefficient, of 1.9 or more and 3.8 or less. [2] The fat metabolism promoter according to [1], wherein R1 is any one group selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, and an n-heptyl group. [3] The fat metabolism promoter according to [1] or [2], wherein R2 is any one group selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, an n-hexyl group, and an n-heptyl group. [4] The fat metabolism promoter according to any one of [1] to [3], wherein the compound represented by the general formula (1) is at least one compound selected from the group consisting of ethyl caproate, methyl caproate, propyl caproate, butyl caproate, pentyl caproate, ethyl caprylate, isoamyl acetate, isoamyl propionate, isoamyl butyrate, isoamyl caproate, pentyl acetate, heptyl acetate, methyl caprylate, ethyl 4-methylvalerate, 2-methylbutyl acetate, and ethyl valerate. [5] The fat metabolism promoter according to any one of [1] to [4], wherein the daily intake amount of the compound represented by the general formula (1) for an adult is 0.017 mg or more and 1.8 mg or less. [6] The fat metabolism promoter according to any one of [1] to [5], wherein the fat metabolism promoter is a fat decomposition promoter. [7] The fat metabolism promoter according to any one of [1] to [5], wherein the fat metabolism promoter is a fat burning promoter. [8] General formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms), wherein the compound represented by general formula (1) has a logPow, which represents an octanol / water partition coefficient, of 1.9 or more and 3.8 or less. [9] For promoting fat metabolism, the general formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms)

[10] A method for producing a fat metabolism promoter, comprising the steps of: [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms)

[11] For promoting body heat production, a compound according to the general formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms)

[12] For producing a body heat production promoter, a compound according to the general formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms)

[13] An agent for treating and / or preventing at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, and obesity, comprising a compound represented by the general formula (1): [ka] A therapeutic and / or prophylactic agent comprising a compound represented by the formula: (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms).

[14] A compound according to the general formula (1): for treating and / or preventing at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, and obesity: [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms)

[15] For producing an agent for treating and / or preventing at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, and obesity, a compound represented by the general formula (1): [ka] (wherein R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms) Effect of the Invention

[0009] According to the present invention, a novel technique capable of promoting fat metabolism can be provided. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the measurement conditions for respiratory quotient (Test 1). [Diagram 2] 1 is a graph showing the rate of change in respiratory quotient versus time (Test 1). [Diagram 3] FIG. 1 shows the conditions for measuring body temperature (Test 2). [Figure 4] 13 is a graph showing the relationship between the skin temperature between the shoulder blades and time (Test 2). [Diagram 5] 1 is a graph showing the relationship between tympanic membrane temperature and time (Test 2). [Figure 6] FIG. 1 shows the conditions for measuring body temperature (Test 3). [Figure 7] 13 is a graph showing the relationship between the skin temperature between the shoulder blades and time (Test 3). [Figure 8] 1 is a graph showing the rate of glycerol release (Test 4). [Figure 9] 1 is a graph showing the maximum change in RFU (ΔRFU) before and after the addition of a promoter (Test 5). [Figure 10] 1 is a graph showing RFU versus time (Test 5). [Figure 11] 1 is a graph showing the change in RFU (ΔRFU) after addition of an inhibitor relative to the RFU before addition of a promoter (Test 5). [Figure 12] Graph showing average respiratory quotient at rest (Test 6). [Figure 13] 1 is a graph showing the average amount of lipid oxidation at rest (Test 6). [Figure 14] Graph showing average respiratory quotient at rest and during exercise (Study 7). [Figure 15] 1 is a graph showing the average amount of lipid oxidation at rest and during exercise (Test 7). [Figure 16]13 is a graph showing the relationship between the skin temperature between the shoulder blades and time (Test 8). [Figure 17] 1 is a graph showing the relationship between tympanic membrane temperature and time (Test 8). [Figure 18] 1 is a graph showing the maximum change in RFU (ΔRFU) before and after the addition of a promoter (Test 9). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In the description of groups and atomic groups in this specification, when the substituted or unsubstituted state is not specified, both those having no substituent and those having a substituent are included. For example, an "alkyl group" without specifying the substituted or unsubstituted state includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group).

[0012] An embodiment of the present invention will now be described. The present embodiment relates to a fat metabolism promoter that promotes fat metabolism.

[0013] The fat metabolism promoter of the present embodiment contains a compound represented by the following general formula (1) (hereinafter also referred to as "compound (1)"). Compound (1) contained in the fat metabolism promoter of the present embodiment has an octanol / water partition coefficient (logPow) of 1.9 or more and 3.8 or less. [ka] In the formula, R1 and R2 each independently represent an alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms.

[0014] Here, "R1 and R2 are each independently" means that the alkyl groups constituting R1 and R2 (alkyl groups having 1, 2, 3, 4, 5, 6, or 7 carbon atoms) may be the same or different.

[0015] The alkyl group of R1 and R2 having 1, 2, 3, 4, 5, 6, or 7 carbon atoms may be linear or branched. The alkyl group of R1 and R2 having 1, 2, 3, 4, 5, 6, or 7 carbon atoms may form a ring or may not form a ring. The alkyl group of R1 and R2 having 1, 2, 3, 4, 5, 6, or 7 carbon atoms is preferably an alkyl group not having a substituent such as a hydroxyl group or a benzyl group. Examples of the alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms for R1 and R2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group (1-methylethyl group), an n-butyl group, a sec-butyl group (1-methylpropyl group), an isobutyl group (2-methylpropyl group), a tert-butyl group (1,1-dimethylethyl group), an n-pentyl group, an isopentyl group (3-methylbutyl group), a 2-methylbutyl group, a sec-pentyl group (1-methylbutyl group), a 3- Examples of such alkyl groups include a pentyl group (1-ethylpropyl group), a tert-pentyl group (1,1-dimethylpropyl group), an n-hexyl group, an isohexyl group (4-methylpentyl group), a sec-hexyl group (1-methylpentyl group), a tert-hexyl group (1,1-dimethylbutyl group), an n-heptyl group, an isoheptyl group (5-methylhexyl group), a sec-heptyl group (1-methylhexyl group), and a tert-heptyl group (1,1-dimethylhexyl group).

[0016] From the viewpoint of promoting fat metabolism, the alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms of R1 is preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, or an n-heptyl group. From the viewpoint of promoting fat metabolism, the alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms of R2 is preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, an n-hexyl group, or an n-heptyl group. From the viewpoint of promoting fat metabolism, the preferred combination of alkyl groups for R1 and R2 is that when the alkyl group for R1 is a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, or an n-heptyl group, the alkyl group for R2 is a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, an n-hexyl group, or an n-heptyl group.

[0017] The octanol / water partition coefficient is the logarithm of the concentration ratio of compound (1) in two solvent phases (1-octanol and water) when compound (1) is added to both 1-octanol and water and reaches equilibrium. It is also expressed as logPow. Pow is a physicochemical index that indicates the hydrophobicity of a chemical substance and is generally expressed as a logarithmic value (logPow). A smaller logPow value indicates hydrophilicity, and a larger logPow value indicates lipophilicity.

[0018] The logPow, which represents the octanol / water partition coefficient, can be measured by the method described in JIS Z 7260-107 (2000). The octanol / water partition coefficient (logPow) may be a value calculated by commercial software using a quantitative structure-activity relationship algorithm, or software on the web. An example of the quantitative structure-activity relationship algorithm is the XLOGP3 algorithm, which is an atom-based approach. XLOGP3 is described in known documents such as "Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge," Journal of Chemical Information and Modeling, 2007, Vol. 47, issue 6, pages 2140-2148. An example of software capable of calculating the octanol / water partition coefficient (logPow) is XlogP (available from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, http: / / WWW.sio-ccbg.ac.cn / software / xlogp3 / ). Furthermore, the results of XlogP calculations are available in the PubChem database (http: / / pubchem.ncbi.nlm.nih.gov / #).

[0019] Examples of compound (1) include ethyl caproate (ethyl hexanoate), methyl caproate (methyl hexanoate), propyl caproate (propyl hexanoate), butyl caproate (butyl hexanoate), pentyl caproate (pentyl hexanoate), ethyl caprylate (ethyl octanoate), isoamyl acetate (3-methylbutyl acetate), isoamyl propionate (3-methylbutyl propanoate), isoamyl butyrate (3-methylbutyl butanoate), isoamyl caproate (3-methylbutyl hexanoate), pentyl acetate, heptyl acetate, methyl caprylate (methyl octanoate), ethyl 4-methylvalerate (ethyl 4-methylpentanoate), 2-methylbutyl acetate, and ethyl valerate (ethyl pentanoate). From the viewpoint of promoting fat metabolism, compound (1) is preferably ethyl caproate, propyl caproate, butyl caproate, pentyl caproate, ethyl caprylate, isoamyl propionate, isoamyl butyrate, isoamyl caproate, pentyl acetate, heptyl acetate, or ethyl 4-methylvalerate, and more preferably ethyl caproate or isoamyl acetate. Note that the fat metabolism promoter of this embodiment may use two or more kinds of compound (1) in combination.

[0020] Ethyl caproate is a compound represented by the following formula (2). [ka]

[0021] Isoamyl acetate is a compound represented by the following formula (3). [ka]

[0022] The compound (1) contained in the fat metabolism promoter of this embodiment may be biosynthesized by an organism or may be chemically synthesized (chemically synthesized). In addition, the compound (1) contained in the fat metabolism promoter of this embodiment may be a commercially available product. For example, ethyl caproate and isoamyl acetate can be biosynthesized by yeast. The biosynthesis of ethyl caproate by yeast is described, for example, in JP-A-2011-182745, and the biosynthesis of isoamyl acetate by yeast is described, for example, in JP-A-10-276767.

[0023] The amount of compound (1) in the fat metabolism promoter of this embodiment is not particularly limited, but is preferably an amount in which the adult's daily intake of compound (1) is 0.0017 mg or more and 1.8 mg or less, and more preferably an amount in which the adult's daily intake of compound (1) is 0.017 mg or more and 0.17 mg or less. The amount of ethyl caproate is more preferably an amount in which the adult's daily intake of compound (1) is 0.017 mg or more and 0.17 mg or less, and the amount of isoamyl acetate is more preferably an amount in which the adult's daily intake of compound (1) is 0.018 mg or more and 0.18 mg or less. The intake of compound (1) per adult's body weight (per day) is preferably 0.028 μg / kg or more and 30 μg / kg or less, and more preferably 0.28 μg / kg or more and 30 μg / kg or less. The intake amount of ethyl caproate (per day) is more preferably 0.28 μg / kg or more and 2.8 μg / kg or less, and the intake amount of isoamyl acetate (per day) is more preferably 0.30 μg / kg or more and 3.0 μg / kg or less. When the intake amount of compound (1) per day is within the above-mentioned range, fat metabolism can be further promoted compared to when it is outside the above-mentioned range. The number of times of intake of the fat metabolism promoter of this embodiment is not particularly limited, but can be, for example, once a day.

[0024] The form of use of the fat metabolism promoter of this embodiment is not particularly limited, and can be any form of use such as medicine, quasi-drug, food and drink, additive, etc. The state of the fat metabolism promoter of this embodiment is not particularly limited, and can be any state such as liquid, solid, semi-solid, gel, etc. The method of taking the fat metabolism promoter of this embodiment can be appropriately set according to the form of use and state, and is not particularly limited, but can be taken orally, for example.

[0025] The fat metabolism promoter of this embodiment may contain, in addition to compound (1), other components other than the compound (1). For example, when the fat metabolism promoter of this embodiment is a drug, a quasi-drug, or a food or drink, the fat metabolism promoter of this embodiment may contain, in addition to compound (1), an excipient, a binder, a stabilizer, a disintegrant, a lubricant, a flavoring agent, a suspending agent, a coating agent, a solvent (e.g., ethanol, etc.), or a component contained in a food or drink.

[0026] In particular, when the fat metabolism promoter of the present embodiment is used as a food or drink, it may be a normal food or drink, but it may also be a special purpose food such as a food for specified health use, a nutritional functional food, or a functional food. Examples of food or drink include nutritional supplements (supplements), milk, milk drinks, soft drinks (e.g., carbonated drinks, non-alcoholic drinks, juices, coffee drinks, tea drinks, mineral water, sports drinks, etc.), soy milk drinks, lactic acid bacteria drinks, cocoa, alcoholic drinks (e.g., beer, sparkling wine, other brewed alcohol, liqueur, sake, sweet sake, wine, shochu, etc.), processed milk, fermented milk, prepared milk powder, drinks prepared from instant powder and other drinks, cereals, yogurt, cheese, bread, pizza crust, ice cream, biscuits, crackers, candy, gummies, gums, and other confectioneries, liquid food, food for the sick, foods such as powdered milk for infants, foods such as powdered milk for breastfeeding women, and feed.

[0027] The dosage form of the fat metabolism promoter of the present embodiment is not particularly limited, and can be appropriately set according to the form and condition of use of the fat metabolism promoter.For example, when the fat metabolism promoter of the present embodiment is made into a food or drink such as a medicine, a quasi-drug, or a supplement, it can be made into a dosage form such as a tablet, a pill, a capsule, a granule, a powder, a powder, a syrup, etc.

[0028] The person who takes the fat metabolism promoter of this embodiment is not limited to humans, but may be an animal other than humans. The animal other than humans may be a higher vertebrate other than humans, particularly a mammal other than humans, and more specifically, may be a pet animal such as a dog or cat, or a livestock animal such as a cow, horse, pig, or sheep. The person who takes the fat metabolism promoter is not particularly limited, but may be a person who adjusts calorie intake by dietary restriction or the like, or a person who adjusts calorie consumption by exercise or the like.

[0029] Here, from the viewpoint of promoting fat metabolism, exercise may be performed after taking the fat metabolism promoter. As an example of exercise, as shown in the examples described later, bicycle pedaling exercise using an exercise bike (registered trademark) can be mentioned. When performing bicycle pedaling exercise, for example, the load can be 30W or more, the rotation speed can be 60rpm or more, and the exercise time can be 30 minutes or more. When performing exercise after taking the fat metabolism promoter, for example, exercise can be started between immediately after taking the fat metabolism promoter and 2 hours after taking it.

[0030] Ingestion of the fat metabolism promoter of the present embodiment described above can promote fat metabolism. In this specification, fat metabolism is a general term for each reaction that occurs until fat is decomposed into water and carbon dioxide. Fat metabolism includes a reaction of decomposing fat into free fatty acids and glycerol (hereinafter also referred to as "fat decomposition") and a reaction of decomposing free fatty acids into carbon dioxide and water (hereinafter also referred to as "fat burning"). In addition, in this specification, promotion of fat metabolism refers to the fact that fat is metabolized more by taking the fat metabolism promoter of the present embodiment compared to the case where the fat metabolism promoter of the present embodiment is not taken. By taking the fat metabolism promoter of the present embodiment, fat metabolism is promoted, and each reaction such as fat decomposition and fat burning is promoted.

[0031] The reason why the fat metabolism promoter of this embodiment promotes fat metabolism is not clear, but the octanol / water partition coefficient (logPow) of compound (1) is in the range of 1.9 to 3.8, so that compound (1) can easily permeate cell membranes, and the number of carbon atoms of the alkyl groups represented by R1 and R2 in compound (1) is 1, 2, 3, 4, 5, 6, or 7, so that compound (1) can interact with the binding site of the ion channel present in the cell even if it is decomposed by esterase in the cell. For this reason, for example, as shown in the examples described later, it is considered that the temperature-sensitive ion channel Transient Receptor Potential Ankyrin 1 (hereinafter also referred to as "TRPA1") expressed in sensory nerves is activated by compound (1), and fat metabolism is promoted by nerve transmission. In addition, another reason for promoting fat metabolism is that compound (1) can easily permeate cell membranes, so that compound (1) absorbed from the digestive tract acts on fat cells (or fat) and promotes fat metabolism.

[0032] One aspect of the fat metabolism promoter of this embodiment includes a composition for promoting fat metabolism that contains compound (1) and the above-mentioned components other than compound (1) (hereinafter also referred to as "other components"). Another aspect of the composition for promoting fat metabolism includes a food and drink composition for promoting fat metabolism that contains compound (1) and other components that may be contained in food and drink (hereinafter also referred to as "food and drink components"). The food and drink composition for promoting fat metabolism may be a normal food and drink, but may also be a special purpose food such as a food for specified health uses, a nutritional functional food, or a functional food. This composition for promoting fat metabolism (or a food and drink composition for promoting fat metabolism) can also promote fat metabolism, similar to the fat metabolism promoter of this embodiment.

[0033] The fat metabolism promoter of the present embodiment can also be used as an additive to be added to other components. The other components to which the fat metabolism promoter has been added as an additive can be used as a fat metabolism promoting composition that promotes fat metabolism. The fat metabolism promoter of the present embodiment can also be used as an additive to be added to food and beverage components. The food and beverage components to which the fat metabolism promoter has been added as an additive can be used as a fat metabolism promoting food and beverage composition that promotes fat metabolism.

[0034] Here, the fat metabolism promoter of the present embodiment can promote the reaction of decomposing fat into free fatty acids and glycerol (lipolysis). Therefore, the fat metabolism promoter of the present embodiment can be used as a lipolysis promoter that promotes the decomposition of fat (that is, it can be made into a lipolysis promoter by the same composition as the fat metabolism promoter). In this specification, promoting the decomposition of fat refers to the fact that fat is decomposed more by taking the fat metabolism promoter (or lipolysis promoter) of the present embodiment compared to the case where the fat metabolism promoter (or lipolysis promoter) of the present embodiment is not taken.

[0035] One embodiment of the lipolysis promoter includes a composition for promoting lipolysis containing compound (1) and other components other than compound (1). Another embodiment of the composition for promoting lipolysis includes a food and drink composition for promoting lipolysis containing compound (1) and other components (food and drink components) that may be contained in food and drink. The food and drink composition for promoting lipolysis may be an ordinary food or drink, but may also be a food for special uses such as a food for specified health uses, a food with nutrient function claims, or a food with functional claims. This composition for promoting lipolysis (or a food and drink composition for promoting lipolysis) can also promote the decomposition of fat, like the lipolysis promoter.

[0036] The lipolysis promoter of the present embodiment can also be used as an additive to be added to other components. The other components to which the lipolysis promoter has been added as an additive can be used as a lipolysis-promoting composition that promotes the decomposition of fat. The lipolysis promoter of the present embodiment can also be used as an additive to be added to food and beverage components. The food and beverage components to which the lipolysis promoter has been added as an additive can be used as a lipolysis-promoting food and beverage composition that promotes the decomposition of fat.

[0037] In addition, the fat metabolism promoter of this embodiment can promote the reaction of decomposing free fatty acids into carbon dioxide and water (fat burning). Therefore, the fat metabolism promoter of this embodiment can be used as a fat burning promoter that promotes the decomposition of free fatty acids (that is, it can be made into a fat burning promoter by the same composition as the fat metabolism promoter). In this specification, promoting fat burning refers to the fact that more fat is burned by taking the fat metabolism promoter (or fat burning promoter) of this embodiment compared to not taking the fat metabolism promoter (or fat burning promoter) of this embodiment.

[0038] An embodiment of the fat burning promoter includes a composition for promoting fat burning, which contains compound (1) and other components other than compound (1). An embodiment of the composition for promoting fat burning includes a food and drink composition for promoting fat burning, which contains compound (1) and other components (food and drink components) contained in the food and drink. The food and drink composition for promoting fat burning may be a normal food or drink, but may also be a food for special uses such as a food for specified health uses, a food with nutritional function claims, or a food with functional claims. This composition for promoting fat burning (food and drink composition for promoting fat burning) can also promote fat burning, like the fat burning promoter.

[0039] The fat burning promoter of this embodiment can also be used as an additive to be added to other components other than compound (1). The other components to which the fat burning promoter has been added as an additive can be used as a fat burning promotion composition that promotes fat burning. The fat burning promoter of this embodiment can also be used as an additive to be added to food and beverage components. The food and beverage components to which the fat burning promoter has been added as an additive can be used as a fat burning promotion food and beverage composition that promotes fat burning.

[0040] In the present embodiment described above, compound (1) is used to promote fat metabolism (including fat decomposition and fat burning) or to produce a fat metabolism promoter (including a fat decomposition promoter and a fat burning promoter). That is, the above-mentioned present embodiment includes the use of compound (1) to promote fat metabolism and the use of compound (1) to produce a fat metabolism promoter. Note that compound (1) used to promote fat metabolism and compound (1) used to produce a fat metabolism promoter have the same configuration as compound (1) of the above-mentioned fat metabolism promoter, so detailed explanations are omitted.

[0041] In addition, as described above, the fat metabolism promoter of the present embodiment can promote fat metabolism (including fat decomposition and fat burning). Promotion of fat metabolism leads to a decrease in the amount of triglycerides and LDL cholesterol in blood, which leads to the treatment and / or prevention of various diseases involving blood triglycerides or LDL cholesterol. Therefore, the fat metabolism promoter of the present embodiment can be used for the treatment and prevention of diseases whose symptoms are improved or whose onset is prevented by promoting fat metabolism. Examples of such diseases include dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome. In other words, the fat metabolism promoter of this embodiment can be used as a therapeutic and / or preventive agent for at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome (with the same configuration as the fat metabolism promoter of this embodiment, it can be used as a therapeutic and / or preventive agent for at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome).

[0042] In the above-mentioned embodiment of the therapeutic agent or preventive agent, compound (1) is used for the treatment and / or prevention of at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome. That is, the above-mentioned embodiment of the therapeutic agent or preventive agent includes the use of compound (1) for the treatment and / or prevention of at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome. Note that compound (1) used for the above-mentioned treatment and / or prevention has the same configuration as compound (1) of the fat metabolism promoter described above, and therefore a detailed description thereof will be omitted.

[0043] In the above-mentioned embodiment of the therapeutic agent or preventive agent, the compound (1) is used to manufacture a therapeutic and / or preventive agent for at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome. That is, the above-mentioned embodiment of the therapeutic agent or preventive agent includes the use of the compound (1) to manufacture a therapeutic and / or preventive agent for at least one disease selected from the group consisting of dyslipidemia, hyperlipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and metabolic syndrome. Note that the compound (1) used to manufacture the above-mentioned therapeutic and / or preventive agent has the same configuration as the compound (1) of the fat metabolism promoter described above, and therefore a detailed description thereof will be omitted.

[0044] Here, the fat metabolism promoter of this embodiment can also be used as a body heat production promoter that promotes the production of body heat (that is, it can be made into a body heat production promoter with the same configuration as the fat metabolism promoter). In this specification, promoting the production of body heat means that by taking the fat metabolism promoter (or the body heat production promoter) of this embodiment, more body heat is produced compared to not taking the fat metabolism promoter (or the body heat production promoter) of this embodiment.

[0045] The reason why the fat metabolism promoter (or body heat production promoter) of this embodiment can promote body heat production is not clear, but it is considered that by taking the fat metabolism promoter (or body heat production promoter) of this embodiment, the free fatty acid generated as a result of the promotion of fat decomposition as described above is decomposed in brown fat cells, etc., and the energy generated at that time promotes the production of body heat. In addition, the fat metabolism promoter of this embodiment can activate TRPA1. It is known that activation of TRPA1 promotes the production of body heat (SawaiS et al., “The effect of carbonated water on body temperature”, Abstracts of the Annual Meeting of the Agricultural Chemistry Society of Japan, 2012, Presentation No.: 3J15a01; Yukiko MASAMOTO et al., “Intragastric Administration of TRPV1, TRPV3, TRPM8, and TRPA1 Agonists Modulates Autonomic Thermoregulation in Different Manners in Mice”, Bioscience, Biotechnology, and Biochemistry, 2009, Volume 73, Issue 5, Pages 1021-1027. Another reason for the promotion of body heat production is that compound (1), absorbed from the digestive tract, acts on fat cells (or fat) and promotes the decomposition of free fatty acids, thereby promoting the production of body heat.

[0046] Here, by taking the fat metabolism promoter (or body heat production promoter) of this embodiment, the production of body heat is promoted, so that the decrease in body temperature can be suppressed compared to the case where the fat metabolism promoter (or body heat production promoter) of this embodiment is not taken. Therefore, the fat metabolism promoter (or body heat production promoter) of this embodiment can improve cold. In this specification, cold refers to a state in which parts such as the hands and feet, the waist, the abdomen, the back, and the shoulders feel cold. There are various reasons for the cause of cold, but a decrease in body heat production is also considered to be one of the causes. In general, feeling cold chronically regardless of the season or outside temperature is called cold sensitivity. Symptoms associated with cold sensitivity include, for example, stiff shoulders, headache, swelling, insomnia, numbness in the hands and feet, pain in the hands and feet, frequent urination, and lower back pain.

[0047] An embodiment of the body heat production promoter includes a composition for promoting body heat production, which contains compound (1) and other components other than compound (1). An embodiment of the composition for promoting body heat production includes a food and drink composition for promoting body heat production, which contains compound (1) and other components (food and drink components) contained in the food and drink. The food and drink composition for promoting body heat production may be a normal food or drink, or may be a special-purpose food such as a food for specified health uses, a nutritionally functional food, or a food with functional claims. This composition for promoting body heat production (or a food and drink composition for promoting body heat production) can also promote the production of body heat, like the body heat production promoter.

[0048] The body heat production promoter of this embodiment can also be used as an additive added to other components other than compound (1). The other components to which the body heat production promoter has been added as an additive can be used as a body heat production promoting composition that promotes the production of body heat. The body heat production promoter of this embodiment can also be used as an additive added to food and beverage components. The food and beverage components to which the body heat production promoter has been added as an additive can be used as a food and beverage composition for promoting body heat production that promotes the production of body heat.

[0049] In the above-mentioned embodiment of the body heat production promoter, compound (1) is used to promote body heat production or to manufacture a body heat production promoter. That is, the above-mentioned embodiment of the body heat production promoter includes the use of compound (1) to promote body heat production and the use of compound (1) to manufacture a body heat production promoter. Note that compound (1) used to promote body heat production and compound (1) used to manufacture a body heat production promoter have the same configuration as compound (1) of the fat metabolism promoter described above, so detailed explanations are omitted. EXAMPLES

[0050] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0051] [Test 1 (Respiratory quotient measurement test - water-based)] In this test, a test was carried out to measure the respiratory quotient. The respiratory quotient is the ratio of the amount of carbon dioxide discharged per unit time to the amount of oxygen consumed per unit time, and in this test, it was measured using an Aeromonitor (registered trademark) (manufactured by Minato Medical Science Co., Ltd.). The specific test method and results of this test are shown below. This test was carried out as a crossover comparative test.

[0052] (Test Method) In this study, each test beverage was administered to three subjects (adult males with a BMI (Body Mass Index) of 18.5 kg / m 2 More than 25kg / m 2 The subjects were given 200 ml of water (Comparative Example 1) and 200 ml of test solutions (Examples 1 to 3) containing ethyl caproate at concentrations of 0.1 ppm, 1 ppm, and 10 ppm, respectively, in water, as test beverages. The test beverages in Examples 1 to 3 correspond to intakes of 0.017 mg, 0.17 mg, and 1.7 mg of ethyl caproate, respectively. The log Pow of ethyl caproate was 2.4 (calculated in the same manner as in Test 9 described below). In Tests 2 to 7 described below, the log Pow (2.4) of ethyl caproate is omitted.

[0053] In the test beverages of Examples 1 to 3, ethanol was used as a solvent for ethyl caproate, so the ethanol concentration of all test beverages of Examples 1 to 3 was standardized to 0.0999%. In addition, the raw materials for the test beverages were "Ethyl hexanoate ≧98%, FCC, food grade" (Sigma-Aldrich), "K alcohol for alcoholic beverages, purity 95.4%" (Daiichi Alcohol), and "Oishii Mizu Tennensui Fujisan" (Asahi Soft Drinks). These raw materials were also used in the test beverages of Tests 2, 3, 6, 7, and 8, which will be described later.

[0054] Prior to the measurement of respiratory quotient in this study, a preliminary measurement was first performed. In the preliminary measurement, the subjects fasted for 12 hours from 9:00 p.m. on the previous day, and then wore a mask for measuring exhaled gas, and the measurement of respiratory quotient was started. After the measurement of respiratory quotient started, the subjects sat in a chair and rested for 10 minutes. During the 10 minutes of sitting and resting after the start of the measurement of respiratory quotient, the average respiratory quotient for 5 minutes from the 6th to the 10th minute was obtained as the baseline respiratory quotient. In this study, the measurement of respiratory quotient was performed in a constant temperature and humidity laboratory set at a temperature of 23±2°C and a humidity of 45±5%. In addition, breathing during the measurement of respiratory quotient was set at 4 seconds per breath, and subsequent measurements were also performed in the same manner.

[0055] On the first day of the test, the subject fasted for 12 hours from 9 p.m. the previous day, and the respiratory quotient was measured according to the conditions shown in FIG. 1. Specifically, the subject first ingested 200 ml of the test beverage of Comparative Example 1 in 2 minutes. After ingesting the test beverage, the subject sat on a chair and rested for 30 minutes. After that, the subject ingested white rice (about 200 kcal) and 100 ml of water in 10 minutes, and put on a mask. After putting on the mask, the measurement of the respiratory quotient was started. The subject sat on a chair and rested for 20 minutes after the start of the measurement of the respiratory quotient. After 20 minutes, the subject sat on an aero bike (registered trademark) (manufactured by Konami Sports Life Co., Ltd.) and rested for 10 minutes, and then exercised on the aero bike (registered trademark) for 30 minutes (30 W, 60 rpm). After the 30 minutes of exercise, the measurement of the respiratory quotient was completed. The respiratory quotient was measured for a total of 60 minutes.

[0056] On the second to fourth days of the test, the respiratory quotient was measured under the same conditions as on the first day of the test, except that the test beverages of Examples 1 to 3 were consumed as the test beverages. The test beverages consumed were changed depending on the test day. Specifically, the subjects were ingested with increasing concentrations of ethyl caproate from the second to fourth days of the test.

[0057] The data to be analyzed were the respiratory quotient for 10 minutes from 11 to 20 minutes out of the 20 minutes of sitting rest from the start of respiratory quotient measurement, and the respiratory quotient for 20 minutes from 11 to 30 minutes out of the 30 minutes of exercise on an exercise bike (registered trademark). The average value of the respiratory quotient was calculated for each minute, and the rate of change [%] of the average value relative to the baseline respiratory quotient was calculated. The rate of change [%] is the rate of change when the baseline respiratory quotient is set to 100%.

[0058] (Test Results) The results are shown in Figure 2. In this study, statistically significant differences between groups were examined by analysis of variance (ANOVA) with repeated measures on the rate of change of the average respiratory quotient every minute on each test day relative to the baseline average respiratory quotient.

[0059] 2, a significant decrease in respiratory quotient was confirmed when the test beverage of Example 1 was consumed compared to when the test beverage of Comparative Example 1 was consumed. Also, a tendency for the respiratory quotient to decrease when the test beverages of Examples 2 and 3 were consumed compared to when the test beverage of Comparative Example 1 was consumed.

[0060] A decrease in respiratory quotient means an increase in the amount of fat consumed. Therefore, the results of this study confirmed that the test beverages of Examples 1 to 3 promoted both fat decomposition and fat burning, and promoted fat metabolism.

[0061] [Test 2 (body temperature measurement test - at rest)] In this study, each subject consumed each test beverage, and the skin temperature between the shoulder blades and the tympanic membrane temperature (hereinafter, in Study 2, these are also referred to as "body temperature") were measured after ingestion. This study was conducted as a single-ingestion crossover comparative study with 10 adult male and female subjects (4 males, 6 females). The specific test method and results of this study are shown below.

[0062] In this test, the skin temperature between the shoulder blades was measured using myBeat (registered trademark) WHS-2 (manufactured by Union Tool Co., Ltd.), and the tympanic membrane temperature was measured using an ear thermometer CE Thermo 2 (manufactured by Nipro Co., Ltd.).

[0063] (Test Method) In this test, 200 ml of water was used as the test beverage of Comparative Example 2. 200 ml of a test liquid containing ethyl caproate in water at a concentration of 1 ppm was used as the test beverage of Example 4. Different test beverages were consumed by each subject on the first and second days of the test. The test beverage of Example 4 was equivalent to an intake of 0.17 mg of ethyl caproate. In addition, since ethanol was used as a solvent for ethyl caproate in the test beverage of Example 4, the ethanol concentration of all test beverages was standardized to 0.0999%.

[0064] In conducting this test, subjects were instructed to abstain from alcohol from the night before the test. In addition, on the day of the test, subjects were prohibited from consuming coffee or spicy foods, had to finish lunch by 12:30, and were prohibited from eating or drinking anything other than water after 12:30. In addition, subjects were required to wear the designated short-sleeved, long-pants clothing during the test.

[0065] Body temperature was measured under the conditions shown in Figure 3, and the same conditions were used on the first and second days of the test. Specifically, the subject entered the measurement room set at a room temperature of 24 ± 0.5 ° C at 14:30, wore a thermometer, and was allowed to acclimate to the environment for 40 minutes. Next, body temperature measurement began at 15:10, and at 15:28, the subject ingested 200 ml of the test beverage warmed to 37 ° C within 2 minutes. After that, the subject remained at rest for 60 minutes and continued to measure body temperature, and the measurement of body temperature was completed at 16:30. In consideration of the diurnal variation of autonomic nerve activity, measurements were taken at the same time on the first and second days of the test.

[0066] The measurement value at 15:30, immediately after drinking the test beverage, was used as the initial value (0 minute data), and the average value ± standard error for each group at each time point was calculated based on the measurement values ​​taken every 10 minutes (10, 20, 30, 40, 50, and 60 minutes) from immediately after drinking the test beverage until 16:30, when the measurements were completed.

[0067] (Test Results) The results are shown in Table 1, Figure 4, Table 2 and Figure 5. Table 1 and Figure 4 show the results for interscapular skin temperature, and Table 2 and Figure 5 show the results for tympanic membrane temperature. In this study, statistically significant differences were tested by paired t-test for differences between groups at the same time. A significance level of p<0.05 was considered to indicate a significant difference. In this study, data analysis was performed using Excel (Microsoft).

[0068] [Table 1]

[0069] [Table 2]

[0070] As shown in Table 1 and Figure 4, the skin temperature between the shoulder blades tended to increase in the group that drank the test beverage of Example 4, especially from 20 minutes after drinking, whereas a similar increasing trend was not observed in the group that drank the test beverage of Comparative Example 2.

[0071] Furthermore, as shown in Table 2 and Figure 5, a downward trend in tympanic membrane temperature was observed in the group that consumed the test beverage of Comparison Example 2, whereas a similar downward trend was not observed in the group that consumed the test beverage of Example 4.

[0072] In the statistical test for the intergroup comparison, in the results shown in Figures 4 and 5, no significant difference was observed between the group that ingested the test beverage of Example 4 and the group that ingested the test beverage of Comparative Example 2 at 0 minutes immediately after drinking. On the other hand, for the skin temperature between the shoulder blades shown in Figure 4, at 60 minutes after drinking, the group that ingested the test beverage of Example 4 was significantly higher than the group that ingested the test beverage of Comparative Example 2. In addition, for the tympanic membrane temperature shown in Figure 5, at 50 minutes and 60 minutes after drinking, the group that ingested the test beverage of Example 4 tended to be higher than the group that ingested the test beverage of Comparative Example 2. In particular, in the intragroup comparison of tympanic membrane temperature shown in Figure 5, the tympanic membrane temperature at 60 minutes was significantly lower in the group that ingested the test beverage of Comparative Example 2 than at 0 minutes, whereas the same result was not observed in the group that ingested the test beverage of Example 4.

[0073] The increase in skin temperature between the scapulae and the suppression of the decrease in tympanic membrane temperature mean that the production of body heat is promoted. In particular, since tympanic membrane temperature is a body temperature that reflects the core body temperature, the suppression of the decrease in tympanic membrane temperature means that the production of body heat is promoted inside the body as well. In addition, since the area between the scapulae is close to brown adipose tissue, the increase in skin temperature between the scapulae means that fatty acids are consumed in the brown adipose tissue and the production of body heat is promoted. Therefore, the results of this test confirmed that the test beverage of Example 4 promoted fat burning and further promoted the production of body heat.

[0074] [Test 3 (body temperature measurement test - during exercise)] In this test, each test subject consumed each test beverage, and the skin temperature between the shoulder blades was measured during exercise. This test was conducted on four adult male subjects. The skin temperature between the shoulder blades was measured using myBeat (registered trademark) WHS-2. The specific test method and results of this test are shown below.

[0075] (Test Method) In this test, a sweet and sour liquid of less than 5 kcal / 100 ml consisting of aspartame, acesulfame K, sucralose, anhydrous citric acid, trisodium citrate, and water was used as the test beverage of Comparative Example 3. A test liquid containing ethyl caproate at a concentration of 1 ppm was used as the test beverage of Example 5. The test beverage of Comparative Example 3 was consumed on the first day of the test, and the test beverage of Example 5 was consumed on the second day of the test. The test beverage of Example 5 corresponds to an intake amount of 0.17 mg of ethyl caproate. In addition, since ethanol was used as a solvent for ethyl caproate in the test beverage of Example 5, the ethanol concentration of all test beverages was unified to 0.0999%.

[0076] In conducting this test, the subjects were instructed to abstain from alcohol from the night before the test. Furthermore, the subjects were required to wear the designated short-sleeved and long-pants clothing during the test.

[0077] The subjects were fasted from 9 p.m. the previous day and the skin temperature between the shoulder blades was measured under the conditions shown in FIG. 6. The same conditions were used for both the first and second days of the test. Specifically, at 8:30 a.m., the subjects were first allowed to enter a constant temperature and humidity laboratory set at a temperature of 23±2°C and humidity of 45±5%, and were made to consume the test beverage and sit in a chair. After sitting in the chair and resting for 30 minutes, the subjects were made to consume white rice (about 200 kcal) and 100 ml of water for 10 minutes and wear a mask for measuring exhaled gas. After wearing the mask, the measurement of the skin temperature between the shoulder blades was started. After the measurement of the skin temperature between the shoulder blades was started, the subjects were made to sit in the chair and rest for 20 minutes, and then sat on an exercise bike (registered trademark) and rested for another 10 minutes. After that, the subjects were made to exercise (30 W, 60 rpm) on the exercise bike (registered trademark) for 30 minutes, and the measurement of the skin temperature between the shoulder blades was completed. Taking into consideration the diurnal variation in autonomic nervous activity, measurements were taken at the same time on the first and second days of the study.

[0078] Based on the measurements of interscapular skin temperature immediately after the start of exercise and every 10 minutes after the start of exercise (measurements at 10, 20, and 30 minutes), the mean value ± standard error for each group at each time point was calculated.

[0079] (Test Results) The results are shown in Table 3 and Figure 7. In this study, statistical significance was tested by paired t-test for the difference between the same time points in each group. A significance level of p<0.05 was considered to indicate a significant difference. Data analysis was performed using Excel (Microsoft).

[0080] [Table 3]

[0081] 7, it was confirmed that the period during which the skin temperature between the shoulder blades was high was longer in the group that ingested the test beverage of Example 5 compared to the group that ingested the test beverage of Comparative Example 3. In particular, statistical tests comparing the groups confirmed that the group that ingested the test beverage of Example 5 tended to have a higher temperature 30 minutes after the start of exercise (i.e., 60 minutes after the start of temperature measurement) compared to the group that ingested the test beverage of Comparative Example 3.

[0082] As mentioned above, an increase in skin temperature between the shoulder blades means that fatty acids are consumed in brown adipose tissue, promoting the production of body heat. Therefore, the results of this test confirmed that the test beverage of Example 5 promoted fat burning through exercise and also promoted the production of body heat.

[0083] [Test 4 (lipolysis test)] In this test, the lipolysis promoting effect of the promoter of this embodiment was examined by quantifying glycerol released into the culture supernatant as a result of the breakdown of fat accumulated in fat cells. The mouse fetus-derived 3T3-L1 cells used in this test are precursor cells of fat cells, and were induced to differentiate into fat cells. This test was performed based on the method described in "Effect of Quercetin Glycoside on a Mouse Diet-Induced Obesity Model-Lipolysis Promoting Effect of Quercetin" (Tateishi et al., Pharmacology and Treatment 2009; 37(2):123-131). The specific test method and results of this test are shown below.

[0084] (Test Method) In this test, first, 3T3-L1 cells were suspended in Dulbecco's Eagle medium (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (hereinafter also referred to as "DMEM medium") supplemented with penicillin-streptomycin (manufactured by Thermo Fisher Scientific) and fetal bovine serum (manufactured by Sigma-Aldrich) to concentrations of 100 Unit / ml, 100 μg / ml, and 10%, respectively, and seeded onto a 12-well plate.

[0085] 3T3-L1 cells were cultured under conditions of 5% CO2 and 37°C until they became confluent (a state in which the cells completely covered the surface of the culture vessel). Two days after becoming confluent, the medium was replaced with DMEM medium supplemented with dexamethasone (Nacalai Tesque), 3-isobutyl-1-methylxanthine (Nacalai Tesque), and insulin (Nacalai Tesque) at 0.25μM, 0.5mM, and 10μg / ml, respectively, and the 3T3-L1 cells were induced to differentiate into adipocytes by culturing for two days at 5% CO2 and 37°C.

[0086] After differentiation induction, the medium was replaced with DMEM medium supplemented with insulin at 5μg / ml every 2 or 3 days, and the cells were cultured at 5% CO2 and 37℃ for a total of 12 days to maintain differentiation. Thereafter, a test medium was prepared by adding penicillin-streptomycin (ThermoFisher Scientific) and fetal bovine serum (Sigma-Aldrich) to a phenol red-free DMEM medium (1.0g / l glucose) (Nacalai Tesque) at concentrations of 100 Unit / ml, 100μg / ml, and 10%, respectively, and each component was added to this test medium at the concentration shown in Table 4 below. The medium of the 3T3-L1 cells after differentiation induction was replaced with a medium supplemented with the components of Comparative Examples 4-5 and Examples 6-8, and the cells were cultured at 5% CO2 and 37℃ for 2 days.

[0087] [Table 4] The ethyl caproate used was manufactured by Tokyo Chemical Industry Co., Ltd., the ethanol used was manufactured by Fuji Film Wako Pure Chemical Industries, Ltd., and the noradrenaline used was manufactured by Nacalai Tesque, Inc.

[0088] After culturing for 2 days, the culture supernatant was collected, and the amount of glycerol released into the culture supernatant was quantified using a Glycerol Assay kit (Cell-Based) (manufactured by Abcam). The ratio of the amount of glycerol in the medium containing the components of Comparative Example 5 and Examples 6 to 8 to the amount of glycerol in the medium containing the components of Comparative Example 4 (hereinafter also referred to as "control ratio") was calculated, and the average value ± standard error was obtained.

[0089] (Test Results) The results are shown in Table 5 and Figure 8. In this study, statistical tests were performed using one-way ANOVA followed by multiple comparison tests using Dunnett's test. A significance level of p<0.05 was considered to indicate a significant difference. All of these analyses were performed using SPSS version 23 (manufactured by SPSS, Inc.).

[0090] [Table 5]

[0091] 8, there was almost no difference in the amount of glycerol released between the supernatants of the culture medium to which the components of Comparative Example 4 and Comparative Example 5 were added. On the other hand, more glycerol was released into the supernatants of the culture medium to which the components of Examples 6 to 8 were added, compared to the supernatant of the culture medium to which the component of Comparative Example 4 was added.

[0092] In addition, in the statistical test, since a significant difference was observed between the groups by one-way ANOVA, a multiple comparison test was performed using Dunnett's test between each of Examples 6 to 8 and Comparative Example 4. As a result, a significant increase in the amount of glycerol released was observed in Example 8, in which the concentration of ethyl caproate added was 10 ppm, and furthermore, a tendency for the amount of glycerol released to increase was observed in Example 7, in which the concentration of ethyl caproate added was 1.0 ppm.

[0093] From the results of this test, it was confirmed that in the media to which the components of Examples 6 to 8 were added, fat decomposition was promoted.

[0094] [Test 5 (TRPA1 activity test)] In this test, the contribution of the fat metabolism promoter of this embodiment to TRPA1 activity was examined by confirming the activation of the temperature-sensitive ion channel TRPA1 using a calcium imaging method. The specific test method and results of this test are shown below.

[0095] (First test method) In this test, first, human fetal HEK293T cells were suspended in DMEM medium supplemented with penicillin-streptomycin (Thermo Fisher Scientific) and fetal bovine serum (Sigma-Aldrich) at concentrations of 100 Unit / ml, 100 μg / ml, and 10%, respectively, and seeded into a 96-well plate at a volume of 100 μl / well. The cells were cultured under conditions of 5% CO2 and 37°C until the cell density reached 70-90%.

[0096] After that, the entire amount of DMEM medium in the well was removed, and OptiMEM medium (ThermoFisher Scientific) containing the gene transfer reagent Lipofectamine2000 (ThermoFisher Scientific) and the hTRPA1 gene expression plasmid was added thereto at a volume of 50 μl / well. Then, the cells were cultured for about 24 hours under conditions of 37°C and 5% CO2, and the TRPA1 gene was introduced into the HEK293T cells. The content of Lipofectamine2000 per 50 μl of OptiMEM medium was 0.3 μl and the content of the hTRPA1 gene expression plasmid was 400 ng. The TRPA1 gene can be confirmed, for example, in a DNA database such as GenBank.

[0097] When the HEK293T cells transfected with the above method (hereinafter referred to as "TRPA1 forced expressing cells") reached a density of 90-100%, 50μl / well of FLIPR Calcium 6 Assay Kit (MOLECULAR DEVICE), a calcium sensitive fluorescent dye, was added and cultured for 2 hours under conditions of 37℃ and 5% CO2. Here, the expression of TRPA1 on the cell membrane was confirmed by the response to cinnamaldehyde (Wako), a known TRPA1 ligand. DMSO was used to dilute cinnamaldehyde, but the DMSO concentration in the well was set to 0.1% in consideration of cytotoxicity.

[0098] The test solution of Example 9 was obtained by adding ethyl caproate to HEPES buffer (10 mM HEPES, 130 mM NaCl, 5 mM KCl, 10 mM glucose, 2 mM CaCl2·2H2O, 1.2 mM MgCl2·6H2O, pH=7.40) and containing ethyl caproate at a concentration of 255 ppm. In addition, HEPES buffer was used as the test solution of Comparative Example 6 as a negative control (NC). Measurement of the fluorescence intensity of the TRPA1 forced expression cells was started, and 20 seconds later, 50 μl of the prepared test solution was added to each of the three wells. After a predetermined period of time, the measurement of the fluorescence intensity was stopped, and the ratio of the fluorescence intensity at each time point after the addition of the test solution to the average value of the fluorescence intensity before the addition of the test solution was calculated from the measured fluorescence intensity (hereinafter, also referred to as "RFU (relative fluorescence units)"), where the average value of the fluorescence intensity before the addition of the test solution was set to 1. Furthermore, the change in RFU before and after the addition of the test solution (hereinafter also referred to as "ΔRFU") was determined for each time point after the addition of the test solution. The fluorescence intensity was measured using FlexStation3 (Molecular Devices). The fluorescence intensity was measured at room temperature, and the test solution added to the wells was also used at room temperature.

[0099] For reference, 50 μl each of the test solutions from Example 9 and Comparative Example 6 were added to HEK293T cells (hereinafter also referred to as "non-transformed cells") that had not been transfected with the TRPA1 gene, and ΔRFU was calculated in the same manner as that used for the cells that were forcibly expressing TRPA1.

[0100] Incidentally, a total of 100 μl of OptiMEM medium and FLIPR Calcium6 Assay Kit had been added to each well immediately before the addition of the test solution, and then 50 μl of the test solution was added, so that the ethyl caproate contained in the test solution of Example 9 was diluted 3-fold in the well. In other words, the concentration of ethyl caproate in the well to which the test solution of Example 9 was added was 100 ppm.

[0101] (First test result) The average value ± standard deviation of the maximum ΔRFU after the addition of the test solution is shown in Table 6 and Figure 9. In this test, data analysis was performed using SoftMaxPro Vr.6 (Molecular Devices) and Excel (Microsoft).

[0102] [Table 6]

[0103] As shown in Table 6 and Figure 9, the test solution of Comparative Example 6 did not induce a cellular response, with a maximum ΔRFU value of about 0.2 for the cells forcibly expressing TRPA1. On the other hand, the test solution of Example 9 did induce a cellular response, with a maximum ΔRFU value of about 3.3 for the cells forcibly expressing TRPA1. From these results, it was confirmed that the test solution of Example 9 activated TRPA1.

[0104] In addition, Fig. 10 shows the change in RFU over time before and after the addition of the test liquid. The maximum value of ΔRFU shown in Table 6 and Fig. 9 is a value calculated based on the RFU shown in Fig. 10. As can be seen from the results shown in Fig. 10, the test liquid of Example 9 induced a cellular response in the cells forced to express TRPA1, whereas the test liquid of Comparative Example 6 did not induced a cellular response in the cells forced to express TRPA1.

[0105] (Second test method) In this test, HC03001 (Sigma-Aldrich), a TRPA1 inhibitor, was further added (co-added) to the wells to which the test solution of Example 9 was added in the first test method. Next, after confirming that the fluorescence intensity in the wells became constant, the RFU (hereinafter also referred to as "RFU after addition of inhibitor") was calculated. The RFU before the addition of the test solution was set to 1, and the change in RFU after the addition of the inhibitor relative to the RFU before the addition of the test solution (hereinafter also referred to as "ΔRFU after addition of test solution") was calculated. DMSO was used to dilute HC03001, but the DMSO concentration in the wells was set to 0.1% in consideration of cytotoxicity.

[0106] (Second test result) Figure 11 shows the average value ± standard deviation of ΔRFU after the addition of inhibitors (with co-addition of HC03001 in Figure 11). For reference, Figure 11 also shows the maximum value ± standard deviation of ΔRFU before the co-addition of inhibitors (without co-addition of HC03001 in Figure 11). Note that SoftMax Pro Vr.6 and Excel were used to analyze the data, as in the first test results.

[0107] As shown in FIG. 11, the cellular response of the cells forcibly expressing TRPA1, which was induced by the addition of the test solution of Example 9, was abolished by the addition of HC03001, a TRPA1 inhibitor.

[0108] From the first and second test results described above, it was confirmed that the test solution of Example 9 activates TRPA1.

[0109] [Test 6 (Respiratory quotient measurement test - sweet and sour solution based)] In this test, each subject ingested each test beverage, and the respiratory quotient and lipid oxidation amount were measured. The respiratory quotient was measured in the same manner as in Example 1. Here, the lipid oxidation amount is the amount of lipid consumed in energy metabolism, and, like the respiratory quotient, was calculated based on the analysis results of exhaled gas obtained by Aeromonitor (registered trademark) (Minato Medical Science Co., Ltd.).

[0110] This study was conducted on 34 adult males (BMI 18.5 kg / m 2 More than 25kg / m 2 The study was conducted as a single-ingestion crossover comparative study with subjects of 100 people (less than 18 years of age) taking the food. The specific test method and results of this study are shown below.

[0111] (Test Method) In this test, the test beverages of Comparative Example 3 and Example 5 used in Test 3 were used, and the test beverage of Example 10 was a test liquid containing ethyl caproate at a concentration of 0.1 ppm in the test beverage (sweet and sour liquid) of Comparative Example 3. The test was conducted three times with an interval of at least one week, and the test beverages were consumed randomly. The test beverages of Examples 5 and 10 correspond to 0.17 mg and 0.017 mg of ethyl caproate as intake amounts, respectively. In addition, since ethanol was used as a solvent for ethyl caproate in the test beverages of Examples 5 and 10, the ethanol concentration of all test beverages was standardized to 0.0999%.

[0112] In conducting this test, subjects were provided with the same meals for three days prior to the test and were instructed to abstain from alcohol the night before. In addition, subjects were prohibited from consuming anything other than water on the day of the test. Each subject was required to wear the same clothing during the test.

[0113] The subjects fasted for 12 hours from 9 p.m. on the previous day, and the respiratory quotient was measured under the conditions shown in Figure 1, as in Evaluation 1. In addition, the amount of lipid oxidation was measured in parallel with the measurement of the respiratory quotient. The measurements of the respiratory quotient and lipid oxidation were continued for 60 minutes. Thereafter, the same measurements were performed two more times with an interval of at least one week. The beverages to be consumed were randomly selected for each subject, and each subject consumed each beverage once.

[0114] The data to be analyzed were the respiratory quotient and lipid oxidation amount during the 10-minute period from the 11th to 20th minute of the 20-minute period of seated rest, which were used as the respiratory quotient at rest and the lipid oxidation amount at rest, respectively, and the average values ​​were calculated.

[0115] (Test Results) The results of the respiratory quotient are shown in Figure 12, and the results of the lipid oxidation amount are shown in Figure 13. In this study, the statistically significant difference between the groups was tested by Dunnett's test for the average value of each group. A significant level of p<0.05 was considered to indicate a significant difference. In this study, data analysis was performed using Excel (Microsoft).

[0116] 12, it was confirmed that the respiratory quotient at rest was significantly lower in the group that drank the test beverage of Example 10 than in the group that drank the test beverage of Comparative Example 3. It was also confirmed that the respiratory quotient was significantly lower in the group that drank the test beverage of Example 5 than in the group that drank the test beverage of Comparative Example 3.

[0117] 13, it was confirmed that the amount of lipid oxidation at rest was significantly higher in the group that drank the test beverage of Example 10 than in the group that drank the test beverage of Comparative Example 3. It was also confirmed that the group that drank the test beverage of Example 5 was significantly higher than the group that drank the test beverage of Comparative Example 3.

[0118] As described above, a decrease in respiratory quotient means that the amount of fat consumed increases, and an increase in the amount of lipid oxidation means that the amount of lipid consumed in energy metabolism increases. Therefore, the results of this test confirmed that the test beverages of Examples 5 and 10 promote both lipolysis and fat burning, and promote fat metabolism.

[0119] [Test 7 (Respiratory quotient measurement test - Carbonated water based)] In this test, each subject ingested each test beverage, and the respiratory quotient and lipid oxidation amount were measured. The respiratory quotient and lipid oxidation amount were measured using Aeromonitor (registered trademark) as in Test 6. This test was conducted on four adult male subjects. The specific test method and results of this test are shown below.

[0120] (Test Method) In this test, each subject consumed a different test beverage on the first and second days of the test. 200 ml of carbonated water (Comparative Example 7) was used as the test beverage on the first day of the test. 200 ml of a test liquid (Example 11) containing ethyl caproate at a concentration of 1 ppm in carbonated water was used as the test beverage on the second day of the test. The test beverage of Example 11 corresponds to an intake amount of 0.17 mg of ethyl caproate. The carbonated water used was "Wilkinson Tansan" (manufactured by Asahi Soft Drinks Co., Ltd.). In addition, since ethanol was used as a solvent for ethyl caproate in the test beverage of Example 11, the ethanol concentration of all test beverages was standardized to 0.0999%.

[0121] In carrying out this test, subjects were instructed to abstain from alcohol from the night before the test. Subjects fasted for 12 hours from 9 p.m. on the previous day, and respiratory quotient was measured under the conditions shown in Figure 1, as in Evaluation 1. In addition, the amount of lipid oxidation was measured in parallel with the measurement of respiratory quotient. The measurements of respiratory quotient and lipid oxidation were carried out in a temperature- and humidity-controlled laboratory set at 23±2°C and humidity 45±5%, and were carried out at the same time and under the same conditions on both the first and second days of the test.

[0122] The data to be analyzed were taken from 11 to 20 minutes of the 20 minutes of seated rest from the start of measurement of respiratory quotient and lipid oxidation amount, and 10 minutes from 11 to 20 minutes were used as the respiratory quotient at rest and the lipid oxidation amount at rest, respectively, and 20 minutes from 11 to 30 minutes of the 30 minutes of exercise were used as the respiratory quotient during exercise and the lipid oxidation amount during exercise, respectively, and the average values ​​of these were calculated.

[0123] (Test Results) The results of the respiratory quotient are shown in Figure 14, and the results of the lipid oxidation amount are shown in Figure 15. In this study, statistical significance was tested by paired t-test of the average values ​​of each group. A significance level of p<0.05 was considered to indicate a significant difference, and p<0.1 was considered to indicate a significant tendency. Data analysis was performed using Excel (Microsoft).

[0124] 14, it was confirmed that the respiratory quotient at rest tended to be lower in the group that ingested the test beverage of Example 11 compared to the group that ingested the test beverage of Comparative Example 7. It was also confirmed that the respiratory quotient during exercise was significantly lower in the group that ingested the test beverage of Example 11 compared to the group that ingested the test beverage of Comparative Example 7.

[0125] 15, it was confirmed that the amount of lipid oxidation at rest was significantly higher in the group that ingested the test beverage of Example 11 than in the group that ingested the test beverage of Comparative Example 7. It was also confirmed that the amount of lipid oxidation during exercise was significantly higher in the group that ingested the test beverage of Example 11 than in the group that ingested the test beverage of Comparative Example 7.

[0126] As mentioned above, a decrease in respiratory quotient means that the amount of fat consumed increases, and an increase in the amount of lipid oxidation means that the amount of lipid consumed in energy metabolism increases. Therefore, the results of this test confirmed that the test beverage of Example 11 promotes both lipolysis and fat burning, and promotes fat metabolism.

[0127] [Test 8 (body temperature measurement test - isoamyl acetate)] In this study, each subject ingested each test beverage, and the skin temperature between the shoulder blades and the tympanic membrane temperature (hereinafter, in Study 8, these are also referred to as "body temperature") were measured after ingestion. This study was conducted as a single-ingestion crossover comparative study with six adult male and female subjects (two males and four females). In this study, the skin temperature between the shoulder blades was measured using myBeat (registered trademark) WHS-2 (manufactured by Union Tool Co., Ltd.), and the tympanic membrane temperature was measured using an ear thermometer CE Thermo 2 (manufactured by Nipro Co., Ltd.).

[0128] (Test Method) In this test, each subject ingested different test beverages on the first and second days of the test. 200 ml of water (Comparative Example 8) was used as the test beverage on the first day of the test. 200 ml of a test liquid (Example 12) containing isoamyl acetate at a concentration of 1 ppm in water was used as the test beverage on the second day of the test. The test beverage of Example 12 corresponds to an intake of 0.18 mg of isoamyl acetate. In addition, since ethanol was used as a solvent for isoamyl acetate in the test beverage of Example 12, the ethanol concentration of all test beverages was unified to 0.0999%. In addition, "Isoamyl acetate ≧ 97%, FCC, food grade" (manufactured by Sigma-Aldrich) was used as the isoamyl acetate raw material for the test beverage. The log Pow of isoamyl acetate was 2.0 (calculated in the same manner as in Test 9 described below).

[0129] In conducting this test, subjects were instructed to abstain from alcohol from the night before the test. In addition, on the day of the test, subjects were prohibited from consuming coffee or spicy foods, had to finish lunch by 12:30, and were prohibited from eating or drinking anything other than water after 12:30. In addition, subjects were required to wear the designated short-sleeved, long-pants clothing during the test.

[0130] Body temperature measurements were performed under the conditions shown in Figure 3, as in Test 2, and were performed at the same time and under the same conditions on both the first and second days of the test.

[0131] The measurement value at 15:30, immediately after drinking the test beverage, was used as the initial value (0 minute data), and the average value ± standard error for each group at each time point was calculated based on the measurement values ​​taken every 10 minutes (10, 20, 30, 40, 50, and 60 minutes) from immediately after drinking the test beverage until 16:30, when the measurements were completed.

[0132] (Test Results) The results are shown in Figures 16 and 17. Figure 16 shows the results for skin temperature between the shoulder blades, and Figure 17 shows the results for tympanic membrane temperature. In this study, statistically significant differences were tested by paired t-tests between the same time points in each group. A significance level of p<0.05 was considered to indicate a significant difference, and p<0.10 was considered to indicate a significant tendency. In this study, data analysis was performed using Excel (Microsoft).

[0133] As shown in Figure 16, the skin temperature between the shoulder blades tended to increase in the group that drank the test beverage of Example 12, especially from 30 minutes after drinking, whereas a similar increasing trend was not observed in the group that drank the test beverage of Comparative Example 8.

[0134] Furthermore, as shown in Figure 17, the tympanic membrane temperature showed a continuing downward trend from 0 minutes after ingestion in the group that ingested the test beverage of Comparison Example 8, whereas the tympanic membrane temperature showed a tendency to rise from 40 minutes after ingestion in the group that ingested the test beverage of Example 12.

[0135] In a statistical test for comparison between groups, at 0 minutes immediately after ingestion, no significant difference was observed in the interscapular skin temperature shown in Figure 16 between the group that ingested the test beverage of Example 12 and the group that ingested the test beverage of Comparative Example 8. However, at 60 minutes after ingestion, the group that ingested the test beverage of Example 12 tended to have a higher interscapular skin temperature shown in Figure 16 than the group that ingested the test beverage of Comparative Example 8.

[0136] In addition, in the intra-group comparison of tympanic membrane temperature shown in Figure 17, it was observed that within the group that consumed the test beverage of Comparison Example 8, the tympanic membrane temperature tended to be lower at 60 minutes than at 0 minutes, whereas no similar tendency was observed within the group that consumed the test beverage of Example 12.

[0137] As described above, the increase in skin temperature between the scapulae and the suppression of the decrease in tympanic membrane temperature mean that the production of body heat is promoted. In particular, since the tympanic membrane temperature is a body temperature that reflects the core body temperature, the suppression of the decrease in tympanic membrane temperature means that the production of body heat is promoted inside the body as well. In addition, since the area between the scapulae is close to brown adipose tissue, the increase in skin temperature between the scapulae means that fatty acids are consumed in the brown adipose tissue and the production of body heat is promoted. Therefore, the results of this test confirmed that the test beverage of Example 12 promoted fat burning and further promoted the production of body heat.

[0138] [Test 9 (TRPA1 activity test)] In this test, the test solutions of Examples 13 to 28 and Comparative Examples 9 to 14 described below were used instead of the test solution used in the first test method of Test 5. Except for this, the change in RFU (ΔRFU) before and after the addition of the test solution was determined for each of the TRPA1-forced expressing cells and the non-transformed cells in the same manner as in the first test method of Test 5.

[0139] The test solutions of Examples 13 to 28 and Comparative Examples 10 to 14 used in this test were obtained by adding each compound shown in Table 7 below to a HEPES buffer. The octanol / water partition coefficient (logPow) of each compound shown in Table 7 was calculated using software XlogP (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, http: / / WWW.sio-ccbg.ac.cn / software / xlogp3 / ) using the XlogP3 algorithm. 50 μl of each of these test solutions was added to the wells, and the concentration of each compound in the wells was set to the concentration shown in Table 7. In addition, for the test solution of Comparative Example 9, a HEPES buffer was used as a negative control (NC), and 50 μl was added to the wells.

[0140] The mean value ± standard deviation of the maximum ΔRFU is shown in Table 7 and Figure 18. In this test, data analysis was performed using SoftMaxProVr.6 (Molecular devices) and Excel (Microsoft).

[0141] As shown in Table 7 and Figure 18, for the test solutions of Comparative Examples 9 to 14, the maximum value of ΔRFU of the cells forcibly expressing TRPA1 was not greater than the maximum value of ΔRFU of the non-transformed cells, and the response of the cells forcibly expressing TRPA1 could not be confirmed. On the other hand, for the test solutions of Examples 13 to 28, the maximum value of ΔRFU of the cells forcibly expressing TRPA1 was greater than the maximum value of ΔRFU of the non-transformed cells (specifically, 2.9 times or more greater), and the cellular response of the cells forcibly expressing TRPA1 could be confirmed. From these results, it was confirmed that the test solutions of Examples 13 to 28 activate TRPA1.

[0142] [Table 7]

[0143] From the results of the above-mentioned tests 1 to 9, it was confirmed that compound (1) having an octanol / water partition coefficient (logPow) in the range of 1.9 to 3.8 promotes fat metabolism such as fat decomposition and fat burning. It was also confirmed that the promotion of fat burning promotes the production of body heat. Although the reason why fat metabolism such as fat decomposition and fat burning is promoted is not clearly understood, it was presumed that one of the reasons is that compound (1) having an octanol / water partition coefficient (logPow) in the range of 1.9 to 3.8 activates TRPA1, promoting fat metabolism through neurotransmission.

Claims

1. A fat metabolism promoter (excluding diet gummies containing Garcinia cambogia extract) containing at least one compound selected from the group consisting of ethyl caproate, butyl caproate, pentyl caproate, isoamyl propionate, isoamyl butyrate, isoamyl caproate, pentyl acetate, heptyl acetate, ethyl 4-methylvalerate, 2-methylbutyl acetate, and ethyl valerate as an active ingredient.

2. 2. The fat metabolism promoter according to claim 1, wherein the daily intake of said compound for an adult is 0.017 mg or more and 1.8 mg or less.

3. The fat metabolism promoter according to claim 1 or 2, which is a fat decomposition promoter.

4. The fat metabolism promoter according to claim 1 or 2, which is a fat burning promoter.

5. The fat metabolism promoter according to any one of claims 1 to 4, which activates the temperature-sensitive ion channel TRPA1.

6. A body heat production promoter comprising, as an active ingredient, at least one compound selected from the group consisting of ethyl caproate, butyl caproate, pentyl caproate, isoamyl propionate, isoamyl butyrate, isoamyl caproate, pentyl acetate, heptyl acetate, methyl caprylate, ethyl 4-methylvalerate, 2-methylbutyl acetate, and ethyl valerate.

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