Composition for activating the sympathetic nervous system

Abstract

The present invention addresses the problem of providing a technique that enables sympathetic nerve activation. A composition for sympathetic nerve activation, said composition containing one or more peptides selected from the group consisting of peptides consisting of any of the following amino acid sequences (SEQ ID NOS: 1-16) and peptides containing these amino acid sequences.　(Amino acid sequences: VAPFPE, HLPLP, VVPPF, HQPHQPLPPT, TEDELQDK, LNPWDQ, IISQE, ANEEEY, VIPY, LPLP, VIESPPEIN, FPQY, LNVPGE, IVPNSAEE, GEPTSTPT and KFQSEEQQQ)

Description

[Technical Field]

[0001] The present invention relates to a composition for activating the sympathetic nervous system, which can be used as a medicine, food or drink, or feed. [Background technology]

[0002] The autonomic nervous system is made up of the sympathetic nervous system and the parasympathetic nervous system. These two nervous systems act almost antagonistically on each organ, tissue, and organ, constantly regulating various functions of the body and maintaining homeostasis. The sympathetic nervous system, which is also known as the fight or flight nerve, controls various active functions of the mind and body through its activation. Specifically, it is known that activating the sympathetic nervous system has effects such as promoting energy consumption, reducing fatigue, improving weakness and fatigue, waking up, improving sleepiness, improving concentration and attention, improving physical activity, improving mental function, improving heat production, increasing body temperature, improving basal metabolism, promoting sweating, suppressing weight gain, and suppressing body fat accumulation (Patent Documents 1 to 3).

[0003] To date, polyphenols, orotic acid, caffeine, and the like have been reported as components that activate the sympathetic nervous system (Patent Documents 4-5, Non-Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2018-87171 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-126683 [Patent Document 3] International Publication No. 2017 / 014120 [Patent Document 4] International Publication No. 2018 / 101231 [Patent Document 5] Japanese Patent Application Laid-Open No. 2012-126683 [Non-patent literature]

[0005] [Non-Patent Document 1] Dulooo AG.et al., Am. J. Clin. Nutr. 1989 49(1) 44-50 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a technique capable of activating the sympathetic nervous system. [Means for solving the problem]

[0007] As a result of intensive research conducted by the present inventors to solve the above problems, they discovered that a peptide having a specific sequence has an excellent sympathetic nervous activation effect, leading to the completion of the present invention.

[0008] That is, the present invention is a composition for activating the sympathetic nervous system (hereinafter also referred to as the "composition of the present invention"), which contains one or more peptides selected from the group consisting of peptides consisting of any of the amino acid sequences shown below (SEQ ID NOs: 1 to 16) and peptides containing the amino acid sequences. (Amino acid sequence: VAPFPE, HLPLP, VVPPF, HQPHQPLPPT, TEDELQDK, LNPWDQ, IISQE, ANEEEY, VIPY, LPLP, VIESPPEIN, FPQY, LNVPGE, IVPNSAEE, GEPTSTPT, KFQSEEQQQ) In a preferred embodiment, the composition of the present invention is used for one or more purposes selected from the group consisting of promoting energy expenditure, reducing fatigue, improving weakness and lethargy, waking up, improving sleepiness, improving concentration and attention, improving physical activity, improving mental function, improving heat production, increasing body temperature, improving basal metabolism, promoting sweating, suppressing weight gain, and suppressing body fat accumulation. In a preferred embodiment, the composition of the present invention is a pharmaceutical product. In a preferred embodiment, the composition of the present invention is a food or drink.

[0009] Another aspect of the present invention is the use of one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence in the production of a composition used for sympathetic nerve activation. Another aspect of the present invention is one or more peptides selected from the group consisting of peptides consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16, and peptides containing said amino acid sequence, which are used for sympathetic nerve activation. Another aspect of the present invention is the use of one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence in activating the sympathetic nervous system. Another aspect of the present invention is a method for activating the sympathetic nervous system, comprising administering to a subject in need of sympathetic nervous activation one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence. The present invention also includes a milk protein hydrolysate containing one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 16 and peptides containing the amino acid sequence. [Effects of the Invention]

[0010] The present invention provides an excellent composition for activating the sympathetic nervous system. The composition of the present invention can be used to achieve various effects obtained by activating the sympathetic nervous system, specifically, promoting energy expenditure, reducing fatigue, improving weakness and fatigue, awakening, alleviating sleepiness, improving concentration and attention, improving physical activity, improving mental function, improving thermogenesis, increasing body temperature, improving basal metabolism, promoting sweating, suppressing weight gain, or suppressing body fat accumulation. Furthermore, the composition of the present invention can be suitably formulated into pharmaceuticals or foods and beverages. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a graph showing the energy consumption of mice administered with the peptide according to the present invention for 60 minutes after administration. [Figure 2] 1 is a graph showing the energy consumption of mice administered with the peptide according to the present invention for 30 minutes after administration. [Figure 3] 1 is a graph showing the amount of spontaneous exercise for 60 minutes after the end of forced exercise in mice administered a casein hydrolysate containing the peptide according to the present invention. [Figure 4] 1 is a graph showing the change in physical sensations experienced by subjects before and after ingesting a casein hydrolysate containing the peptide according to the present invention for two weeks. [Figure 5] 1 is a graph showing changes in body composition before and after a 4-week intake period of a subject who took a casein hydrolysate containing the peptide according to the present invention. [Figure 6] 1 is a graph showing the effects experienced by subjects who took a casein hydrolysate containing the peptide according to the present invention for two weeks. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention will now be described in detail. However, the present invention is not limited to the following embodiments and can be freely modified within the scope of the present invention.

[0013] The composition for activating the sympathetic nervous system of the present invention contains, as an active ingredient, one or more peptides selected from the group consisting of peptides consisting of any of the amino acid sequences shown below (SEQ ID NOs: 1 to 16) and peptides containing the amino acid sequences (hereinafter also referred to as "peptides of the present invention"). (Amino acid sequence: VAPFPE, HLPLP, VVPPF, HQPHQPLPPT, TEDELQDK, LNPWDQ, IISQE, ANEEEY, VIPY, LPLP, VIESPPEIN, FPQY, LNVPGE, IVPNSAEE, GEPTSTPT, KFQSEEQQQ) Here, in the above amino acids, A represents an alanine residue, N represents an asparagine residue, D represents an aspartic acid residue, Q represents a glutamine residue, E represents a glutamic acid residue, G represents a glycine residue, H represents a histidine residue, I represents an isoleucine residue, L represents a leucine residue, K represents a lysine residue, F represents a phenylalanine residue, P represents a proline residue, S represents a threonine residue, W represents a tryptophan residue, Y represents a tyrosine residue, and V represents a valine residue. The peptide according to the present invention may be contained in the form of a salt thereof.

[0014] The peptide of the present invention may be a protein hydrolysate obtained by hydrolyzing proteins derived from milk, soybeans, eggs, wheat, barley, rice, potatoes, sweet potatoes, peas, corn, livestock meat, fish meat, seafood, etc. Alternatively, the peptide of the present invention may be further isolated and purified from the hydrolyzed product. Alternatively, the peptide of the present invention may be obtained by chemical synthesis or biosynthesis.

[0015] In the present invention, a peptide comprising an amino acid sequence shown in any one of SEQ ID NOs: 1 to 16 refers to a peptide having one or more amino acid residues added to the N-terminus or C-terminus of the sequence, more specifically, a peptide having 1 to 10 residues, preferably 1 to 5 residues, and even more preferably 1 to 3 residues added, and the sequence preferably has a sympathetic nervous activation effect.

[0016] The composition of the present invention has a sympathomimetic activity. Sympathetic nervous activation can be confirmed by, for example, increases in energy consumption, oxygen intake, and blood adrenaline levels, and can also be confirmed by measuring autonomic nervous activity using well-known electrophysiological techniques. Furthermore, in the present invention, "activating" the sympathetic nervous system includes increasing the amount of sympathetic nervous activity by enhancing it from its normal activity level, restoring the sympathetic nervous system activity level that has decreased due to various causes and increasing the amount of sympathetic nervous activity to normal or even higher, and / or enhancing the amount of sympathetic nervous activity compared to the parasympathetic nervous system.

[0017] Activation of the sympathetic nervous system increases energy consumption. Therefore, the composition of the present invention has the effect of promoting energy consumption. Generally, homeostasis of human energy balance is maintained within 1% of daily energy intake and expenditure (Takashi Ando, ​​Physical Fitness and Sports Science, Vol. 67, No. 5, 327-344, (2018)). When energy consumption increases by more than 1%, it can be considered that energy consumption has been promoted. Energy expenditure can be determined by indirect calorimetry. Energy expenditure can be calculated using the following formula, according to the method of Tadaishi et al. PLoS One. 2011 6(12) e28290. Energy expenditure (cal / min) = 3.91 VO2 (ml / min) + 1.10 VCO2 (ml / min)

[0018] In the present invention, energy consumption refers to, but is not limited to, energy consumption due to basal metabolism, energy consumption due to diet-induced thermogenesis resulting from eating, energy consumption due to non-exercise activity thermogenesis resulting from daily physical activity, and thermogenesis resulting from exercise. In this specification, exercise refers to competitive exercise as well as activities such as sports, walking, and jogging that are undertaken in a planned and intentional manner for health, physical training, and enjoyment, and physical activity refers to physical activity in daily life excluding exercise for work, housework, commuting to work or school, hobbies, etc. In addition, in the present invention, promoting energy consumption includes increasing energy consumption by increasing it from a normal energy consumption level, restoring an energy consumption level that has decreased due to various causes and increasing energy consumption to normal or even higher, and / or further promoting energy consumption that increases after exercise.

[0019] In addition, activation of the sympathetic nervous system promotes the secretion of adrenaline, which has the effects of waking up, reducing fatigue, improving weakness and lethargy, alleviating drowsiness, improving concentration and attention, improving physical activity, and improving mental function. Here, physical activity includes improving athletic ability or extending exercise duration, shortening the time required in competitions and sports where the time required is short, and suppressing a decline in reflex ability.

[0020] In addition, activating the sympathetic nervous system and promoting energy consumption as a result can have effects such as improved heat production, increased body temperature, improved basal metabolism, promoted sweating, suppressed weight gain, and suppressed body fat accumulation. As a result, it is expected to prevent and improve hypothermia and improve peripheral blood flow. Furthermore, it is expected to improve and prevent diseases such as hypotension, decreased visceral function (constipation, diarrhea), decreased immunity, poor circulation (chills, stiff shoulders, lower back pain, joint pain), sleep disorders, and decreased metabolism (obesity) caused by persistent hypothermia and poor peripheral circulation.

[0021] Therefore, in a preferred embodiment, the composition of the present invention is used to improve conditions involving sympathetic nervous activity, specifically, to promote energy consumption, reduce fatigue, improve weakness and lethargy, have an awakening effect, improve sleepiness, improve concentration and attention, improve physical activity, improve mental function, improve heat production, increase body temperature, improve basal metabolism, promote sweating, suppress weight gain, suppress body fat accumulation, etc.

[0022] The compositions of the present invention for treating the above-mentioned conditions or diseases can be applied to humans or non-human animals (particularly mammals). The application may be for therapeutic or non-therapeutic purposes. The term "non-therapeutic" does not include medical procedures, i.e., treatment of the human body through therapy. That is, another aspect of the present invention is a method for activating the sympathetic nervous system, comprising the step of administering the composition for activating the sympathetic nervous system of the present invention to a subject.Furthermore, the sympathetic nervous system activation may be a method for promoting energy consumption, reducing fatigue, improving weakness and fatigue, awakening, improving sleepiness, improving concentration and attention, improving physical activity, improving mental function, improving thermogenesis, increasing body temperature, improving basal metabolism, promoting sweating, suppressing weight gain, or suppressing body fat accumulation.

[0023] As used herein, "improvement" or "amelioration" refers to improving a condition or preventing or delaying the worsening of a condition. In addition, in this specification, the term "prevention" refers to preventing or delaying the onset of a disease or symptom.

[0024] The present invention can also be said to involve the use of one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence in the production of a composition used for sympathetic nerve activation. The present invention can also be said to be one or more peptides selected from the group consisting of peptides consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1 to 16, and peptides containing the amino acid sequence, which are used for sympathetic nerve activation. The present invention can also be said to be the use of one or more peptides selected from the group consisting of peptides consisting of an amino acid sequence shown in any one of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence in activating the sympathetic nervous system. The present invention can also be said to be a method for activating the sympathetic nervous system, which comprises administering one or more peptides selected from the group consisting of peptides consisting of the amino acid sequence set forth in any of SEQ ID NOs: 1 to 16 and peptides containing said amino acid sequence to a subject in need of sympathetic nervous activation.

[0025] The content of the peptide according to the present invention in the composition for activating the sympathetic nervous system of the present invention can be set to 0.0000001 to 100% by mass, preferably 0.000001 to 20% by mass, more preferably 0.000005 to 10% by mass, and even more preferably 0.000005 to 5% by mass, relative to the final composition. Furthermore, when the peptide of the present invention is contained in the form of a protein hydrolysate in the composition for activating the sympathetic nervous system of the present invention, the content of the hydrolysate can be set to 0.00001 to 50% by mass, preferably 0.0001 to 20% by mass, and more preferably 0.0005 to 10% by mass, relative to the final composition. In this specification, the term "final composition" refers to the composition when administered to or ingested by a subject.

[0026] The content of the peptide of the present invention in the final composition can be measured by the following method. (a) The final composition is diluted and dissolved in 0.2% formic acid aqueous solution to a concentration of 1.0 mg / mL, and LC / MS analysis is performed under the following measurement conditions. Meanwhile, solutions of chemically synthesized standard peptides (manufactured by Bio-Synthesis) of each peptide sequence of SEQ ID NOs: 1 to 16 are prepared at several concentrations, and LC / MS analysis is performed under the following measurement conditions to create a calibration curve. Among the peaks in the analysis of the final composition solution, those that match the molecular weight and retention time of the peaks of the standard peptides are identified as the peptide sequences present in the final composition. The peak areas of the standard peptides and the peak areas of the final composition are compared to determine the content of each peptide in the final composition. (b) LC / MS equipment Mass spectrometer: TSQ Quantum Discovery MAX (Thermo Fisher Scientific). High-performance liquid chromatograph: Prominence (Shimadzu Corporation), column: TSKgel ODS-100V φ2.0 mm × 250 mm, 5.0 μm (TOSOH Corporation). (c)LC / MS measurement conditions Mobile phase A: 0.2 wt% formic acid-water solution Mobile phase B: 0.2 wt% formic acid-acetonitrile solution Sample injection volume: 10 μL, column temperature: 40°C, liquid flow rate: 200 μL / min Analysis mode: SRM measurement. Product Mass and Parent Mass: Set to the m / z of each of the peptides of SEQ ID NOs: 1 to 16.

[0027] In the present invention, the dosage or intake of the peptide of the present invention to a subject varies depending on age, symptoms, etc., but is preferably 0.00001 to 100 mg / kg body weight / day, more preferably 0.0001 to 50 mg / kg body weight / day, and even more preferably 0.0001 to 30 mg / kg body weight / day. The peptide of the present invention may be administered or taken in one to three divided doses per day.

[0028] The composition of the present invention can preferably be in the form of a pharmaceutical product. Such pharmaceuticals can be for the prevention, improvement and / or treatment of sympathetic nervous activation and / or decreased sympathetic nervous activity, or for the improvement or enhancement of conditions involving decreased sympathetic nervous activity as described above.

[0029] The route of administration of pharmaceuticals may be either oral or parenteral, with oral administration being preferred. Parenteral administration includes intravenous injection, rectal administration, inhalation, and the like. Such pharmaceuticals can be formulated into a desired dosage form depending on the administration method. For example, for oral administration, pharmaceuticals can be formulated into solid preparations such as powders, granules, tablets, and capsules; or liquid preparations such as solutions, syrups, suspensions, and emulsions. Furthermore, for parenteral administration, pharmaceuticals can be formulated into suppositories, ointments, and the like. In preparing the formulation, in addition to the peptide according to the present specification, components commonly used in formulations, such as excipients, pH adjusters, colorants, and flavoring agents, can be used. It is also possible to use in combination with known or future drugs having the above-mentioned sympathetic nervous system activating action, drugs for improving lipid metabolism disorders, drugs for treating hyperlipidemia, and the like. In addition, formulation can be carried out by a known method as appropriate depending on the dosage form. When formulating, a pharmaceutical carrier may be appropriately blended to form the formulation.

[0030] Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and carboxymethyl cellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.

[0031] Examples of binders include gelatin, polyvinylpyrrolidone, macrogol, and the like, in addition to the above-mentioned excipients.

[0032] Examples of disintegrants include the above-mentioned excipients as well as chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone.

[0033] Examples of lubricants include talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; waxes such as pea gum and gaelt; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and starch derivatives.

[0034] Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid; and the like.

[0035] Examples of flavoring agents include sweeteners, acidulants, and fragrances. In the case of a liquid preparation for oral administration, examples of the carrier to be used include solvents such as water.

[0036] The timing of taking the pharmaceutical of the present invention is not particularly limited, and it may be taken before meals, after meals, between meals, during exercise, or at rest.

[0037] The composition of the present invention can preferably be in the form of a food or drink. Such food and drink products can be offered and sold as food and drink products labeled for their use in activating the sympathetic nervous system or for improving or ameliorating conditions involving sympathetic nervous activity.

[0038] Such "indication" acts include all acts for informing consumers of the aforementioned uses, and any expression that can recall or infer the aforementioned uses falls under the category of "indication" acts of the present invention, regardless of the purpose of the indication, the content of the indication, the object or medium on which it is displayed, etc. Furthermore, it is preferable that the "labeling" be done in an expression that allows consumers to directly recognize the intended use. Specifically, this includes acts of transferring, delivering, displaying for the purpose of transferring or delivering, or importing food and beverage products or product packaging on which the intended use is stated, displaying or distributing advertisements, price lists, or transaction documents related to the products and including the intended use, or providing information containing the above-mentioned content by electromagnetic means (such as the Internet).

[0039] On the other hand, it is preferable that the content of the labeling be one approved by the government, etc. (for example, a labeling approved based on various systems established by the government and made in a manner based on such approval.) It is also preferable that such content of the labeling be affixed to promotional materials at the point of sale, such as packaging, containers, catalogs, pamphlets, POP displays, and other documents.

[0040] "Labeling" also includes labeling as health food, functional food, enteral nutritional food, special dietary food, health functional food, food for specified health uses, food with nutrient functions, food with functional claims, quasi-drug, etc. Among these, labeling approved by the Consumer Affairs Agency, such as labeling approved under systems related to foods for specified health uses, foods with nutrient functions, or foods with functional claims, or similar systems, can be cited. Specific examples include labeling as a food for specified health uses, labeling as a conditional food for specified health uses, labeling that indicates an effect on the structure or function of the body, labeling that reduces disease risk, and labeling of functionality based on scientific evidence. More specifically, typical examples include labeling as a food for specified health uses (especially labeling of health uses) and similar labeling as defined in the Cabinet Office Ordinance on Permission for Labeling for Special Uses Provided in the Health Promotion Act (Cabinet Office Ordinance No. 57 of August 31, 2009). Examples of such labeling include, for people who are exercising and / or dieting, labeling such as "for those who want to improve energy consumption," "for those who want to improve metabolism," "for those who want to reduce body fat," "for those who feel fatigued," "to make the body less prone to fatigue," "to improve weakness and fatigue / when you feel mentally or physically sluggish," "to improve drowsiness," "for those who want to improve concentration and attention," "to improve physical activity," "to improve mental function," "for a constitution that sweats easily," "to prevent excessive weight gain," "for those concerned about visceral fat," "for those concerned about a decline in basal metabolic rate," "for those who want to warm up the body," "for those who are prone to feeling cold," etc.

[0041] Furthermore, the peptide according to the present specification or a protein hydrolysate containing the peptide of the present invention may be incorporated into a food or drink product, thereby processing the food or drink product into one embodiment of the present invention.

[0042] Such foods and beverages include tablet confectionery, liquid food, feed including for pets, regardless of whether they are in liquid, paste, solid, powder or other form, as well as, for example, flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, compound seasonings and foods, frozen foods, confectionery, beverages, and other commercially available foods. Examples of the wheat flour products include bread, macaroni, spaghetti, noodles, cake mix, fried chicken flour, breadcrumbs, etc. Examples of the instant foods include instant noodles, cup noodles, retort / prepared foods, canned foods, microwave foods, instant soup / stew, instant miso soup / cleaning liquid, canned soup, freeze-dried foods, and other instant foods. Examples of the processed agricultural products include canned agricultural products, canned fruit, jams and marmalades, pickles, boiled beans, dried agricultural products, and cereals (processed grain products). Examples of the processed seafood products include canned seafood, fish ham and sausage, fish paste products, seafood delicacies, and tsukudani (fish stew). Examples of the processed livestock products include canned livestock products, pastes, livestock ham, sausages, etc. Examples of the milk and dairy products include processed milk, milk drinks, yogurts, lactic acid bacteria drinks, cheese, ice creams, infant formula, cream, and other dairy products. Examples of the fats and oils include butter, margarines, vegetable oils, and the like. Examples of the basic seasonings include soy sauce, miso, sauces, tomato-processed seasonings, mirin, vinegars, and the like. Examples of the compound seasonings and foods include cooking mixes, curry bases, sauces, dressings, noodle soups, spices, and other compound seasonings. Examples of the frozen food include frozen ingredient foods, semi-cooked frozen foods, and cooked frozen foods. Examples of the confectionery include caramel, candy, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice confectionery, bean confectionery, dessert confectionery, and other confectionery. Examples of the beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks containing fruit juice, fruit pulp drinks, fruit drinks containing fruit pieces, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, sports drinks, nutritional drinks, alcoholic drinks, and other beverages. Other commercially available foods include baby food, furikake, and ochazuke nori seaweed. [Example]

[0043] The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

[0044] <1> Confirmation of sympathetic nervous activation effect of the peptide according to the present invention 1 Food intake increases energy expenditure (diet-induced thermogenesis), and it has been reported that thermogenesis has two phases: an early phase (up to approximately 45 minutes after ingestion) that occurs primarily through sympathetic nervous activity, and a second phase (after 45 minutes) that occurs primarily due to the digestion, absorption, oxidation, and storage of nutrients (P. Diamond et al., Am. J. Physiol., 1987, Jun; 252(6 Pt 1): E719-26.). Therefore, in the following experiments, we measured energy expenditure for 30 or 60 minutes after administration of the test sample, which is thought to correspond to the early phase of thermogenesis, and used this as an index of sympathetic nervous activity. Male C57BL / 6J mice (n=9) were fasted for 1 hour and then orally administered 1 μg / g body weight of peptides (synthetic peptides of SEQ ID NOS: 1-16) or an equivalent volume of water. Breath samples were collected continuously for 60 minutes after administration, and energy expenditure was calculated from the oxygen and carbon dioxide concentrations in the breath using indirect calorimetry. Energy expenditure was calculated using the following formula, according to the method of Tadaishi et al. PLoS One. 2011 6(12) e28290. Energy expenditure (cal / min) = 3.91 VO2 (ml / min) + 1.10 VCO2 (ml / min) The relative values ​​of energy expenditure (AUC) for 60 minutes after administration to the water-administered group are shown in Figure 1. Compared to the water-administered group, energy expenditure increased in each peptide-administered group. These results demonstrate that the peptides of SEQ ID NOS: 1 to 16 have a sympathetic nervous activation effect.

[0045] <2> Confirmation of sympathetic nervous activation effect of the peptide according to the present invention 2 Using peptides of SEQ ID NOs: 1, 7, 9 and 13 to 15, <1> A crossover study was conducted with n=8 for each group. The relative values ​​of energy expenditure (AUC) for 30 minutes after administration to the water-administered group are shown in Figure 2. Compared to the water-administered group, energy expenditure increased in each peptide-administered group. These results demonstrate that the peptides of SEQ ID NOs: 1, 7, 9, and 13 to 15 have a sympathetic nervous activation effect.

[0046] <3> Obtaining casein hydrolysate containing the peptide according to the present invention Casein (Fonterra) was dissolved in water to prepare an aqueous casein solution with a concentration of approximately 10% by mass. The aqueous casein solution was heat-sterilized by conventional methods, and then the temperature and pH were adjusted to the optimum range. A commercially available protease was added to initiate the hydrolysis reaction. When the casein hydrolysis rate reached 20-30%, the enzyme was inactivated by heating to terminate the enzymatic reaction. The hydrolysate was then concentrated and powdered by conventional methods. It was confirmed that the resulting hydrolysate contained two or more peptides of SEQ ID NOS: 1-16, each at 0.0005-1.5% by mass of the total hydrolysate.

[0047] <4> Confirmation of the fatigue-reducing effect of casein hydrolysate containing the peptide of the present invention The amount of spontaneous movement in a running wheel after forced exercise in mice is known to be an indicator of fatigue (Y. Takahashi, et al., J. Phys. Fitness Sports Med., 2(3), 373-379 (2013)). Based on this, the fatigue-reducing effect of the peptide was confirmed in the following experiment. Male BALB / c mice were divided into two groups: a water-administered group and a casein hydrolysate-administered group. <3> The mice were used in the study. After fasting for 4 hours and 30 minutes, 1.0 mg / g body weight of casein hydrolysate or the same amount of water was orally administered. 30 minutes after oral administration, the mice were forced to exercise for 30 minutes at a speed of 20 m / min using a treadmill device (Muromachi Kikai Co., Ltd.). After the forced exercise, the amount of spontaneous exercise (number of revolutions / min) for 60 minutes was measured from the number of revolutions of the running wheel placed in the breeding cage. This experiment was conducted as a crossover design with n=8 per group. Figure 3 shows the amount of spontaneous motor activity during the 60 minutes after forced exercise. Compared to the water-administered group, the casein hydrolysate group showed higher spontaneous motor activity. These results demonstrate that casein hydrolysate containing peptides of SEQ ID NOS: 1 to 16 reduces exercise-induced fatigue. Furthermore, spontaneous exercise in a wheel chair stimulates exercise motivation, suggesting that it has the effects of improving weakness and fatigue, stimulating activity, improving physical activity, and improving mental function.

[0048] <5> Confirmation of the physical effects and effects on body composition by taking the peptide of the present invention The casein hydrolysate containing the peptide according to the present invention was continuously ingested for two weeks to examine changes in physical sensation and changes in body composition after four weeks of ingestion. Specifically, the subjects were women who exercised regularly at least three times a week. <3> The subjects were asked to continuously consume a powdered drink containing casein hydrolysate prepared as described above for two weeks (5000 mg of casein hydrolysate per serving) or four weeks (10,000 mg of casein hydrolysate per serving). The subjects were instructed to dissolve the powdered drink in approximately 70 ml of water per 1,000 mg of casein hydrolysate before consuming. The subjects were also asked to maintain the same exercise regimen and duration during the intake period as before starting the intake. Subjects (38 people) who had taken the supplement for two weeks were asked to evaluate the three items of fatigue, wakefulness, and physical condition before and after the start of intake using a visual analog scale (VAS). Figure 4 shows the results of changes in physical sensations. Compared to before intake, the VAS scores for fatigue, wakefulness, and physical condition improved. These results demonstrate that casein hydrolysates containing peptides of SEQ ID NOS: 1 to 16 have the effect of reducing fatigue, improving weakness and lethargy, and improving wakefulness and drowsiness. The body weight, body fat percentage, and fat mass of subjects (257 people) who continued taking the supplement for four weeks were measured before and after the start of intake. The results of changes in body composition are shown in Figure 5. Compared to before intake, body weight, body fat percentage, and fat mass decreased, indicating an effect of suppressing weight gain and body fat accumulation.

[0049] <6> Investigation into the bodily effects of taking the peptide according to the present invention Targeted at 35 adult women <3> The subjects were instructed to take the powdered drink containing casein hydrolysate prepared as the main ingredient (2500 mg of casein hydrolysate per serving) for two weeks, and the effects they felt after taking the drink were investigated. The subjects were instructed to dissolve the powdered drink in approximately 100 to 250 ml of water before taking it. The results are shown in Figure 6. In response to the questions "I feel like my fatigue doesn't carry over into the next day," "I feel like I'm in better physical condition," and "I feel like I've started sweating more," 49%, 49%, and 57% of the subjects answered "I think so / I somewhat think so," respectively. Since improvements were observed in subjective fatigue and physical condition, it was shown that casein hydrolysates containing peptides of SEQ ID NOS: 1 to 16 have the effect of reducing fatigue and improving weakness and malaise. Furthermore, since fatigue and physical condition are affected by mental state, it was shown to have the effect of improving mental function. Furthermore, many subjects experienced sweating, indicating a sweating effect as well as an effect of increasing body temperature and heat production, which are the underlying causes of sweating.

Claims

1. A composition for activating the sympathetic nervous system, comprising a milk protein hydrolysate, The milk protein hydrolysate contains, as an active ingredient, one or more peptides selected from the group consisting of peptides having an amino acid sequence represented by any one of SEQ ID NOs: 1 to 16, It is used for one or more purposes selected from the group consisting of reduction of fatigue, improvement of weakness and fatigue, awakening, improvement of sleepiness, improvement of concentration and attention, improvement of physical activity, improvement of mental function, improvement of heat production, increase in body temperature, improvement of basal metabolism, promotion of sweating, suppression of weight gain, and suppression of body fat accumulation, composition.

2. The composition of claim 1 which is a pharmaceutical.

3. The composition according to claim 1 , which is a food or drink.

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