JP6772064B2 - Functional oral composition containing polyphenols - Google Patents

Description

The present invention relates to a functional oral composition containing a polyphenol as an active ingredient, and a dosage and administration for effectively expressing the action of the composition in the body of a subject. More specifically, the present invention relates to an oral composition having an action of controlling energy metabolism (energy metabolism controlling action), and a usage for effectively expressing the energy metabolism controlling action of the oral composition in the body of a subject. And dose (eg, single dose, dose, frequency of administration, duration of administration, duration of administration, duration of treatment, etc.).

The functional oral composition targeted by the present invention includes an oral composition having an action of activating energy metabolism (activator of energy metabolism) and an oral composition having an action of suppressing the accumulation of visceral fat (visceral). Fat accumulation inhibitor), oral composition for preventing or ameliorating obesity (anti-obesity agent), and oral composition having an action of preventing or ameliorating lifestyle-related diseases (preventing or ameliorating agent for lifestyle-related diseases) included. The lifestyle-related diseases include physical conditions such as obesity, metabolic syndrome, hyperlipidemia, hyperglycemia, hypertension, and inflammation. Therefore, the preventive or ameliorating agent for lifestyle-related diseases targeted by the present invention includes an oral composition used for suppressing or preventing the transition to or aggravation of the physical condition. In addition, the functional oral composition targeted by the present invention includes, as another aspect described above, an oral composition having an action of maintaining body energy or body fat (body energy or body fat maintaining agent).

In Japan, the proportion of lifestyle-related diseases such as obesity and metabolic syndrome is on the rise. For this reason, the Ministry of Health, Labor and Welfare of Japan has announced the dietary intake standards of Japanese people to raise public awareness, and has taken measures such as obliging companies to undergo health examinations, nutritional guidance, and exercise guidance. It shows the guideline to take. In the last 20 years, the average energy intake of the Japanese people has decreased, but the fact is that there is no clear tendency for the proportion of lifestyle-related diseases to decrease. On the other hand, the rate of obesity is increasing in the world as well, and it is said that more than tens of millions of people are obese, especially in the United States, China, and India. As measures against obesity, restrictions on energy intake and exercise are recommended, but as in Japan, the tendency for the rate of obesity to decrease has not been clearly shown. Obesity is a state in which white adipose tissue is excessively increased and accumulated, and due to obesity, for example, glucose tolerance disorder, dyslipidemia, hypertension, hyperuricemia, coronary artery disease, cerebral infarction, fatty liver, etc. Menstrual abnormalities, pregnancy complications, sleep apnea syndrome, obesity hypoventilation syndrome, lumbar pain, osteoarthritis, obesity-related kidney disease, non-alcoholic steatohepatitis (NASH), colon cancer, breast cancer, and biliary tract It is known that the incidence of various diseases such as obesity increases.

Restricting energy intake and exercising, which are recommended as a preventive or ameliorating method for obesity, require enduring appetite and changing the living environment including eating habits, and it is difficult to start or continue due to the awkwardness. Yes, no effect can be expected. In addition, ingestion or administration of a drug is difficult to start or continue due to the possibility of side effects and high cost, and no effect can be expected. Therefore, instead of these methods, as a simple, safe and inexpensive means for preventing or ameliorating lifestyle-related diseases such as obesity, diabetes and metabolic syndrome, the energy metabolism of the body is increased and the accumulation of visceral fat is suppressed. A way to do this is desired.

Polyphenols are edible materials that can be safely and inexpensively ingested, and many research results focusing on their physiologically active effects have been reported in the past. In particular, cacao-derived polyphenols contained in chocolate and the like have various physiologically active actions, and their high utility value is attracting attention. For example, among the polyphenols derived from cacao, procyanidins have an effect of suppressing an increase in blood glucose (Patent Document 1), and flavan-3-ol has an effect of improving blood glucose control and vasodilation. (Patent Document 2). In addition, the water extract of cacao seed shell has a cell activating effect, an ultraviolet damage alleviating effect, and a melanin production suppressing effect (Patent Document 3). Furthermore, the processed product derived from cacao has a preventive effect on diabetic complications (Patent Document 4). In addition, polyphenols are expected to have effects such as prevention, treatment and improvement of cardiovascular diseases and diabetes, and skin beautification.

Japanese Unexamined Patent Publication No. 09-291039 Special Table 2009-538342 Japanese Unexamined Patent Publication No. 03-181496 JP-A-2002-128685

An object of the present invention is to provide a functional oral composition that is safe, inexpensive, and easily ingested, and a dosage and administration for effectively expressing and enjoying the action of the oral composition.

More specifically, it is an object of the present invention to provide an oral composition having an action of controlling energy metabolism (energy metabolism controlling action) (for example, an activator of energy metabolism and an activity maintaining agent of energy metabolism). To do. Another object of the present invention is to provide a safe, inexpensive and convenient usage and dosage for effectively expressing the energy metabolism control action of the oral composition in vivo.

When the body's energy metabolism is activated and enhanced, the accumulation of visceral fat is suppressed, and lifestyle-related diseases such as obesity and metabolic syndrome can be effectively prevented or ameliorated. Therefore, it is an object of the present invention to provide an agent for suppressing the accumulation of visceral fat and an agent for preventing or ameliorating lifestyle-related diseases as a functional oral composition which is safe, inexpensive and easily ingested. Furthermore, it is an object of the present invention to provide a dosage and administration for effectively expressing and enjoying the action of these oral compositions in the body of a subject.

In addition, by ingesting polyphenols in a specific dosage and administration, the energy metabolism of the body can be controlled, thereby suppressing the accumulation of visceral fat, and the transition to and aggravation of lifestyle-related diseases such as obesity and metabolic syndrome. No research results have been reported that have demonstrated the suppression of obesity.

In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and administered or ingested polyphenol in the morning for nocturnal mammals and in the evening for diurnal mammals by a simple method. Found to activate the body's energy metabolism, according to such usage of polyphenols, it suppresses the accumulation of visceral fat in the target mammal, prevents or eliminates obesity, and prevents or improves lifestyle-related diseases. I was convinced that I could do it. In addition, according to a series of studies, the present inventors have conducted energy metabolism in the body even if polyphenol is administered or ingested at night for nocturnal mammals and in the morning for diurnal mammals, contrary to the above. It was confirmed that the body energy and body fat were maintained without being activated. From this, it was confirmed that the above-mentioned energy metabolism-activating action of polyphenols is a peculiar effect selectively obtained by administering (ingesting) polyphenols at night for diurnal mammals. Completed the invention.

That is, the present invention includes the following embodiments.
Hereinafter, the term "administration" in the present specification includes the meaning of "ingestion" or "taking", which is an act voluntarily performed by the target mammal (subject). The term "dose" also includes the meaning of "intake" or "dose", and the term "dose period" also includes the meaning of "dose period" or "dose period".

(I) Functional Oral Composition (I-1) A functional oral composition for diurnal mammals containing polyphenol as an active ingredient.
(I-2) The functional oral composition according to (I-1), wherein the polyphenol contains at least cacao polyphenol.
(I-3) The functional oral composition according to (I-1) or (I-2), wherein the daily dose is 0.3 mg to 5 g in terms of the total amount of polyphenols.
(I-4) The functional oral composition according to any one of (I-1) to (I-3), which is administered continuously every day.
(I-5) The functional oral composition according to any one of (I-1) to (I-4), wherein the administration period is at least 3 days.
(I-6) It is packaged in a fractionated or divided state for each daily dose, and contains a total amount of 0.3 mg to 5 g of polyphenol in the daily dose of one diurnal mammal. The functional oral composition according to any one of (I-1) to (I-5).
(I-7) A functional oral composition at a dose of at least 3 days for a diurnal mammal is contained in a container or package, or a set of doses for at least 3 days. The functional oral composition according to (I-6).
(I-8) The functional oral composition according to any one of (I-1) to (I-7), which is an energy metabolism regulator of the body.
(I-9) The functional oral composition according to any one of (I-1) to (I-8), which is administered at night.
(I-10) The functional oral composition according to (I-9), wherein the nighttime is a time zone from sunset to bedtime in the time zone from sunset to sunrise.
(I-11) The functional oral composition according to (I-9), wherein the nighttime is a time zone from sunset to sunrise, which is a time zone from after dinner to bedtime.
(I-12) The functional oral composition according to any one of (I-9) to (I-11), which is an activator of energy metabolism.
(I-13) The functional oral composition according to any one of (I-9) to (I-12), which is an agent for suppressing the accumulation of visceral fat, an anti-obesity agent, or a preventive or ameliorating agent for lifestyle-related diseases. ..
(I-14) The functional oral composition according to any one of (I-1) to (I-8), which is administered in the morning.
(I-15) The functional oral composition according to (I-14), wherein the morning is between 8 hours from sunrise in the time zone from sunrise to sunset.
(I-16) The functional oral composition according to (I-14), wherein the morning is between 8 hours from sunrise and 7 hours after breakfast.
(I-17) The functional oral composition according to any one of (I-14) to (I-16), which is an internal energy or body fat maintaining agent.

(II) Usage of Functional Oral Composition The functional oral composition according to any one of (II-1) (I-1) to (I-8) activates energy metabolism in diurnal mammals. It is a usage for administration of the functional oral composition to a diurnal mammal at night.
(II-2) The usage according to (II-1), wherein the night is the time zone from sunset to bedtime in the time zone from sunset to sunrise.
(II-3) The usage according to (II-1), wherein the night is the time zone from sunset to sunrise, which is the time zone from after dinner to bedtime.
(II-4) The daily dose of the functional oral composition according to any one of (I-1) to (I-8) for one diurnal mammal is converted into the total amount of polyphenols. The usage according to any one of (II-1) to (II-3), which is 0.3 mg to 5 g.
(II-5) The functional oral composition according to any one of (I-1) to (I-8) is continuously administered to diurnal mammals every day, (II-1) to (II-1). The usage described in any of II-4).
(II-6) Any of (II-1) to (II-5), wherein the administration period of the functional oral composition according to any one of (I-1) to (I-8) is at least 3 days. Usage to be described in.
(II-7) Diurnal Mammals, characterized in that the functional oral composition according to any one of (I-1) to (I-8) is administered to a diurnal mammal in the morning. Usage to maintain the body's energy or fat in the animal.
(II-8) The usage according to (II-7), wherein the morning is between 8 hours from sunrise in the time zone from sunrise to sunset.
(II-9) The usage according to (II-7), wherein the morning is between 7 hours after breakfast in the time zone of 8 hours from sunrise.
(II-10) The daily dose of the functional oral composition according to any one of (I-1) to (I-8) for one diurnal mammal is converted into the total amount of polyphenols. The usage according to any one of (II-7) to (II-9), which is 0.3 mg to 5 g.
(II-11) The functional oral composition according to any one of (I-1) to (I-8) is continuously administered to diurnal mammals daily, (II-7) to (II-7). The usage described in any of II-10).
(II-12) Any of (II-7) to (II-11), wherein the administration period of the functional oral composition according to any one of (I-1) to (I-8) is at least 3 days. Usage to be described in.

(III) A method for controlling energy metabolism in diurnal mammals (III-1) The functional oral composition according to any one of (I-1) to (I-8) is applied to diurnal mammals at night. A method of activating energy metabolism in a diurnal mammal, comprising the step of administering to.
(III-2) The method according to (III-1), wherein the night is the time zone from sunset to bedtime in the time zone from sunset to sunrise.
(III-3) The method according to (III-1), wherein the night is the time zone from sunset to sunrise, which is the time zone from after dinner to bedtime.
(III-4) The daily dose of the functional oral composition according to any one of (I-1) to (I-8) for one diurnal mammal is converted into the total amount of polyphenols. The method according to any one of (III-1) to (III-3), which is 0.3 mg to 5 g.
(III-5) The functional oral composition according to any one of (I-1) to (I-8) is continuously administered to diurnal mammals daily, (III-1) to (III-1) to ( The method described in any of III-4).
(III-6) Any of (III-1) to (III-5), wherein the administration period of the functional oral composition according to any one of (I-1) to (I-8) is at least 3 days. How to describe.
(III-7) Diurnal Mammal, characterized in that the functional oral composition according to any one of (I-1) to (I-8) is administered to a diurnal mammal in the morning. How to maintain an animal's body energy or body fat.
(III-8) The method according to (III-7), wherein the morning is between 8 hours from sunrise in the time zone from sunrise to sunset.
(III-9) The method according to (III-7), wherein the morning is between 8 hours from sunrise and 7 hours after breakfast.
(III-10) The daily dose of the functional oral composition according to any one of (I-1) to (I-8) for one diurnal mammal is converted into the total amount of polyphenols. The method according to any one of (III-7) to (III-9), which is 0.3 mg to 5 g.
(III-11) The functional oral composition according to any one of (I-1) to (I-8) is continuously administered to diurnal mammals daily, (III-7) to (III-7). The method according to any one of III-10).
(III-12) Any of (III-7) to (III-11), wherein the administration period of the functional oral composition according to any one of (I-1) to (I-8) is at least 3 days. How to describe.

(IV) Use of Functional Oral Composition The energy metabolism regulator for diurnal mammals according to any one of (IV-1), (I-1) to (I-7). Use for manufacturing.
(IV-2) The use according to (IV-1), wherein the functional oral composition is administered to a diurnal mammal at night.
(IV-3) The use described in (IV-2), wherein the above night is the time from sunset to bedtime in the time zone from sunset to sunrise.
(IV-4) The use described in (IV-2), wherein the above night is the time from sunset to sunrise in the time zone from after dinner to bedtime.
(IV-5) The use according to any one of (IV-1) to (IV-4), wherein the energy metabolism regulator is an energy metabolism activator.
(IV-6) The use according to (IV-5), wherein the energy metabolism activator is a visceral fat accumulation inhibitor, an anti-obesity agent, or a preventive or ameliorating agent for lifestyle-related diseases.
(IV-7) The use according to (IV-1), wherein the functional oral composition is administered to a diurnal mammal in the morning.
(IV-8) The use according to (IV-7), in which the morning is the time zone from sunrise to 8 hours.
(IV-9) The use according to any one of (IV-1), (IV-7) or (IV-8), wherein the energy metabolism regulator is a body energy or body fat maintainer.

(V) Functional oral composition used to control energy metabolism (V-1) Used to control energy metabolism in diurnal mammals (I-1)-(I-7) The functional oral composition according to any one of.
(V-2) The functional oral composition according to (V-1), wherein the functional oral composition is administered to a diurnal mammal at night.
(V-3) The functional oral composition according to (V-2), wherein the night is the time zone from sunset to bedtime in the time zone from sunset to sunrise.
(V-4) The functional oral composition according to (V-2), wherein the night is the time zone from sunset to sunrise, which is the time zone from after dinner to bedtime.
(V-5) The functional oral according to any one of (V-1) to (V-4), which is used to positively control and activate the energy metabolism of diurnal mammals. Composition.
(V-6) For diurnal mammals, it is used to suppress the accumulation of visceral fat, prevent or improve obesity, or prevent or improve lifestyle-related diseases, (V-1) to The functional oral composition according to any one of (V-5).
(V-7) The functional oral composition according to (V-1), wherein the functional oral composition is administered to a diurnal mammal in the morning.
(V-8) The functional oral composition according to (V-7), wherein the morning is a time zone from sunrise to 8 hours.
(V-9) The functionality described in any of (V-1), (V-7) or (V-8), used to maintain body energy or body fat in diurnal mammals. Oral composition.

When administered to a diurnal mammal at night, the functional oral composition of the present invention acts to activate the energy metabolism of the body of the diurnal mammal. That is, in such a usage, the functional oral composition of the present invention functions effectively as an energy metabolism activator for diurnal mammals. Such an energy metabolism activator is used by administering it to a diurnal mammal at night, thereby suppressing the accumulation of visceral fat in the mammal and causing lifestyle-related diseases such as obesity and / or metabolic syndrome. Can be effectively prevented or ameliorated. In other words, the functional oral composition (energy metabolism activator) of the present invention can be administered to diurnal mammals at night to prevent visceral fat accumulation, anti-obesity, prevent lifestyle-related diseases, or It functions effectively as an improving agent. In particular, the functional oral composition (energy metabolism activator) of the present invention does not induce excessive thinning and can be ingested easily, inexpensively and safely on a daily basis. Regardless, it can be widely used.

When administered to a diurnal mammal in the morning, the functional oral composition of the present invention acts to maintain the body energy and / or body fat of the diurnal mammal. That is, in such a usage, the functional oral composition of the present invention effectively functions as a body energy or body fat maintainer (hereinafter, also simply referred to as “body energy maintainer”) for diurnal mammals. Such body energy maintainers provide body energy and / or body to daytime mammals, especially patients with various diseases such as emaciation (thinness), loss of appetite, malnutrition, the elderly, and hypermetabolic disorders. It can be suitably used for retaining fat.

The present invention provides a usage (dosage, dosage) for exerting the above-mentioned various functions and functions with respect to the functional oral composition of the present invention. The functional oral composition of the present invention capable of exerting such various functions and functions is a pharmaceutical, non-pharmaceutical product, cosmetic, or food or drink (health functional food [for specified health use] for the purpose of maintaining or promoting beauty and health. Foods, foods with functional claims, foods with nutritional function], nutritional supplements, health supplements, nutritionally adjusted foods, health foods, supplements, medicinal foods and drinks).

Mice are fed a normal diet (C) or a high-fat diet (H), and the cocoa extract is fed in the morning (9:00) (Fig. 1 (A)) or evening (17:00) (Fig. 1 (B)) for one week. It is a figure which shows the plasma GLP-1 concentration at the time of administration over. In the legend of the figure, "0" and "10" mean the dose of cocoa extract (CLPr) (0 mg / kg body weight, 10 mg / kg body weight). Mice are fed a normal diet (C) or a high-fat diet (H), and the cocoa extract is fed in the morning (9:00) (Fig. 2 (A)) or evening (17:00) (Fig. 2 (B)) for one week. It is a figure which shows the plasma adiponectin concentration at the time of administration over. In the legend of the figure, "0", "1" and "10" mean the dose of cacao extract (CLPr) (0 mg / kg body weight, 1 mg / kg body weight, 10 mg / kg body weight) (hereinafter, FIG. 3). ~ 11 is the same). Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 3 (A)) or evening (17:00) (Fig. 3 (B)) for one week. It is a figure which shows the phosphorylated AMPK / total AMPK (relative ratio with respect to the control group [C-0]) of soleus muscle when it was administered over. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 4 (A)) or evening (17:00) (Fig. 4 (B)) for one week. It is a figure which showed the expression level of the PPAR-α gene of the gastrocnemius muscle at the time of administration over the control group [C-0] as a relative ratio. Mice are fed a normal diet (C) or a high-fat diet (H), and the cocoa extract is fed in the morning (9:00) (Fig. 5 (A)) or evening (17:00) (Fig. 5 (B)) for one week. It is a figure which showed the expression level of the PGC-1α gene of the gastrocnemius muscle as a relative ratio with respect to a control group [C-0] when it was administered over. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 6 (A)) or evening (17:00) (Fig. 6 (B)) for one week. It is a figure which showed the expression level of the Clock gene of the gastrocnemius muscle at the time of administration over the control group [C-0] as a relative ratio. Mice are fed a normal diet (C) or a high-fat diet (H) and the cacao extract is fed in the morning (9:00) (Fig. 7 (A)) or evening (17:00) (Fig. 7 (B)) for one week. It is a figure which showed the relative expression level of the Bmal1 gene of the gastrocnemius muscle at the time of administration over the control group [C-0] as a relative ratio. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 8 (A)) or evening (17:00) (Fig. 8 (B)) for one week. It is a figure which showed the expression level of the Period1 (Per1) gene of the gastrocnemius muscle at the time of administration over the control group [C-0] as a relative ratio. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 9 (A)) or evening (17:00) (Fig. 9 (B)) for one week. It is a figure which showed the expression level of the Period2 (Per2) gene of the gastrocnemius muscle at the time of administration over the control group [C-0] as a relative ratio. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 10 (A)) or evening (17:00) (Fig. 10 (B)) for one week. It is a figure which showed the expression level of the Cryptochrome1 (Cry1) gene of the gastrocnemius muscle as a relative ratio with respect to a control group [C-0] when it was administered over. Mice are fed a normal diet (C) or a high-fat diet (H), and the cacao extract is fed in the morning (9:00) (Fig. 11 (A)) or evening (17:00) (Fig. 11 (B)) for one week. It is a figure which showed the expression level of the Cryptochrome2 (Cry2) gene of the gastrocnemius muscle as a relative ratio with respect to a control group [C-0] when it was administered over. Mice were administered cacao extract (CLPr) four times daily (ZT3 (11:00), ZT9 (17:00), ZT15 (23:00), ZT21 (5:00)) 180 minutes later. The results of measuring the expression levels of the Per1 gene, Per2 gene, Per3 gene, Bmal1 gene, Dbp gene, and PPAR-α gene (Ppar-α) are shown together with the results when distilled water is administered instead of the cacao extract. It is a figure. Each figure is shown as a relative ratio when the average value of the expression levels of each gene at the total measurement time is set to 1 for each individual mouse. Mice were administered cacao extract (CLPr) four times daily (ZT3 (11:00), ZT9 (17:00), ZT15 (23:00), ZT21 (5:00)) 180 minutes later. The figure showing the results of measuring the expression levels of the Cry1 gene, Cry2 gene, Clock gene, Rev-erba gene, and PGC1-α gene (Pgc1-α) together with the results when water was administered instead of the cocoa extract. is there. Each figure is shown as a relative ratio when the average value of the expression levels of each gene at the total measurement time is set to 1 for each individual mouse.

(I) Functional Oral Composition The functional oral composition of the present invention is an edible composition that is orally administered to mammals, and is characterized by containing polyphenol as an active ingredient.

Mammals in the present invention include diurnal mammals such as humans, chimpanzees, monkeys, and rabbits; nocturnal mammals such as guinea pigs, mice, rats, dogs, and cats. The mammal targeted by the present invention is preferably a diurnal mammal, more preferably a human.

(A) Active ingredient (polyphenol) and its preparation method Polyphenol is a compound having a plurality of phenolic hydroxyl groups in the same molecule, and most of them are components derived from plants. The polyphenols of the present invention may be edible, and may be monomers or polymers thereof. Further, it may be composed of one kind of polyphenol, or may be a mixture of two or more polyphenols.

Specific examples of polyphenols include procyanidins, epicatechins, epigallocatechins, epicatechin gallates, epigallocatechin gallates, theaflavin, thealvidin, catechins, lignins, tannins, anthocyanidins, resveratrol, rutin, isoflavone, and chlorogenic acid. Examples thereof include cartamine, hesperidin, lignan, coumarin, curcumin, ellagic acid, daizein, genestine, genistine, puerulin, mylicetin, fizechin, kenferol, galangin, and quercetin.

In the present invention, the polyphenol is preferably a polyphenol derived from cacao beans, more preferably a polyphenol derived from cacao mass (hereinafter, these are referred to as "cacao polyphenols"). Cacao polyphenols include flavonoids containing at least catechins such as catechins and epicatechins; dimeric procyanidins such as procyanidins B2 and procyanidins B5, trimeric procyanidins such as procyanidins C1, and cinnamtannin A2 and the like. It contains proanthocyanidins such as catechin procyanidins (see, for example, "Science and Function of Chocolate Cocoa" by Fukuba et al., IK Corporation Publishing, November 2004, etc.). Proanthocyanidins contained in cacao polyphenols are multimers such as 4 → 8 bonds with epicatechin as the basic skeleton, and their structure is simple as compared with proanthocyanidins extracted from other plants. Therefore, there is an advantage that it is stable and easy to manage in the manufacturing process.

The ratio of catechin, epicatechin, procyanidin B2, procyanidin B5, procyanidin C1 and cinnamtannin A2 contained in cocoa polyphenol is the total of catechin and epicatechin: 45 to 65 weight when the total amount thereof is 100% by weight. %, Procyanidin B2: 15-25% by weight, procyanidin B5: 2-8% by weight, procyanidin C1: 10-20% by weight, cinnamtannin A2: 5-10% by weight. The ratio of these 6 types of polyphenols to 100% by weight of the total polyphenols contained in the cocoa mass is not limited, but 8 to 50% by weight, preferably 10 to 40% by weight can be exemplified.

Further, the cacao polyphenol is a mixture of a monomer and a polymer (including a polymer of at least a dimer to a polymer) as illustrated in Table 2 described later. The proportion of the monomer to heptamer contained in the cocoa polyphenol is not limited, but when the total amount of the monomer to the heptameric is 100% by weight, the monomer: 35 to 50% by weight, 2 amounts. Body: 15-25% by weight, Dimer: 10-20% by weight, Quader: 5-15% by weight, 5-mer: 1-10% by weight, Hexa: 0.5-5% by weight, A ratio of 7-mer: 0.1 to 3% by weight can be exemplified. Further, a ratio of monomer to trimer absorbed in the intestine: 60 to 95% by weight and tetramer to heptamer not absorbed in the intestine: 5% to 33% by weight can be exemplified. However, these ratios are not particularly limited.

The method for preparing cacao polyphenols is not particularly limited, but can be prepared and obtained by extracting cacao beans (hereinafter, also referred to as “cacao”) as a raw material using an extraction solvent such as water or an organic solvent.

More specifically, cacao polyphenols can be prepared by extracting cacao mass prepared by fermenting, drying, roasting and grinding cacao bean endosperm with an extraction solvent described later. Since cocoa mass contains about 50% by weight of cocoa butter, it is degreased in advance by squeezing method or using a non-polar organic solvent such as hexane prior to extraction with an extraction solvent. It is desirable to carry out the treatment to prevent excess lipid from being extracted from the cocoa mass during the extraction treatment.

The extraction solvent used for extracting the cacao polyphenol may be any extraction solvent generally used for extracting the polyphenol from the plant, and is not particularly limited. Preferably, a polar solvent is used. Examples of the polar solvent include water; lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propanol, isopropyl alcohol and butanol; polyhydric alcohols such as 1,3-butylene glycol, glycerin and polyethylene glycol; acetone; ethyl. Examples include ether; ethyl acetate; methyl acetate and the like. These extraction solvents may be used alone or in combination of two or more. The extraction solvent is preferably water, a lower alcohol having 1 to 5 carbon atoms, and a mixture of lower alcohol having 1 to 5 carbon atoms and water; more preferably, water, ethanol, and ethanol from the viewpoint of food hygiene. A mixture of water; particularly preferably a mixture of ethanol and water.

As the extraction method, a commonly used method for extracting a plant extract can be adopted, and specific examples thereof include a dipping method (standing or shaking dipping); a stirring method; or a percolation method.

The extraction conditions for cacao polyphenols are not particularly limited, and any of cold temperature, room temperature, and heating conditions can be adopted. As an example, in the case of water, it is preferable to heat it at 40 to 100 ° C., preferably 50 to 90 ° C. When an aqueous ethanol solution is used as the solvent, it is preferably heated at 0 to 80 ° C, preferably 40 to 70 ° C.

In the preparation of cacao polyphenols, the crude extract obtained in the extraction process contains components such as amino acids, theobromine, and protein components in addition to polyphenols. In order to remove these components other than polyphenols and obtain higher-purity cocoa polyphenols, a cation exchange resin obtained by substituting the crude extract with hydrogen ions (for example, Diaion (registered trademark) HP-2MG column). A method of contacting with [manufactured by Mitsubishi Chemical Corporation] or the like) and then eluting with a solvent containing no ionic substance (for example, a lower alcohol such as water or ethanol) can be used. By concentrating or drying the eluted fraction thus obtained, a high-purity cacao polyphenol (cacao extract) containing abundant polyphenols such as proanthocyanidins can be prepared and obtained. If necessary, these methods may be repeated.

Incidentally, although not particularly limited, in order to stabilize the cacao polyphenol, a stabilizer containing at least one of ellagic acid or punicarazine may be used in the above preparation step. These stabilizers can be applied, for example, to a step of preparing a crude extract of cocoa from cocoa beans, preferably a heating step. As the heating step, for example, a step of heating at 37 ° C. or higher, preferably a step of heating at 120 ° C. or higher can be exemplified. Further, in the process of preparing cacao polyphenols, when the pH of the preparation (liquid substance) is 4 or more, undesired phenomena such as epimerization of epicatechins and decrease in the content of procyanidins are observed. Therefore, in order to suppress or ameliorate this phenomenon, the above-mentioned stabilizer is in a state in which the composition containing polyphenol is in a state of pH 2 to 8, preferably pH 4 to 7.5, and more preferably pH 5.5 to 6.5. It can be suitably applied when there is. In such a case, these stabilizers can be used in a proportion of 1.5 parts by weight or more of ellagic acid or 5 parts by weight or more of punicarazine with respect to 100 parts by weight of polyphenol.

(B) Other Ingredients and Forms of Functional Oral Composition The functional oral composition of the present invention is a pharmaceutical composition (oral pharmaceutical), a cosmetic composition (including oral cosmetics), or Food and beverage compositions (for example, foods with health claims [foods for specified health use, foods with functional claims, foods with nutritional claims], nutritional supplements, health supplements, nutritionally adjusted foods, health foods, supplements, medicinal foods and drinks, etc. Can be prepared and provided as. It is preferably an oral pharmaceutical composition and a food and drink composition, and more preferably a food and drink composition.

These functional oral compositions are made from the above-mentioned polyphenols, preferably cacao extracts containing cacao polyphenols, as raw materials, and are solid-liquid separated, dried (freeze-dried, spray-dried), mixed, based on the common general knowledge of the art. It can also be a processed product prepared by combining one or more various operations such as kneading, granulation, and molding (locking, etc.). Furthermore, carriers, additives and the like can be blended according to a conventional method according to a desired form and dosage form. Additives include excipients, binders, disintegrants, lubricants, odorants, flavoring agents, sweeteners, solubilizers, suspensions, emulsifiers, stabilizers (stabilizers), thickeners, Examples thereof include gelling agents, acidulants, preservatives, antioxidants, pH adjusters, bases, flavoring agents, coloring agents and the like. The specific components of each of these additives are not particularly limited, and those commonly used in the art can be used in the same manner.

Examples of the form or dosage form of the functional oral composition according to the present invention include a form or dosage form that can be orally ingested or administered by a mammal. For example, in the form or dosage form of oral medicines or foods and drinks, tablets, pills, granules, powders (powdered preparations), capsules, chewable tablets, troches, liquids (syrups), jellies, dry syrups, and A formulation form such as a paste-like formulation can be exemplified. Among such preparation forms, tablets, chewing tablets, jelly agents, or paste-like preparations are preferable. From the viewpoint of storage, tablets and chewable tablets are more preferable.

The functional oral composition according to the present invention can also be prepared in the form of general food and drink. Examples of such foods and drinks include instant noodles, retort foods, canned foods, microwave foods, instant soups / miso juices, freeze-dried foods and other instant foods; soft drinks, fruit juice drinks, vegetable drinks, soy milk drinks, coffee drinks and cocoa drinks. , Tea beverages, powdered beverages, concentrated beverages, alcoholic beverages and other beverages; bread, pasta, noodles, cake mixes, bread flour and other wheat flour products; candy, caramel, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers Confectionery such as Japanese confectionery and dessert confectionery; seasonings such as sauce, tomato processed seasoning, flavor seasoning, cooking mix, sauces, dressings, soups, curry and stew ingredients; processed fats and oils, butter, margarine, Oils and fats such as mayonnaise; dairy beverages, fermented milk (yogurt, etc.), lactic acid bacteria beverages, natural cheese, process cheeses, ice creams, creams and other dairy products; canned agricultural products; jams, marmalades, chocolate cream and other toasts Spreads; processed agricultural products such as cereals; frozen foods and the like. Preferably, chocolate, chocolate cake (gateau au chocolat, etc.), chocolate-containing confectionery, chocolate cream (toast spread), cocoa beverage, chocolate beverage, and the like can be exemplified.

The functional oral composition of the present invention contains polyphenols, preferably cacao polyphenols, in a total amount of 0.3 mg to 5 g in a daily dose of one mammal (one human) regardless of its form or dosage form. It is preferable to include it. The daily dose can be appropriately set within this range, and examples thereof include the range of 0.6 mg to 4 g, 1 mg to 3 g, 3 mg to 2 g, and 6 mg to 1 g. As another embodiment, the range of 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, and 4 g to 5 g can be mentioned. From the viewpoint of flavor and safety, the daily dose to be administered to humans is preferably 0.6 mg to 1.8 g.

The functional oral composition of the present invention is convenient and convenient so that a daily required amount of polyphenol can be continuously administered to a mammal every day in order to exert its action simply and effectively and to be enjoyed by the mammal. It is preferable that the form is provided. Such a form is not limited, but the functional oral composition is fractionated or divided for each daily dose in one container or packaging (hereinafter, collectively referred to as "container packaging"). It can be mentioned that the container is housed in a state of being packed. Specifically, the functional oral composition is incised (eg, for ease of division), cut, molded, or individually packaged (or individually packaged) at each daily dose. Examples thereof include a mode in which a dose of one to several days is stored or filled in one container / wrapping tool in a state of being filled in a container. Here, the "molded state" includes, but is not limited to, a formulation form such as a tablet or the like. The "individually packaged (or filled in a container) state" is not limited to, for example, a state in which granules or powders for a daily dose are packaged in a capsule base material or a packaging tool, and This includes a state in which a container or packaging tool is filled with a liquid substance for a daily dose. In yet another embodiment, the functional oral compositions individually packaged (or container-filled) for each daily dose, without limitation, were combined for 2 to tens of days (or 2 to several days). Aspect, which is traded as a combination or set product.

The functional oral composition of the present invention is preferably administered continuously (continuously) for at least 3 days in order to effectively exert its action. It is preferably 5 days or more, more preferably 1 week or more, still more preferably 10 days or more, particularly preferably 20 days or more, still more preferably 30 days or more. Therefore, the functional oral composition of the present invention also has 1 to 3 days, 5 days, 1 week, 10 days, 20 days, or 30 days in one container and packaging tool. It is possible to have an embodiment in which a dose is contained or a combination (set) of these days is contained.

(C) Uses, Usage and Dose of Functional Oral Composition The functional oral composition of the present invention is continuously administered to a diurnal mammal at night, so that the body of the diurnal mammal is administered. It exerts the action and effect of activating the energy metabolism of. As a result, the energy metabolism of the body of diurnal mammals is enhanced, the accumulation of visceral fat and subcutaneous fat is suppressed, and obesity can be prevented or eliminated. It can also prevent or ameliorate obesity, especially lifestyle-related diseases caused by the accumulation of visceral fat. On the other hand, the functional oral composition of the present invention does not activate (enhance) energy metabolism even when administered to diurnal mammals in the morning, but rather acts to maintain body energy and body fat. .. Therefore, in order to retain body energy and body fat in diurnal mammals, it is preferable to administer (take) the functional oral composition of the present invention in the morning.

In this sense, the functional oral composition of the present invention can be called a "body energy metabolism regulator" because of its action and effect, and is used exclusively for the purpose of controlling the energy metabolism of the body of diurnal mammals. Can be done.

Based on the above, the body energy metabolism regulator can be classified into two types, (1) body energy metabolism activator, and (2) body energy or body fat maintainer, depending on how it is used. it can. These will be described below.

(1) Body Energy Metabolite Activator The energy metabolism activator of the present invention has the following characteristics.
(A) Polyphenol, preferably cacao polyphenol is contained as an active ingredient.
(B) Administered to diurnal mammals at night.
(C) The daily dose is 0.3 mg to 5 g in terms of the total amount of polyphenols.
(D) It is continuously administered daily for 3 days or more.

In (b) above, "nighttime" is a time zone in which there is little activity for diurnal mammals, and usually means a time zone from sunset to sunrise. It is preferably a time zone from sunset to bedtime, and more preferably a time zone from after dinner to bedtime. In addition, "after supper" means a time zone after the end of supper, and may be immediately after the end of supper, or one hour after the end of supper. Although it depends on the season, for example, the time zone from sunset to sunrise is from 6:00 pm (18:00) to 6:00 am (6:00) the next day, from sunset to bedtime. The time zone is "7:00 pm (19:00) to 1:00 am (1 pm) the next day", and the time zone from after sunset to bedtime is "7:00 pm (19:00) to midnight the next day (19:00) The time zone of "0 o'clock)" can be mentioned, but it is not particularly limited.

In order to surely obtain the effect of the energy metabolism activator of the present invention, it is necessary that the usage and dosage of (b) to (d) are observed. In order to carry out and comply with this reliably and easily, it is preferable that the energy metabolism activator of the present invention has the form described in (B) above with respect to the functional oral composition of the present invention. Specifically, it is packaged in a fractionated or divided state for each daily dose, and at least 3 days' worth of energy metabolism activator is contained in one container or package, or a combination ( This is a set) mode. The above description (B) in this regard can be incorporated herein by reference.

The daily dose of the energy metabolite activator of the present invention is 0.3 mg to 5 g in terms of the total amount of polyphenols as described in (B), and the age, sex and administration of mammals within this range. It can be set as appropriate according to the physical condition and the like. For example, it can be appropriately set from the range of 0.6 mg to 4 g, 1 mg to 3 g, 3 mg to 2 g, 6 mg to 1 g, etc., and the range of 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, 4 g to 5 g. From the viewpoint of flavor and safety, the daily dose to be administered to humans is preferably in the range of 0.6 mg to 1.8 g. The energy metabolism activator of the present invention may be administered in the above-mentioned predetermined amount per day, and the number of administrations thereof is not particularly limited. The above dose may be administered once, or may be administered in two to several divided doses.

In addition, the energy metabolism activator of the present invention is administered over a period of at least 3 days in order to enhance the energy metabolism of the body of a diurnal mammal and to effectively maintain and continue the increased energy metabolism. It is preferable to administer the dose continuously at night. It is more preferably a continuation of 5 days or more, still more preferably 1 week (7 days) or more, particularly preferably 10 days or more, 20 days or more, and 30 days or more. By doing so, it suppresses the accumulation of excess visceral fat due to high energy (high calorie), high sugar and / or high fat diet, and / or lack of exercise, and leads to lifestyle-related diseases such as obesity and metabolic syndrome. Can effectively prevent or ameliorate the transition or aggravation of the disease.

In the present invention, energy metabolism includes glucose metabolism, lipid metabolism and the like. Therefore, the "activator of energy metabolism" according to the present invention also acts as an "improving agent of glucose metabolism and / or lipid metabolism" and accompanies or causes a decrease in at least one of glucose metabolism and lipid metabolism. It can be expected to be effective as a preventive agent or an ameliorating agent for a physical condition or disease that causes prevention or improvement by improving at least one of glucose metabolism and lipid metabolism. Examples of the physical condition or disease include glucose tolerance disorder, dyslipidemia, hypertension, hyperuricemia, coronary artery disease, cerebral infarction, fatty liver, menstrual abnormality, pregnancy complications, sleep apnea syndrome, obesity hypoventilation syndrome. , Lumbago, osteoarthritis, obesity-related kidney disease, non-alcoholic steatohepatitis (NASH), colon cancer, breast cancer, biliary tract cancer and the like can be exemplified. Further, the "activator of energy metabolism" according to the present invention is not only for obese persons with excess visceral fat, but also for healthy persons (non-obese persons) who do not have excess visceral fat, and / or high sugar content. Even when eating a fat diet, it can be used as a composition for improving glucose metabolism and / or lipid metabolism of the healthy person.

Although the mechanism of action of the energy metabolism activator of the present invention in the body is not clear, activation of AMPK induces PGC-1α and promotes or suppresses the expression of various clock genes to GLP. -1 It is considered that it promotes secretion. Here, the clock gene whose expression is promoted by the energy metabolism activator of the present invention is at least one of the Lockk gene, the Per2 gene, and the Cry2 gene. However, the mechanism of action is only a hypothesis, and the present invention is not limited to the mechanism of action.

AMPK (AMP-Activated protein kinase) monitors the energy state of cells in peripheral nerve tissues such as liver, muscle, and adipose tissue and the hypothalamus, and regulates the metabolism of sugars and lipids according to the state. It is an enzyme. When AMPK is activated, the energy production pathway (sugar transport, fatty acid conversion) is enhanced, and the energy consumption pathway (protein synthesis) is blocked, so that intracellular ATP is restored. Known actions by AMPK activation include, for example, suppression of gluconeogenesis in the liver, uptake of sugar in muscle, and promotion of oxidation and decomposition of fatty acids in adipose tissue, liver and muscle.

PGC-1α (Peroxisome proliferative activated receptor, γ-coactivator 1α) is a nuclear receptor coactivator and a coactivator that controls energy metabolism and clock genes. Known actions of PGC-1α include, for example, promotion of mitochondrial formation, promotion of lipolysis, suppression of active oxygen, and muscle strengthening.

The clock gene is a group of genes that control the circadian rhythm, and specifically, the Lock gene, the Bmal (Brain and Mastlent-Like protein) gene, the Period (hereinafter, may be abbreviated as "Per") gene, and the gene. Examples thereof include a Cryptchrome (hereinafter, sometimes abbreviated as “Cry”) gene, an albumin site D-binding protein (hereinafter, sometimes abbreviated as “Dbp”) gene, an E4BP4 gene, and an Npass2 gene. There are three types of Per genes: Period1 gene (Per1 gene), Period2 gene (Per2 gene), and Period3 gene (Per3 gene). In mammals (for example, humans, cats, dogs, guinea pigs), clock genes include genes encoding the four core proteins of the Lock gene, Bmal1 gene, Per gene (Per1, Per2, Per3), and Cry gene. , Promotion or suppression of transcription of various clock genes is involved.

Genes of factors that promote ticking of the biological clock include, for example, the Lock gene and the Bmal gene. On the other hand, the gene group of the factor that suppresses the ticking of the biological clock includes, for example, the Per gene, the Cry gene, and the Chrono gene.
The control center of circadian rhythm exists in the suprachiasmatic nucleus of the hypothalamus, but the mechanism that controls circadian rhythm also exists in most peripheral tissues such as the liver and muscles. Both work on a similar system. These clock genes control physiological and behavioral phenomena such as respiration, blood pressure, body temperature, hormone secretion, sleep, and arousal in humans. The Bmal1 gene is involved in promoting the synthesis and suppressing the degradation of fatty acids and cholesterol. In addition to functioning as a clock gene, the Per1 gene, Per2 gene, and Per3 gene are also involved in stress response and obesity.

PPAR-α is a receptor protein that is strongly expressed in the liver, retina, gastrointestinal mucosa, muscle brown adipose tissue, heart, and kidney, and is activated by physiological ligands such as free fatty acids, cholesterol and It is involved in the decrease in triglyceride synthesis. Specific actions of PPAR-α include promotion of β-oxidation and ω oxidation of fatty acids, increase of fatty acid transport activity and acyl-CoA synthase activity, promotion of apoprotein A1 synthesis, increase of serum HDL cholesterol and enhancement of LPL synthesis. , Suppression of apoprotein C-3 synthesis, decreased activity of acyl-CoA carboxylase / fatty acid synthase, suppression of inflammation, etc. are known.

The energy metabolism activator of the present invention is a pharmaceutical, non-pharmaceutical product, cosmetics, or food or drink (health functional food [for specified health use], which is orally administered, similarly to the above-mentioned "functional oral composition". Foods, foods with functional claims, foods with nutritional function], nutritional supplements, health supplements, nutritionally adjusted foods, health foods, supplements, medicinal foods and drinks).

These various products include the energy metabolism activator of the present invention so that consumers can recognize them in the distribution (including sales) in the market in the method and range permitted for each product according to the system of each country. Active ingredient (functional ingredient); use, efficacy, function, and blending amount of the active ingredient; administration method (administration time, number of administrations, dose, etc.) and the like are preferably displayed.

Here, the "display" may be any method that can be recognized by the consumer, and any means is included as long as it is. It also includes means for recalling or inferring the use, efficacy or function of the active ingredient (functional ingredient) regardless of the purpose or intention of the labeling. The objects (mediums) to be displayed include, for example, product containers, product packaging materials, product manuals, product advertisements, product transaction documents, product homepages (Internet, etc.), product catalogs, and product products. Pamphlets, product POPs, etc. can be exemplified, and in the place of this display, the product itself, the inside / outside of the store where the product is sold, the exhibition / briefing session to introduce the product, etc. can be exemplified.

In the present invention, the "label" is preferably an explanation or expression approved by the administration or system of each country. For example, in Japan, the explanation or expression approved by the Consumer Affairs Agency or the food system for specified health uses. Is. Specifically, labeling of foods for specified health use stipulated in the Health Promotion Law (especially labeling of health uses), labeling of foods for specified health use with conditions, labeling to the effect that it affects the structure and function of the body, There are indications to reduce the risk of illness.

For example, the active ingredient (functional ingredient) of the energy metabolism activator of the present invention; use, efficacy, function, and content of the active ingredient; typical example of administration method (administration time, number of administrations, dose, etc.) The summary is as follows.
Active ingredient (functional ingredient); Use, efficacy, and function of cacao polyphenol active ingredient: Energy metabolism activation effect, visceral fat accumulation suppression effect, anti-obesity effect, or prevention / improvement effect of lifestyle-related diseases Combination of active ingredients Amount: 0.3 mg to 5 g of polyphenol in total in daily dose Administration method (administration time, number of administrations, dose, etc.): 0.3 mg to 5 g in terms of total polyphenol amount as daily dose. Take orally at night (from sunset to bedtime) in one or more divided doses. Ingest continuously for 3 days or more.

(2) Body Energy or Body Fat Maintaining Agent The body energy or body fat maintaining agent of the present invention (hereinafter collectively referred to as “body energy maintaining agent”) has the following characteristics.
(A) Polyphenol, preferably cacao polyphenol is contained as an active ingredient.
(B') Administered in the morning to diurnal mammals.
(C) The daily dose is 0.3 mg to 5 g in terms of the total amount of polyphenols.
(D) It is continuously administered daily for 3 days or more.

In the above (b'), "morning" is an active time zone for diurnal mammals, and usually means a time zone from sunrise to 8 hours. It is preferably the time zone from after breakfast to 7 hours in the time zone from sunrise to sunset. As an example, the time zone from "6:00 am to 2:00 pm" can be mentioned as the time zone from sunrise to 8 hours, but there is no particular limitation.

In order to surely obtain the effect of the body energy maintaining agent of the present invention, it is necessary to comply with the usage and dosage of the above (b') to (d). In order to carry out and comply with this reliably and easily, it is preferable that the internal energy maintaining agent of the present invention has the form described in (B) above with respect to the functional oral composition of the present invention. Specifically, it is packaged in a fractionated or divided state for each daily dose, and at least 3 days' worth of body energy maintenance agent is contained in one container or packaging, or a combination (set). ). The above description (B) in this regard can be incorporated herein by reference.

The daily dose of the body energy maintenance agent of the present invention is 0.3 mg to 5 g in terms of the total amount of polyphenols as described in (B), and the age, sex and body of the mammal to be administered are within this range. It can be set appropriately according to the state and the like. For example, it can be appropriately set from the range of 0.6 mg to 4 g, 1 mg to 3 g, 3 mg to 2 g, 6 mg to 1 g, etc., and the range of 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, 4 g to 5 g. From the viewpoint of flavor and safety, the daily dose to be administered to humans is preferably in the range of 0.6 mg to 1.8 g. The body energy maintenance agent of the present invention may be administered in the above-mentioned predetermined amount per day, and the number of administrations thereof is not particularly limited. The above dose may be administered once, or may be administered in two to several divided doses.

In addition, in order to continuously maintain energy and / or body fat in the body by the body energy maintenance agent of the present invention, the above dose of the maintenance agent is continuously administered in the morning for at least 3 days. Is preferable. It is more preferably a continuation of 5 days or more, still more preferably 1 week (7 days) or more, particularly preferably 10 days or more, 20 days or more, and 30 days or more. This can prevent significant energy depletion or loss of body fat without forcing changes to a high-energy (high-calorie), high-carbohydrate and / or high-fat diet. It is possible.

The body energy maintenance agent of the present invention is also an orally administered pharmaceutical, non-pharmaceutical product, cosmetic, or food or drink (health functional food [food for specified health use], similar to the above-mentioned “functional oral composition”. , Functional foods, functional foods], nutritional supplements, health supplements, nutritionally adjusted foods, health foods, supplements, medicinal foods and drinks).

The internal energy maintainer of the present invention can be suitably used for humans who should actively ingest energy. Such subjects include cachexia, loss of appetite, rehabilitation (chronic obstructive pulmonary disease (COPD), liver failure, rheumatoid arthritis, chronic heart failure, chronic renal failure, lower limb amputation, and femoral neck fracture. , Diabetes, stroke, cancer (cachexia), disuse syndrome, Parkinson's disease, aspiration pneumonia, elderly people with pressure ulcers), patients with diseases that increase energy metabolism (eg thyroid abnormalities), etc. Can be exemplified. For such subjects, the body energy maintenance agent of the present invention is a drug, a non-medicinal product, or a food or drink (supplement, etc.) having a formulation form such as a tablet (troche tablet), a chewing agent, a granule or an ampol. In addition to being able to be administered as a liquid food (oral nutritional supplement, nutritional drink, enteral nutritional supplement), nursing food, food for people with swallowing difficulties, confectionery such as chocolate, beverages containing chocolate, or foods and drinks such as beverages containing cocoa (health) It can be administered as a functional food, dietary supplement, health supplement, medicinal food or drink, etc.).

The internal energy maintenance agent is also labeled as described above.
For example, a typical example of the active ingredient (functional ingredient) of the energy maintaining agent in the body of the present invention; the use, efficacy, function, and content of the active ingredient; the administration method (administration time, number of administrations, dose, etc.). The summary is as follows.
Active ingredient (functional ingredient); Use / efficacy / function of cacao polyphenol active ingredient: Maintenance of body energy, maintenance of body fat Amount of active ingredient: 0.3 mg to 5 g of polyphenol in total in daily dose Administration method (administration time, number of administrations, dose, etc.): As a daily dose, 0.3 mg to 5 g in terms of total polyphenol amount is orally divided into one or more doses in the morning (from sunrise to 8 hours). Ingest. Ingest continuously for 3 days or more.

(II) Method for Controlling Energy Metabolism in Diurnal Mammals The present invention relates to a method for controlling energy metabolism in diurnal mammals including humans. Such a method can be carried out by administering (taking) the above-mentioned functional oral composition of the present invention to a diurnal mammal.

(A) Method for activating energy metabolism As a method for positively controlling and activating energy metabolism in a diurnal mammal, the functional oral of the present invention containing a predetermined amount of polyphenol in the target diurnal mammal. A method of administering the composition at night can be mentioned. Here, "night" is usually a time zone from sunset to sunrise, but is preferably a time zone from sunset to bedtime, preferably after dinner after sunset to bedtime. The daily dose of the functional oral composition for one diurnal mammal may be 0.3 mg to 5 g in terms of the total amount of polyphenols. Within this range, it can be appropriately set according to the age, sex, physical condition of the mammal to be administered, and the like. For example, it can be appropriately set from the range of 0.6 mg to 4 g, 1 mg to 3 g, 3 mg to 2 g, 6 mg to 1 g, etc., and the range of 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, 4 g to 5 g. From the viewpoint of flavor and safety, the daily dose to be administered to humans is preferably in the range of 0.6 mg to 1.8 g. The functional oral composition of the present invention may be administered to a diurnal mammal in the above-mentioned predetermined amount per day, and the number of administration thereof is not particularly limited. For example, the above dose may be administered once, or may be administered in two to several divided doses.

In addition, in order to activate the energy metabolism of diurnal mammals and effectively maintain and continue the increased energy metabolism, the above dose of the functional oral composition of the present invention is administered at night for at least 3 days. It is preferable to carry out continuously over the period. It is more preferably a continuation of 5 days or more, still more preferably 1 week (7 days) or more, particularly preferably 10 days or more, 20 days or more, and 30 days or more.

By doing so, it suppresses the accumulation of excess visceral fat due to high energy (high calorie), high sugar and / or high fat diet, and / or lack of exercise, and leads to lifestyle-related diseases such as obesity and metabolic syndrome. Can effectively prevent or ameliorate the transition or aggravation of the disease.

According to the method of the present invention, glucose metabolism and / or lipid metabolism can be improved, so that a physical condition or disease, or sugar, accompanied by or caused by a decrease in at least one of glucose metabolism and lipid metabolism. It can be used as a method for preventing or improving a physical condition or disease that can be expected to be prevented or improved by improving at least one of metabolism and lipid metabolism. Examples of the physical condition or disease include glucose tolerance disorder, dyslipidemia, hypertension, hyperuricemia, coronary artery disease, cerebral infarction, fatty liver, menstrual abnormality, pregnancy complications, sleep apnea syndrome, obesity hypoventilation syndrome. , Lumbago, osteoarthritis, obesity-related kidney disease, non-alcoholic steatohepatitis (NASH), colon cancer, breast cancer, biliary tract cancer and the like can be exemplified. In addition, the method of the present invention can be used not only for obese persons with excess visceral fat, but also for healthy persons (non-obese persons) who do not have excess visceral fat, even when they eat a high-sugar and / or high-fat diet. It can be used to improve glucose metabolism and / or lipid metabolism of the healthy person and prevent obesity.

(B) Method for maintaining body energy or body fat In order to maintain the body energy and / or body fat of the target diurnal mammal, the functional oral composition of the present invention containing a predetermined amount of polyphenol is prepared in the morning. Can be mentioned as a method of administration to. Here, "morning" is a time zone from sunrise to 8 hours, preferably a time zone from after breakfast after sunrise to 8 hours. The daily dose of the functional oral composition for one diurnal mammal may be 0.3 mg to 5 g in terms of the total amount of polyphenols. Within this range, it can be appropriately set according to the age, sex, physical condition of the mammal to be administered, and the like. For example, it can be appropriately set from the range of 0.6 mg to 4 g, 1 mg to 3 g, 3 mg to 2 g, 6 mg to 1 g, etc., and the range of 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, 4 g to 5 g. From the viewpoint of flavor and safety, the daily dose to be administered to humans is preferably in the range of 0.6 mg to 1.8 g. The functional oral composition of the present invention may be administered to a diurnal mammal in the above-mentioned predetermined amount per day, and the number of administration thereof is not particularly limited. For example, the above dose may be administered once, or may be administered in two to several divided doses.

In addition, in order to maintain the body energy and / or body fat of diurnal mammals, the morning administration of the above dose of the functional oral composition of the present invention should be continuously performed for at least 3 days. Is preferable. It is more preferably a continuation of 5 days or more, still more preferably 1 week (7 days) or more, particularly preferably 10 days or more, 20 days or more, and 30 days or more. By doing so, it is possible to prevent significant depletion of body energy or loss of body fat without actively consuming a high-energy (high-calorie), high-carbohydrate and / or high-fat diet. ..

According to the method of the present invention, energy in the body and fat in the body can be maintained, so that it can be suitably used for humans who should actively ingest energy. As mentioned above, such a target person. Examples include emaciated people, anorexic people, and rehabilitation patients.

Hereinafter, the present invention will be described in more detail based on Production Examples and Examples. However, the present invention is not limited to these examples and the like, and various modifications can be made without departing from the technical idea of the present invention.

[Manufacturing Example 1]
<Preparation of cacao extract>
The cacao extract was made from 1.0 kg of cacao mass prepared from 1.9 kg of cacao beans. 5 L of n-hexane was added to 1.0 kg of cocoa mass, and the mixture was defatted by stirring at room temperature for 30 minutes to obtain 875 g of defatted cocoa mass. 6 L of hydrous acetone (acetone content 70% by volume) was added to 875 g of the obtained defatted cocoa mass for extraction, and then acetone was evaporated and removed under reduced pressure using an evaporator. The obtained aqueous fraction was extracted with 9 times the volume of n-butanol, and the obtained n-butanol phase was concentrated to obtain a Diaion® HP-2MG column (15 cm × 10 cm ID) (Mitsubishi Chemical Corporation). It was used for adsorption (manufactured by the company). Then, the column is provided with hydrous ethanol containing 0.1% (v / v) of trifluoroacetic acid (ethanol content of 15% (v / v)) to elute theobromine, and then hydrous methanol (methanol). The content was 80% (v / v)). The hydrous methanol-eluted fraction thus obtained was concentrated to dryness to obtain 17 g of a cacao extract, which is a proanthocyanidin-rich fraction. This cacao extract is hereinafter abbreviated as "CLPr" as "cacao liquor proanthocyanidin". The total polyphenol content of 17 g of the obtained cacao extract was determined by the Prussian blue method (Price, LM, et al., Rapid visual estimation and spectrophotometric determination of tannin content of sorghum grain. J. Agric. Food Chem., 1977, 25, When epicatechin was measured as a standard product in 1268-1273), it was 628.1 mg / g (equivalent to epitecin).

In addition, ethanol can be used instead of the acetone or methanol used above.

Table 1 shows the content (mg) of each polyphenol per 1 g of total polyphenol contained in this cacao extract. The polyphenol content is described in the paper by Natsume et al. (Natsume, M. et al., Analysis of Polyphenols in Cacao Liquor, Cocoa, and Chocolate by Normal-Phase and Reversed-Phase HPLC, Bioscience Biotechnology and Biochemistry 2000, 64, 2581- It was measured according to the description of 2587).

Table 2 shows the amounts (mg) of the monomers and multimers (dimers to heptamerics) contained in 1 g of the total polyphenols of this cacao extract. The molecular weight of this polyphenol is described in the paper by Kelm et al. (Kelm, MA et al., High-performance liquid chromatography separation and purification of cacao (Theobroma cacao L.) procyanidins according to degree of polymerization using a diol stationary phase. J Agric It was measured according to the description of Food Chem 2006, 54, 1571-1576).

[Example 1]
<Verification of the effect of plasma GLP-1 concentration on polyphenol intake time>
The effect of polyphenol intake time (morning and evening) on plasma GLP-1 concentration was investigated using mice. The mouse is a nocturnal mammal, and its circadian rhythm (intrinsic rhythm) is reversed from that of humans and other diurnal mammals by 12 hours.

(1) Test mouse After one week (acclimation period) has passed since the C57BL / 6 mouse (male 5-week-old Japan SLC) was obtained, 40 mice were divided into the following 8 groups (5 mice in each group). The animals were bred under the conditions of room temperature 25 ± 2 ° C. and lighting time / day from 8:00 to 20:00 (light / dark cycle: light period 8:00 to 20:00, dark period 20:00 to 8:00). Since the mouse is a nocturnal mammal as described above, the light period corresponds to the sleep / fasting time zone and the dark period corresponds to the activity / feeding time zone in the light / dark cycle.

In the following, the symbols "A" and "B" mean the morning administration and the evening administration of the cocoa extract, respectively. Further, the symbols "C" and "H" mean a normal diet and a high-fat diet, respectively.
No. 1 (A / C-0): No administration of cacao extract (0 mg / kg body weight) (control)
No. 2 (A / C-10): Morning administration of cacao extract (10 mg / kg body weight)
No. 3 (A / H-0): No administration of cacao extract (0 mg / kg body weight) (control)
No. 4 (A / H-10): Morning administration of cacao extract (10 mg / kg body weight)
No. 5 (B / C-0): No administration of cacao extract (0 mg / kg body weight) (control)
No. 6 (B / C-10): Cacao extract evening administration (10 mg / kg body weight)
No. 7 (B / H-0): No administration of cacao extract (0 mg / kg body weight) (control)
No. 8 (B / H-10): Cacao extract evening administration (10 mg / kg body weight)

Specifically, 40 mice were first divided into two groups, a cocoa extract morning administration group (A: No. 1 to 4) and a cocoa extract evening administration group (B: No. 5 to 8), as described above. These groups were further divided into a normal diet feeding group (C) and a high fat diet feeding group (H), respectively. In addition, each group (morning administration / normal diet feeding group [A / C], morning administration / high-fat diet feeding group [A / H], evening administration / normal diet feeding group [B / C], evening administration / high-fat diet In both the feeding group [B / H]), a cocoa extract non-administration group (control) was provided with respect to the cocoa extract administration group.

(2) Test Method The cacao extract (hereinafter, also referred to as “CLPr”) prepared in Production Example 1 was diluted 10-fold with distilled water, and this was diluted with No. 1 above. 2. No. 4, No. 6 and No. Eight mice were orally administered so that the amount of CLPr was 10 mg / kg body weight (total amount of polyphenols was 6 mg / kg body weight). The control groups of these mice (No. 1, No. 3, No. 5 and No. 7) were administered distilled water at a rate of 10 mg / kg body weight instead of CLPr. In the morning (9:00), the mice in groups 1 to 4 were given No. In the evening (17:00), 5 to 8 mice were all administered CLPr or distilled water once a day.

During the above experiment, No. 1-2 and No. For 5 to 6, a normal diet (D12450B (lipid energy ratio 10%), Research Diet Co., Ltd.) was used as No. 3-4 and No. A high-fat diet (D12492 (lipid energy ratio 60%), Research Diet Co., Ltd.) was allowed to be freely ingested in 7 to 8.

On the 7th day (1 hour after the oral administration on the 7th day) from the start of the oral administration of CLPr, the mice in each group were sacrificed by collecting cardiac blood under Nembutal anesthesia. Blood collected from each group of mice was centrifuged (9,700 g, 10 minutes, 4 ° C.) to obtain plasma. Using the plasma thus prepared, the plasma GLP-1 concentration of each group of mice was measured using a measurement kit of Levis (R) GLP-1 (Active) (Shibayagi Co., Ltd.). GLP-1 is a glucagon-like peptide that promotes insulin secretion involved in blood glucose metabolism. Therefore, an increase in plasma GLP-1 concentration leads to insulin secretion, which means that glucose metabolism is enhanced.

(3) Test Results The plasma GLP-1 concentration of the mouse in the morning administration group (A) is shown in FIG. 1 (A), and the plasma GLP-1 concentration of the mouse in the evening administration group (B) is shown in FIG. 1 (B). As shown in FIG. 1 (A), in the morning-administered group, the CLPr-administered group was compared with the CLPr-non-administered group regardless of whether the normal diet-fed group (C) or the high-fat diet-fed group (H) was administered. Plasma GLP-1 concentration was significantly higher. On the other hand, in the evening administration group, there was no significant difference in plasma GLP-1 concentration between the CLPr non-administration group and the CLPr administration group in both the normal diet group (C) and the high-fat diet group (H). From this result, it was clarified that ingestion or administration of CLPr to mice in the morning promotes the secretion of GLP-1 and enhances glucose metabolism (energy metabolism). Applying this result to diurnal mammals (including humans) whose circadian rhythm is opposite to that of mice, in the case of diurnal mammals, ingestion or administration of cacao extract (polyphenol) after the evening. Therefore, it is considered that the secretion of GLP-1 is promoted and glucose metabolism (energy metabolism) is enhanced.

[Example 2]
Using mice, the effects of polyphenol intake time (morning and evening) on plasma adiponectin concentration, phosphorylated AMPK / total AMPK, adipose tissue amount in each organ, and clock gene expression level were investigated. As the polyphenol, the cacao extract (CLPr) prepared in Production Example 1 was used as in Example 1.

(1) Test mouse C57BL / 6 mouse (male 5 weeks old, Japan SLC) was obtained, and after 1 week (acclimation period), 60 mice were divided into 12 groups (5 mice in each group), and the following. It was classified as.
No. 1 (A / C-0): CLPr not administered (0 mg / kg body weight) (control)
No. 2 (A / C-1): CLPr morning administration (1 mg / kg body weight)
No. 3 (A / C-10): CLPr morning administration (10 mg / kg body weight)
No. 4 (A / H-0): CLPr non-administration (0 mg / kg body weight) (control)
No. 5 (A / H-1): CLPr morning administration (1 mg / kg body weight)
No. 6 (A / H-10): CLPr morning administration (10 mg / kg body weight)
No. 7 (B / C-0): CLPr not administered (0 mg / kg body weight) (control)
No. 8 (B / C-1): CLPr evening administration (1 mg / kg body weight)
No. 9 (B / C-10): CL Pr evening administration (10 mg / kg body weight)
No. 10 (B / H-0): CLPr not administered (0 mg / kg body weight) (control)
No. 11 (B / H-1): CLPr evening administration (1 mg / kg body weight)
No. 12 (B / H-10): CLPr evening administration (10 mg / kg body weight)

Specifically, 60 mice were first classified into two groups, a morning administration group (A: No. 1 to 6) and an evening administration group (B: No. 7 to 12), as described above. The groups were further classified into two groups, a normal diet group (C) and a high-fat diet group (H). In addition, each group classified into these four groups (morning administration / normal diet feeding group [A / C], morning administration / high-fat diet feeding group [A / H], evening administration / normal diet feeding group [B / C], The evening administration / high fat diet group [B / H]) was further classified into two CLPr administration groups (1 mg / kg administration group and 10 mg / kg administration group) and one CLPr non-administration group (control).

(2) Test method The cacao extract (CLPr) prepared in Production Example 1 was diluted 10-fold with distilled water, and the above No. 2. No. 5, No. 8 and No. So that the amount of CLPr is 1 mg / kg body weight (total amount of polyphenols 0.6 mg / kg body weight) with respect to 11 mice, and the above No. 3, No. 6, No. 9 and No. Twelve mice were orally administered so that the amount of CLPr was 10 mg / kg body weight (total amount of polyphenols 6 mg / kg body weight). The control groups of these mice (No. 1, No. 4, No. 7 and No. 10) were administered distilled water at a rate of 10 mg / kg body weight instead of CLPr. In addition, No. For mice 1 to 6, in the morning (9 o'clock), No. In the evening (17:00), 7 to 12 mice were all administered CLPr or distilled water once a day.

During the above experiment, No. 1-3 and No. For 7 to 9, a normal meal (D12450B) was used, and No. 4-6 and No. 10-12 were allowed to freely ingest a high-fat diet (D12492).
On the 7th day (1 hour after the oral administration on the 7th day) from the start of the oral administration of CLPr, the mice in each group were sacrificed by cardiac blood sampling under Nembutal anesthesia. Blood collected from each group of mice was centrifuged (9,700 g, 10 minutes, 4 ° C.) to obtain plasma.
Using the plasma thus prepared, the plasma adiponectin concentration of each group of mice was measured using a measurement kit of Levis adiponectin (Shibayagi Co., Ltd.). In addition, phosphorylated AMPK / total AMPK was measured by Western blotting. Adiponectin is a protein specifically secreted by adipocytes, and an increase in plasma adiponectin concentration means that insulin sensitivity is increased, that is, glucose metabolism is activated. An increase in phosphorylated AMPK / total AMPK indicates that AMPK is activated and phosphorylation is progressing.

In addition, for each group of mice, after weighing, white adipocytes (visceral fat [suprabody fat, mesenteric fat, perineal fat], subcutaneous fat), brown adipocytes, and muscles (peritoneal muscle, flatfish). Muscle) was removed and these weights (g / 100g weight) were compared between each group. A Tukey-Kramer multiple comparison test was used for statistical processing, and p <0.05 was determined to be significant.

[Measurement result]
(1) Plasma adiponectin concentration The plasma adiponectin concentrations of the morning administration group (A) and the evening administration group (B) are shown in FIGS. 2 (A) and 2 (B), respectively. As shown in FIG. 2 (A), in the morning (9:00) administration of CLPr, the plasma adiponectin concentration tended to increase depending on the dose of CLPr in the normal diet group (C). Also in the high-fat diet group (H), the plasma adiponectin concentration tended to increase with the administration of CLPr. In the CLPr non-administered group, the plasma adiponectin concentration in the high-fat diet group (H-0) tended to be lower than that in the normal diet group (C-0), but in the CLPr-administered group, the high-fat diet group. The plasma adiponectin concentration was similar between the dietary group (H-1, H-10) and the normal diet group (C-1, C-10) (that is, CLPr administration to the high-fat diet group). Means that the plasma adiponectin concentration is increased). On the other hand, as shown in FIG. 2 (B), in the evening (17:00) administration of CLPr, the plasma adiponectin concentration was similar in all groups, and no effect of administration of CLPr was observed.

From this result, it was clarified that ingestion or administration of CLPr to mice in the morning increased the plasma adiponectin concentration, that is, promoted the secretion of adiponectin.

(2) Phosphorylated AMPK / total AMPK
The ratio of phosphorylated AMPK divided by total AMPK (phosphorylated AMPK / total AMPK) for each of the morning administration group (A) and the evening administration group (B) is shown in FIGS. 3 (A) and 3 (B), respectively. Both (A) and (B) show the results of evaluating phosphorylated AMPK / total AMPK in each group, with the normal diet group (C-0) not administered with CLPr as 1 (control). As shown in FIG. 3 (A), in the morning (9:00) administration of CLPr, phosphorylated AMPK / total AMPK tends to increase depending on the amount of CLPr in both the normal diet group and the high-fat diet group. It was observed. On the other hand, in the evening (17:00) administration, phosphorylated AMPK / total AMPK did not tend to increase depending on the CLPr dose in the high-fat diet group.

(3) Weight of adipocytes The body weight (g) of the mice in the morning administration group (A) and the evening administration group (B) and the weight of adipocytes per 100 g of body weight (g / 100 g body weight) are shown in Tables 3 and 4, respectively. Shown in. In Tables 3 and 4, "white adipocytes (g / 100 g body weight)" refers to epididymal fat, intestinal membrane fat, perrenal fat (above, visceral fat), and subcutaneous fat per 100 g of body weight. Means the total amount (g) of. The symbols given for each value in each table mean that there is a significant difference between the groups with different symbols.

Both the mice in the morning-administered group (A) and the evening-administered group (B) had white adipocytes of visceral fat (upper testicular fat, intestinal fat, and perirenal fat) in the high-fat diet group (H). The weights were higher than those in the normal diet group (C).

In the morning administration group (A), the CLPr high-administration group (CLPr: 10 mg / kg body weight) of the high-fat diet was white fat as compared with the CLPr-non-administration group (CLPr: 0 mg / kg body weight) of the same feeding group. There was a tendency for the weight of cells to decrease. The weight of white adipocytes in this CLPr high-administered group is about the same as that in the same group in the normal diet group. In the morning administration group, the CLPr low-administration group (CLPr: 1 mg / kg body weight) of the high-fat diet was compared with the CLPr-non-administration group (CLPr: 0 mg / kg body weight) of the same feeding group. There was a tendency for the weight to decrease (see Table 3).

On the other hand, in the evening administration group (B), the weight of white adipocytes in the CLPr high-administration group (CLPr: 10 mg / kg body weight) of the high-fat diet was the CLPr non-administration group (CLPr: 0 mg / kg body weight) of the same diet. And it tended to be higher than that of the CLPr high-administered group on a normal diet (Table 4).

From this result, it was clarified that ingestion or administration of CLPr to mice in the morning efficiently suppressed the accumulation of visceral fat even when ingesting a high-fat diet. In addition, by ingesting or administering CLPr to mice in the morning, there was no tendency for the amount of subcutaneous fat and visceral fat to be excessively reduced even when the normal diet was ingested (Table 3). From this, it can be seen that it is safe for the body to ingest or administer CLPr in the morning.

(4) RNA extraction and measurement of gene expression In Example 1, a difference was observed in the secretion of GLP-1, which promotes insulin secretion involved in glucose metabolism, depending on the administration time of CLPr. The effects on the expression of genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2), PGC-1α gene, and PPAR-α gene were confirmed.

[Method]
25 mg of gastrocnemius muscle collected from mice was weighed into a microtube, 500 μL of TRIzol Reagent was added, and the tissue was pulverized with a polytron homogenizer. To this, 100 μL of chloroform was added, thoroughly mixed with a vortex mixer, and allowed to stand at room temperature (25 ° C. ± 5 ° C.) for 10 minutes. Then, it was centrifuged (12,000 g, 15 minutes, 4 ° C.) to obtain a supernatant. The supernatant was collected in a new microtube, 300 μl of 2-propanol was added, mixed by inversion, and allowed to stand at room temperature for 10 minutes. Then, the RNA fraction was precipitated by centrifugation (12,000 g, 10 minutes, 4 ° C.), and the precipitated RNA fraction was washed with ethanol and then centrifuged to dryness in a concentrated centrifuge. Then, the total RNA that had been centrifuged and dried was redissolved in 30 μL of deionized -distilled water and treated with DNase (DNase1 recombinant RNase-free). CDNA was synthesized from 5 μL of this DNase-treated RNA using the reverse transcriptase ReverTra Ace® qPCR RT Kit (TOYOBO). The synthesized cDNA was measured by Real time PCR (TaKaRa PCR Thermal Cycler Dice, Takara Bio Inc.) using SYBR Green premix Taq. GAPDH was used as the internal standard. The expression level of each gene (PGC-1α gene, PPAR-α gene, Lock gene, Bmal1 gene, Per1 gene, Pre2 gene, Cry1 gene, Cry2 gene) of the CLPr non-administered group of the normal diet (C) was set to 1 ( As a control), the expression level of each gene in each group (CLPr-administered group of normal diet (C), CLPr-non-administered group of high-fat diet (H), and CLPr-administered group) was relatively evaluated. For statistical processing, Tukey-Kramer multiple comparison test was used, and p <0.05 was determined to have a significant difference.

[result]
The relative expression levels of the PPAR-α gene in the morning administration group and the evening administration group are shown in FIGS. 4 (A) and 4 (B), respectively. In the morning administration, the relative expression level of the PPAR-α gene tended to be increased by the administration of CLPr in both the normal fat diet group (C) and the high fat diet group (H) (FIG. 4 (A)). )). On the other hand, in the evening administration, the relative expression level of the PPAR-α gene did not tend to increase depending on the dose of CLPr in the high-fat diet group (H) (FIG. 4 (B)). ).

The relative expression levels of the PGC-1α gene in the morning administration group and the evening administration group are shown in FIGS. 5 (A) and 5 (B), respectively. In the morning administration, in the high-fat diet group (H), the relative expression level of the PGC-1α gene tended to increase depending on the dose of CLPr (FIG. 5 (A)). On the other hand, in the evening administration, the relative expression level of the PGC-1α gene did not tend to increase depending on the dose of CLPr (FIG. 5 (B)).

The relative expression levels of the Clock gene in the morning administration group and the evening administration group are shown in FIGS. 6 (A) and 6 (B), respectively. In the morning administration, the relative expression level of the Clock gene tended to increase significantly depending on the dose of CLPr in the high-fat diet group (H) (FIG. 6 (A)). On the other hand, in the evening administration, the relative expression level of the Clock gene did not tend to increase depending on the dose of CLPr (FIG. 6 (B)).

The relative expression levels of the Bmal1 gene in the morning administration group and the evening administration group are shown in FIGS. 7 (A) and 7 (B), respectively. In the morning administration, the relative expression level of the Bmal1 gene tended to increase depending on the dose of CLPr in the high-fat diet group (H) (FIG. 7 (A)). On the other hand, in the evening administration, although the relative expression level of the Bmal1 gene was increased by the administration of CLPr, it did not tend to increase depending on the dose (FIG. 7 (B)).

The relative expression levels of the Per1 gene in the morning administration group and the evening administration group are shown in FIGS. 8 (A) and 8 (B), respectively. No significant difference was observed between the groups in the morning administration (Fig. 8 (A)). On the other hand, in the evening administration, the relative expression level of the Per1 gene tended to increase depending on the dose of CLPr in the normal diet group (C) (FIG. 8 (B)). However, in the high-fat diet group (H), the relative expression level of the Per1 gene did not tend to increase depending on the dose of CLPr (FIG. 8 (B)).

The relative expression levels of the Per2 gene in the morning administration group and the evening administration group are shown in FIGS. 9A and 9B, respectively. In the morning administration, the relative expression level of the Per2 gene tended to increase depending on the dose of CLPr in the high-fat diet group (Fig. 9 (A)). On the other hand, in the evening administration, the relative expression level of the Per2 gene did not tend to increase depending on the dose of CLPr (FIG. 9 (B)).

The relative expression levels of the Cry1 gene in the morning administration group and the evening administration group are shown in FIGS. 10 (A) and 10 (B), respectively. In both the morning administration and the evening administration, the relative expression level of the Cry1 gene did not tend to increase depending on the dose of CLPr.

The relative expression levels of the Cry2 gene in the morning administration group and the evening administration group are shown in FIGS. 11A and 11B, respectively. In the morning administration, the relative expression level of the Cry2 gene tended to increase depending on the dose of CLPr in the high-fat diet group (H) (FIG. 11 (A)). On the other hand, in the evening administration, the relative expression level of the Cry2 gene did not tend to increase depending on the dose of CLPr (FIG. 11 (B)).

From these results, ingestion or administration of cocoa extract (polyphenol) to mice in the morning increases sugar (glucose) uptake as compared with ingestion or administration of cocoa extract (polyphenol) in the evening. That is, it was suggested that sugar (glucose) metabolism was enhanced. Furthermore, by ingesting or administering a cacao extract (polyphenol) to mice in the morning, even if a high-fat diet is ingested, excess visceral fat is accumulated without excessively (abnormally) lowering body fat. It was confirmed that can be effectively suppressed in a short period of time. That is, it was confirmed that ingestion or administration of cacao extract (polyphenol) to mice in the morning promotes lipid metabolism. The mechanism of action is that AMPK is phosphorylated and activated, the PCG-1α gene is induced, and the expression of the Clock gene, Per2 gene, and Cry2 gene among the time genes is promoted. It can be thought that it enhances energy metabolism, suppresses the accumulation of visceral fat, and prevents or improves lifestyle diseases such as obesity and metabolic syndrome.

Applying these results to diurnal mammals (including humans) whose circadian rhythm is opposite to that of mice, in the case of diurnal mammals, ingestion or administration of cacao extract (polyphenol) at night. It is considered that the above phenomenon occurs, glucose metabolism and fat metabolism (energy metabolism) are promoted, the accumulation of visceral fat is suppressed, and lifestyle-related diseases such as obesity and metabolic syndrome can be prevented or ameliorated.

[Example 3]
<Relationship between polyphenol administration time and expression level of various genes>
Using mice, the relationship between the administration time of polyphenols and the expression levels of clock genes and energy metabolism-related genes was evaluated. As clock genes, the Period gene (Per1 gene, Per2 gene, Per3 gene), Bmal1 gene, Dbp gene (D-binding protein gene), Cryptochrome gene (Cry1 gene, Cry2 gene), and Lockk gene, which are clock genes of the liver, are used. Using. Further, as energy metabolism-related genes, PPAR-α gene (Ppar-α), Rev-erba gene, and PGC1-α gene (Pgc1-α) were used. Further, as the polyphenol, the cacao extract (CLPr) prepared in Production Example 1 was used.

[Method]
Number of genes (Per1, Per2, Per3, Bmal1, Dbp, Cry1, Cry2, Crock, Ppar-arufwa, Rev-erba, and Pgt1-α genes) for measuring C57BL / 6 mice (7-week-old male Japan SLC) Each group was further divided into a CLPr-administered group and a CLPr-non-administered group (control) (each group n = 5). The CLPr-administered group was administered 150 mg / kg body weight (90 mg of total polyphenol amount) as the CLPr amount per administration. Mice in each of these groups were bred under the conditions of room temperature of 25 ± 2 ° C. and lighting time / day from 8:00 to 20:00 (light-dark cycle: light-light period 8:00 to 20:00, dark-time 20:00 to 8). : 00).

Under this light-dark cycle, four times a day (ZT3 (11:00), ZT9 (17:00), ZT15 (23:00), ZT21 (5:00) as zeitgeber time), CLPr administration group In the above amount of CLPr, distilled water (6.7 mL / kg body weight) was forcibly orally administered to the CLPr non-administered group by gastric sonde. In addition, 180 minutes after each of these administrations (ZT6 (14:00), ZT12 (20:00), ZT18 (2:00), ZT24 (= ZT0) (8:00)), mice of each group were added. After slaughter, liver, adipose tissue, and muscle were collected, and the mRNA expression levels of clock genes and energy metabolism-related genes expressed in each tissue were measured by RT-PCR according to a conventional method.

[result]
The relationship between the administration time of CLPr and the expression levels of Per1, Per2, Per3, Bmal1, Dbp, and Ppar-α genes is shown in FIG. The relationship between the administration time of CLPr and the expression levels of Cry1, Cry2, Crock, Rev-erba, and Pgc1-α genes is shown in FIG. In each of these figures, the average value of the gene expression levels for all the measurement times was obtained for each individual, and the relative ratio when it was set to 1 is shown as the increase / decrease amount of each gene expression level.

As shown in FIGS. 12 and 13, when CLPr was administered to light-season ZT3 in mice which are nocturnal mammals, the expression levels of Per1, Per2, Per3, Dbp and Pparα genes were significantly increased in the liver (each). (Indicated by * in the figure), and the expression levels of Cry2 and Pgc1-α genes showed an increasing tendency. On the other hand, the expression level of the Bmal1 gene was significantly decreased, and the expression level of the Cry1 gene showed a decreasing tendency. However, the expression levels of these genes did not change significantly even when CLPr was administered at a time other than the light period ZT3.

From this, it was found that the influence of the cacao extract (polyphenol) on the expression level of the clock gene and the energy metabolism-related gene differs depending on the administration timing (time zone). From this, it was suggested that the expression of genes involved in glucose metabolism and lipid metabolism (energy metabolism) of cacao extract (polyphenol) changes depending on the administration timing (administration time zone). Specifically, in mice, the expression of hepatic clock genes Per1, Per2, Per3, Dbp, and Ppar-α genes increased in a short time after administration by CLPr administration in the light period (3 hours after ingestion). Ingestion of cocoa extract (polyphenol) during this time period (light period) changes gene expression related to glucose metabolism and lipid metabolism, and it is easy to suppress visceral fat accumulation. It was suggested. In addition, when cacao extract (polyphenol) is ingested at other times (dark period), there is no particular effect on the expression of clock genes, genes involved in glucose metabolism and lipid metabolism, and body energy and body fat are maintained. It was suggested that it could be done.

Since mice are nocturnal mammals, if this result is applied to diurnal mammals (including humans), in the case of diurnal mammals, it will be in the dark period (from sunset to sunrise). Ingestion or administration of cocoa extract (polyphenol) suppresses visceral fat accumulation, and conversely, ingestion or administration of cocoa extract (polyphenol) in the light period (sunset to about 8 hours) causes internal energy and energy. It is thought that body fat can be maintained.

[Example 4]
<Manufacturing of the composition of the present invention>
Several types of compositions (mixtures) containing cocoa polyphenol extract extracted with ethanol, cocoa mass, whole milk powder, cocoa butter, sugar, and lecithin were produced. When the total polyphenol content of these compositions was measured by the Prussian blue method using epicatechin as a standard product, the polyphenol content (total amount) was 0.4 mg by weight to 107 mg by weight. When this was ingested by 10 members of the specialized panel, it was evaluated that the flavor and texture were all good.

The functional oral composition of the present invention enhances the body's energy metabolism and accumulates visceral fat by ingesting or administering it to diurnal mammals at night (from sunset to sunrise). It acts to suppress obesity and can effectively prevent or ameliorate lifestyle-related diseases such as obesity and metabolic syndrome. In addition, the functional oral composition of the present invention maintains energy or fat in the body by ingesting or administering it to diurnal mammals in the morning (up to about 8 hours from sunrise). The consumption of body energy can be effectively suppressed. The functional oral composition of the present invention can be used as a new pharmaceutical composition or food and drink composition.

Claims (4)

A body energy metabolism regulator containing cocoa polyphenols as an active ingredient, which is a nocturnal or morning dose for oral use in daytime mammals (however, the mass ratio of cocoa polyphenols to tea catechins is 5: 1 to 5: 8). (Excluding body fat reducing agents and body fat reducing foods) contained in
When it is a nocturnal agent, it functions as an energy metabolism activator and
Acts as body energy or body fat maintainer if it is a morning dose,
The energy metabolism regulator . Claimed, packaged in fractions or divided states for each daily dose, containing a total of 0.3 mg to 5 g of cocoa polyphenols in a daily dose of one diurnal mammal. The energy metabolism regulator according to 1. The energy metabolism regulator according to claim 1 or 2 , which is an energy metabolism activator used as a nocturnal administration agent for diurnal mammals. The energy metabolism regulator according to claim 1 or 2 , which is an internal energy or body fat maintenance agent used as a morning administration agent for diurnal mammals.

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