Oral composition containing thermogenesis-promoting agent and thermogenesis-promoting agent

Abstract

To provide a high-safety thermogenesis-promoting agent that quickly increases a deep-body temperature to improve hypothermia.SOLUTION: A thermogenesis-promoting agent has macromolecular black tea polyphenol as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a thermogenesis promoter containing high molecular weight black tea polyphenols as an active ingredient, and an oral composition containing the thermogenesis promoter. [Background technology]

[0002] Warm-blooded animals have two types of body temperature: "skin temperature" and "core body temperature." Skin temperature (shell temperature), which is the temperature at the surface of the skin, fluctuates with changes in the external temperature, and also fluctuates with changes in the strength of heat dissipation to maintain a constant core body temperature. On the other hand, core body temperature refers to the temperature inside the body, such as the brain and internal organs, and is regulated to a nearly constant state. Core body temperature reflects the amount of body heat produced in life-sustaining activities, i.e., the amount of energy (ATP) produced in cells.

[0003] Thermoregulation is controlled by the thermoregulatory center in the hypothalamus in response to changes in skin temperature and core body temperature. When body temperature drops or cold stimuli that induce hypothermia are detected, homeostatic mechanisms are activated to maintain a constant core body temperature. One type of homeostatic mechanism is heat production through skeletal muscle contraction, known as shivering thermogenesis, and the other type is heat production called non-shivering thermogenesis. Non-shivering thermogenesis primarily involves heat production in brown adipose tissue through stimulation of the neurotransmitter norepinephrine via sympathetic nerve activation, i.e., heat production through activation of mitochondrial uncoupling protein 1 (UCP1) via stimulation of β3-adrenergic receptors expressed on the surface of brown adipose cells. In humans, brown adipose tissue is abundant in infants, whose muscles are not yet fully developed, and decreases with growth; therefore, heat production in brown adipose tissue in adults is limited.

[0004] As described above, warm-blooded animals maintain a constant body temperature, but if they are exposed to a cold environment for a long period of time, their body heat production cannot keep up, causing a drop in core body temperature (the temperature inside the body, such as the brain and internal organs), a condition known as "hypothermia."Hypothermia begins with symptoms such as severe shivering and impaired judgment, and as the body temperature drops further, it can cause muscle stiffness, a decrease in pulse and breathing, and a drop in blood pressure, but because the condition progresses unconsciously, if left untreated, the animal can fall into a coma, and the body's metabolism will stop, leading to death.

[0005] In recent years, hypothermia in everyday life has become a problem. It has been pointed out that hypothermia is related to malnutrition, weight loss, and muscle loss due to aging and excessive dieting. Chronic mild hypothermia is also considered a health problem, and the average body temperature of Japanese people is on the decline. In recent years, elderly people have become less sensitive to drops in indoor temperatures, leading to an increase in cases of death from hypothermia in winter.

[0006] Prolonged mild hypothermia impairs the physiological function of various organs, increasing the risk of infectious diseases, cerebrovascular disease, diabetes, and other metabolic disorders due to a weakened immune system. It also contributes to poor health, including indigestion, decreased physical strength, and loss of appetite. Skeletal muscle, the largest organ in the human body and the tissue that produces the most body heat, decreases basal metabolic rate and body heat production. Decreased body heat production also reduces peripheral blood flow to maintain core body temperature. Thus, a decrease in skeletal muscle mass can result in a decrease in peripheral skin temperature, or "sensitivity to cold." As can be seen from this relationship, maintaining core body temperature by increasing body heat production and peripheral blood flow to maintain peripheral skin temperature can improve and prevent sensitivity to cold, cardiovascular disease, metabolic disorders, and other conditions, as well as maintain a strong immune system, making it important for maintaining good health.

[0007] In addition to moderate exercise, bathing, and appropriate cold protection, proactive use of foods and cooking methods that warm the body is recommended as a method of preventing hypothermia. Diet-induced thermogenesis (DIT) is thermogenesis induced by food intake, and includes both heat production through the metabolism of nutrients derived from ingested food (specific dynamic action) and heat production through sensory stimuli and non-nutrients associated with food intake. Sensory stimuli associated with food intake include the taste and smell of food and the number of times one chews, while non-nutrients that have a thermogenic effect include caffeine and capsaicin.

[0008] Capsaicin, the pungent component of chili peppers, activates capsaicin receptor (TRPV1)-expressing sensory neurons that control internal organs such as the gastrointestinal tract, and this nerve stimulation activates the sympathetic nervous system via the central nervous system. Sympathetic nervous system activation by capsaicin promotes the secretion of the thermogenic hormones adrenaline and noradrenaline, while also activating UCP1 in brown adipose tissue, a heat-producing organ, thereby increasing body heat production (Non-Patent Document 1). Food-derived components such as caffeine, which is abundant in coffee and tea; limonene, an aromatic component abundant in citrus fruits; oleuropein, a polyphenolic component found in olives; and non-polymer catechins, which are abundant in green tea, have also been reported to promote body heat production by activating UCP1 in brown adipose tissue via the sympathetic-adrenal pathway (Non-Patent Document 2, Patent Document 1). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Application Laid-Open No. 2007-70301 [Non-patent literature]

[0010] [Non-Patent Document 1] J.Physiol.Sci.,2017,Vol.67,No.5,p.549-560. [Non-patent document 2] Korean J.Obes.,2016,Vol.25,No.3,p.109-114 Summary of the Invention [Problem to be solved by the invention]

[0011] As mentioned above, some food ingredients are known to have the effect of promoting body thermogenesis. However, for example, capsaicin has a strong stimulating effect, and caffeine is addictive, limiting their versatility as safe functional food ingredients. No other food ingredients have been confirmed to have a strong body thermogenesis-promoting effect that can rapidly increase core body temperature through oral ingestion. Therefore, there is a need for a body thermogenesis promoter that utilizes food ingredients that are habitually consumed and widely consumed, is highly safe, and rapidly increases core body temperature to improve hypothermia.

[0012] Therefore, an object of the present invention is to provide a body heat production promoter and an oral composition containing the body heat production promoter, which are useful for preventing or ameliorating hypothermia. [Means for solving the problem]

[0013] To solve the above problems, the present inventors conducted extensive research into food-derived substances that can rapidly increase core body temperature. As a result, they discovered that black tea extracts containing high molecular weight black tea polyphenols have an excellent effect of increasing core body temperature, and that this effect is due to activation of adrenergic β2 receptors, which increase body heat production in skeletal muscle. This led to the completion of the present invention. That is, the present invention encompasses the following: [1] A thermogenic agent containing high molecular weight black tea polyphenols as its active ingredient. [2] The body heat production promoter according to [1], which is due to the promotion of adrenaline secretion. [3] The body heat production promoter according to [1], which increases the amount of body heat produced in skeletal muscle. [4] An oral composition containing the body heat production promoter described in any one of [1] to [3]. [5] The oral composition according to [4], which is for dieting or improving sensitivity to cold. [Effects of the Invention]

[0014] The body heat production promoter and oral composition containing the body heat production promoter of the present invention increase body heat production in skeletal muscles through the secretion-promoting effect of adrenaline, thereby exerting the effect of rapidly raising core body temperature. Therefore, they are useful for preventing or ameliorating hypothermia-induced conditions such as decreased immunity, decreased basal metabolism, impaired blood flow and lymphatic flow, decreased metabolism, and imbalance of the autonomic nervous system. They are also useful for preventing obesity by increasing basal metabolism and for preventing or ameliorating symptoms such as sensitivity to cold and edema by improving blood flow. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the results of Test Example 1. [Figure 2] FIG. 2 shows the results of Test Example 2. [Figure 3] FIG. 3 shows the results of Test Example 3. [Figure 4] FIG. 4 shows the results of Test Example 4. [Figure 5] FIG. 5 shows the results of Test Example 5. [Figure 6] FIG. 6 shows the results of Test Example 6. [Figure 7] FIG. 7 shows the results of Test Example 7. [Figure 8] Figure 8 shows the process leading up to an increase in body temperature after ingestion of high molecular weight black tea polyphenols. DETAILED DESCRIPTION OF THE INVENTION

[0016] The body heat production promoter of the present invention is characterized by containing high molecular weight black tea polyphenols as an active ingredient, and promotes body heat production in skeletal muscle through its adrenaline secretion-promoting effect, thereby rapidly increasing core body temperature. Therefore, it can be used as a body heat production promoter and an oral composition containing a body heat production promoter, which are useful for preventing or ameliorating hypothermia. Furthermore, because the promotion of body heat production in skeletal muscle through its adrenaline secretion-promoting effect improves energy metabolism, it can also be used as an oral composition for dieting. In this invention, "dietary" refers to the purpose of improving or preventing obesity, specifically, to inhibit or reduce weight gain and fat accumulation.

[0017] As used herein, "prevention" refers to preventing or delaying the onset of a disease or symptom, or reducing an individual's risk of developing a disease or symptom. "Amelioration" refers to improving a disease, symptom, or condition, preventing or delaying the worsening of a disease, symptom, or condition, or reversing, preventing, or delaying the progression of a disease, symptom, or condition.

[0018] In the present invention, "core body temperature" refers to the temperature inside the body (e.g., rectum, esophagus, heart, brain, etc.), and is usually rectal temperature. In humans, core body temperature can be estimated from axillary temperature, oral (sublingual) temperature, tympanic temperature, etc. Causes of hypothermia include mineral, vitamin, or protein deficiency, lack of exercise, poor circulation or autonomic nervous system disorders due to excessive stress, aging, etc., and the causes of hypothermia for which the present invention is effective are not particularly limited to these. The body heat production promoter of the present invention is suitable for preventing or ameliorating hypothermia caused by weight loss or muscle mass loss, as well as by stress such as fasting and malnutrition.

[0019] (High molecular weight black tea polyphenols) The "high molecular weight black tea polyphenols" that are the active ingredient in the body heat production promoter of the present invention refer to high molecular weight polyphenols that include oligomers (e.g., theasinensins, theaflavins, etc.) formed by the oxidative polymerization of catechins (e.g., epicatechin, catechin gallate, catechin gallate, epigallocatechin, gallocatechin, epigallocatechin gallate, and gallocatechin gallate) present in the leaves and stems of the tea plant (Camellia sinensis) by the action of oxidative enzymes during the black tea production process, and compounds (thearubigins) with an unknown structure that are formed by the complex polymerization of these components as fermentation progresses, and are components unique to black tea.

[0020] The active ingredient in the thermogenesis promoter of the present invention, high molecular weight black tea polyphenols, is a component that can be quantified by the HPLC method described below. In the HPLC method, a single peak consisting of the elution of multiple high molecular weight polyphenols can be quantified using free theaflavin as a standard substance (reference: Nutrition, 27, pp. 287-292). Free theaflavin (CAS number: 4670-05-7, molecular formula: C29H24O12, molecular weight: 564.49) is available as a commercially available reagent. It can also be obtained by isolation and purification from black tea leaves or by a synthetic method in which catechins are combined through a chemical reaction. Other components derived from black tea can be analyzed by known methods.

[0021] High molecular weight black tea polyphenols are contained in black tea leaves (including highly fermented oolong tea) obtained by oxidative fermentation of tea plant leaves and stems, as well as in processed products and extracts thereof. Extracts can be used in the present invention. Extracts are obtained by extracting black tea leaves or other raw materials with water or an organic solvent. Extracts with increased high molecular weight polyphenol content using known methods, such as partitioning between liquid phases or column treatment with an adsorbent, are also suitable for use in the present invention. Other suitable materials for use in the present invention include fresh tea plant leaves and stems, extracts obtained by extracting them, catechin preparations with increased catechin content, and artificially produced high molecular weight polyphenols by oxidative polymerization using enzymes or other methods, using purified catechins as raw materials.

[0022] High-molecular-weight black tea polyphenols can be obtained, for example, from commercially available black tea leaves. Examples of black tea leaves that can be used include Assam and Darjeeling tea leaves from India, Uva and Dimbula tea leaves from Sri Lanka, and tea leaves from Kenya and Malawi in Africa, China, and Indonesia. From the perspective of increasing core body temperature by promoting body heat production through the promotion of adrenaline secretion, highly fermented tea leaves with a high content of high-molecular-weight black tea polyphenols are preferred, such as Assam and Kenyan black tea leaves. In addition to these tea leaves, other black tea extracts that can be used include "Black Tea Extract Powder MN-H10" (manufactured by Mitsui Norin Co., Ltd.), "Black Tea Extract Powder MN-C3" (manufactured by Mitsui Norin Co., Ltd.), the low-caffeine "Black Tea Extract Powder BCL" (manufactured by Mitsui Norin Co., Ltd.), and "Polyphenon-TF35" (manufactured by Mitsui Norin Co., Ltd.), which is high in high-molecular-weight black tea polyphenols. When the black tea extract is a mixture containing high molecular weight black tea polyphenols, the content of high molecular weight black tea polyphenols in the extract is preferably 10 to 100% (mass %), more preferably 20 to 100%, and even more preferably 30 to 100%. Furthermore, the content of high molecular weight polyphenols in the extract of total polyphenols is preferably 50 to 100%, more preferably 70 to 100%, and even more preferably 80 to 100%. When the content of high molecular weight polyphenols is within this range, the core body temperature elevating effect can be efficiently achieved.

[0023] High molecular weight black tea polyphenols are preferably ingested at a concentration effective for the purpose of increasing core body temperature by promoting body heat production through the promotion of adrenaline secretion. For example, the intake amount is preferably 20 to 2,000 mg / day of high molecular weight black tea polyphenols per adult, more preferably 100 to 1,000 mg / day, and even more preferably 150 to 500 mg / day. This intake amount can be adjusted appropriately based on factors such as body weight, gender, and age. In the present invention, the above amount is preferably administered or ingested one to several times a day, preferably once a day.

[0024] (Thermogenesis promoter and oral composition containing thermogenesis promoter) The thermogenic agent containing high molecular weight black tea polyphenols as an active ingredient aims to increase core body temperature through thermogenic activity, and can be incorporated into pharmaceutical preparations, foods and beverages, food supplements, pharmaceuticals, quasi-drugs, or raw materials for preparing these to form oral compositions containing the thermogenic agent (hereinafter sometimes simply referred to as "oral compositions"). In this specification, oral compositions refer to those that are unlikely to pose a risk to human health and are taken orally or by administration through the digestive tract in normal social life.

[0025] The foods and beverages to which thermogenesis promoters are added are not particularly limited, but specific examples of the foods and beverages that can be used include tea drinks, coffee drinks, carbonated drinks, fruit drinks, fruit liquors, vegetable drinks, soft drinks, dairy drinks, lactic acid bacteria drinks, energy drinks, sports drinks, soy milk, and other beverages; desserts such as ice cream, ice milk, lacto ice cream, frozen desserts, yogurt, pudding, and jelly; confectioneries such as steamed buns, sweet bean paste, caramel, candy, candy tablets, snacks, crackers, biscuits, cookies, pies, chocolate, and chewing gum; soups such as Japanese soups, Western soups, Chinese soups, and miso soups; breads; jams; seasonings such as mayonnaise and dressings; and retort foods such as retort curry. Additionally, supplement foods can be prepared in the form of powders, granules, tablets, capsule tablets, and the like. Furthermore, the food and drink containing the body heat production promoter of the present invention can be made into a functional food or a food for specified health uses for purposes such as promoting body heat production.

[0026] When used as a pharmaceutical, the active ingredient can be combined with additives such as pharmaceutically acceptable carriers to form an oral composition primarily intended for thermogenesis. Formulations include tablets, granules, fine granules, pills, powders, capsules, lozenges, chewable tablets, and liquids (drinks). It can also be incorporated into pharmaceuticals for other indications. The pharmaceuticals to be incorporated are listed in the Japanese Pharmacopoeia, are not particularly limited as long as they are not contraindicated for high molecular weight black tea polyphenols and can be taken orally. When used as a quasi-drug, the active ingredient can be combined with desired additives to form oral liquids, health drinks, vitamin-containing health supplements, and other similar products. When incorporated into quasi-drugs, the quasi-drugs to be incorporated are not particularly limited as long as they are designated by the Minister of Health, Labor, and Welfare, are not contraindicated for high molecular weight black tea polyphenols, and can be taken orally. Examples of such products include oral liquids, health drinks, and vitamin-containing health supplements. These medicines and quasi-drugs are effective in preventing and improving various diseases caused by hypothermia. [Example]

[0027] <About notation> The actual tests performed are described in detail below. In the description, "%" means "% by mass" unless otherwise specified. Furthermore, the numerical range of "lower limit value to upper limit value" means a numerical range of "not less than the lower limit value and not more than the upper limit value" unless otherwise specified. <Test sample> The test sample was a black tea extract (product name: TF35, manufacturer: Mitsui Norin Co., Ltd.) containing 71.6% high-molecular-weight black tea polyphenols. The control sample was a green tea extract (product name: Polyphenon 70S, manufacturer: Mitsui Norin Co., Ltd.) containing 83.6% catechins. The amount of high-molecular-weight black tea polyphenols in the samples was analyzed using the following method (Reference 1: Nutrition, 27, pp. 287-292). Total polyphenols were measured using the ferric tartrate spectrophotometric method described in the "Seventh Edition of the Standard Tables of Food Composition in Japan, 2015 Edition (Seventh Edition) Analysis Manual and Commentary" (supervised by the Ministry of Education, Culture, Sports, Science and Technology, Kenpakusha, published February 2016). The eight catechins (EC, C, EGC, GC, ECg, Cg, EGCg, GCg) and caffeine were measured using the conditions described in Reference 2 (JP Patent Publication No. 2018-134052). The four theaflavins (TF1, TF2A, TF2B, and TF3) were measured under the conditions described in Reference 3 (JP 2010-35548 A). The measurement results (composition of the components in the tea extract) are shown in Table 1.

[0028] [Analysis conditions for high molecular weight black tea polyphenols (HPLC method)] Standard substance: Free theaflavin (Mitsui Norin Co., Ltd.'s in-house preparation) Equipment: Alliance 2695 Separations Module (Waters) Column: Develosil C30-UG-5 (4.6 mm I.D. x 250 mm, particle size 5 μm, manufactured by Nomura Chemical Co., Ltd.) Column temperature: 40℃ Mobile phase: (A) H2O / MeCN / H3PO4 = 1000 / 25 / 0.5 (volume ratio), (B) MeCN Gradient conditions (binary gradient): 0-8 min; (B) 17%, 8-9.5 min; (B) 17-100%, 9.5-16 min; (B) 100%, 16-17 min; (B) 100-80%, 17-20 min; (B) 80%, 20-21 min; (B) 80%-17%, 21-35 min; (B) 17% ·Flow rate: 1.0mL / min Detection: 280nm ·Injection volume: 7.0μL

[0029] [Table 1]

[0030] <Test Example 1> Effect of administration of high molecular weight black tea polyphenols on changes in core body temperature [method] The effects of administration of high molecular weight black tea polyphenols on changes in core body temperature were examined. The above black tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 to a concentration of 13.8 mg / ml (10.0 mg of total polyphenols in 13.8 mg of black tea extract containing 72.3% high molecular weight black tea polyphenols). Saline containing 10% ethanol and 10% Tween 80 was used as a control. Twenty-two C57BL / 6J mice were fasted for 5 hours after being fully acclimated for at least 5 days, and their rectal temperatures were measured. Based on the rectal temperature measurements, they were divided into two groups, each consisting of 11 mice: a group receiving high-molecular-weight black tea polyphenols (100 mg / kg total polyphenol dose) and a control group. Thirty minutes after rectal temperature measurement, each group received an intragastric administration of 10 ml of each of the above solutions per kg of body weight. Rectal temperatures were then measured every hour for up to 3 hours.

[0031] [result] In the group administered high molecular weight black tea polyphenols, core body temperature (rectal temperature) increased significantly 1 and 2 hours after administration compared to before administration (Fig. 1(A)), and increased by approximately 0.9°C 1 hour after administration (Fig. 1(B)). This increase in body temperature was observed up to 2 hours after administration, and the cumulative change 3 hours after administration (Fig. 1(C)) was also significantly higher than in the control group.

[0032] <Test Example 2> Effect of catechin administration on changes in core body temperature [method] The effects of catechin administration on core body temperature were investigated. The green tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 at concentrations of 11.4 mg / ml and 22.7 mg / ml (10.0 mg and 20.0 mg of total polyphenols in 11.4 mg and 22.7 mg of green tea extract, containing 88.0% total polyphenols and 83.6% catechins). Saline containing 10% ethanol and 10% Tween 80 was used as a control. Twenty-four C57BL / 6J mice were fasted for 5 hours after acclimation for at least 5 days, and then their rectal temperatures were measured. Based on the rectal temperature measurements, they were divided into three groups: catechin-treated groups (100 mg / kg and 200 mg / kg total polyphenols) and a control group (8 mice each). Immediately after measuring rectal temperature, each group received an intragastric administration of 10 ml / kg of each solution, with the total polyphenols administered at a dose of 100 mg / kg or 200 mg / kg of body weight. Rectal temperatures were then measured every hour for three hours.

[0033] [result] As shown in Figure 2, unlike the results of Test Example 1, in the catechins-administered group (green tea extract-administered group), not only was no increase in core body temperature observed in the 100 mg / kg administration group, which is the same total polyphenol amount as in Test Example 1, but no increase in core body temperature was observed in the 200 mg / kg administration group, which is twice the amount. These results confirmed that the structure of polyphenols is involved in the effect of promoting body heat production, and that catechins are essential polymerized high-molecular-weight polyphenols.

[0034] <Test Example 3> Effect of afferent vagus nerve on the deep body temperature increase caused by administration of high molecular weight black tea polyphenols

[0035] [method] The influence of the afferent vagus nerve on the effect of administration of high molecular weight black tea polyphenols on the increase in core body temperature confirmed in Test Example 1 was investigated. Twelve C57BL / 6J male mice were used, in which the dorsal afferent vagus nerve trunk below the diaphragm was transected (RVx), and 11 sham-operated mice (Sham) in which the afferent vagus nerve trunk was exposed but not transected.A one-week recovery period was allowed after surgery.

[0036] The above black tea extract was dissolved at a concentration of 13.8 mg / ml in physiological saline containing 10% ethanol and 10% Tween 80. As a control, physiological saline containing 10% ethanol and 10% Tween 80 was used.

[0037] The above-mentioned dorsal afferent vagotomized (RVx) mice and sham-operated (Sham) mice were fully acclimated for 5 days or more, and then rectal temperatures were measured after a 5-hour fast. Based on the rectal temperature measurements, the vagotomized mice were divided into two groups: one group administered high-molecular-weight black tea polyphenols (6 mice) and one control group (6 mice). The sham-operated mice were divided into two groups: one group administered high-molecular-weight black tea polyphenols (5 mice) and one control group (6 mice). Immediately after rectal temperature measurement (hour 0), each group was intragastrically administered 10 ml of each of the above solutions per kg of body weight (total polyphenol dose: 100 mg / kg body weight). Rectal temperatures were then measured every hour for up to 3 hours.

[0038] [result] In sham-operated mice (Sham), core body temperature (rectal temperature) significantly increased in the group administered high molecular weight black tea polyphenols, as in Test Example 1 (Figure 3(A)). On the other hand, in mice in which the dorsal afferent vagus nerve trunk was cut (RVx), no increase in core body temperature was observed in the group administered high molecular weight black tea polyphenols (Figure 3(B)). Furthermore, the cumulative change in core body temperature (AUC) 3 hours after administration significantly increased in the group administered high molecular weight black tea polyphenols in sham-operated mice, but no significant difference was observed between the group administered high molecular weight black tea polyphenols and the control group in mice in which the dorsal afferent vagus nerve trunk was cut (Figure 3(C)). In other words, it was revealed that the information about the ingestion of high molecular weight black tea polyphenols is immediately transmitted from the digestive tract to the brain via the afferent vagus nerve, resulting in a rapid rise in core body temperature, which persists for two hours after administration.

[0039] <Test Example 4> Effect of administration of high molecular weight black tea polyphenols on blood catecholamine levels

[0040] [method] The effects of administration of high molecular weight black tea polyphenols on blood catecholamine concentrations were examined. The black tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 at a concentration of 27.7 mg / ml. Saline containing 10% ethanol and 10% Tween 80 was used as a control. Fourteen C57BL / 6J mice were divided into two groups of seven mice each, and after fasting for five hours, 10 ml of each of the solutions was administered intragastrically (total polyphenol dose of 200 mg / kg body weight) to the mice. One hour after administration, blood was collected from the inferior vena cava under isoflurane anesthesia, and the concentrations of adrenaline and noradrenaline in the blood were measured.

[0041] [result] In the group administered high molecular weight black tea polyphenols, blood adrenaline levels increased significantly (Figure 4 (A)), but there was no change in blood noradrenaline levels (Figure 4 (B)). These results confirmed that high molecular weight black tea polyphenols promote the secretion of only adrenaline, one of the catecholamines secreted by the adrenal medulla.

[0042] <Test Example 5> Effect of blood adrenaline on changes in core body temperature (rectal temperature) in mice after administration of high molecular weight black tea polyphenols

[0043] [method] The relationship between the effect of high molecular weight black tea polyphenols on increasing core body temperature confirmed in Test Example 1 and the effect of promoting adrenaline secretion confirmed in Test Example 3 was investigated.

[0044] The above black tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 to a concentration of 13.8 mg / ml. Saline containing 10% ethanol and 10% Tween 80 was used as a control.

[0045] Seventy-eight C57BL / 6J mice were fasted for 5 hours after rectal temperature measurement, and after 5 days of adequate acclimation. Based on the rectal temperature measurements, the high molecular weight black tea polyphenol-treated and control groups were divided into groups without receptor inhibitor treatment (control: n = 11, high molecular weight black tea polyphenol: n = 11), treated with a nonselective β-adrenergic receptor inhibitor (propranolol, 10 mg / 5 ml / kg) (control: n = 11, high molecular weight black tea polyphenol: n = 10), treated with a β-adrenergic receptor inhibitor (butoxamine, 5 mg / 5 ml / kg) (control: n = 6, high molecular weight black tea polyphenol: n = 5), and treated with a β-adrenergic receptor inhibitor (L-748,337, 5 mg / 5 ml / kg) (control: n = 12, high molecular weight black tea polyphenol: n = 12). Immediately after rectal temperature measurement at -30 minutes, a saline solution containing the receptor inhibitor was administered intraperitoneally to the receptor inhibitor-treated group, and saline to the non-treated group. Then, 30 minutes after this intraperitoneal administration, the polymer black tea polyphenol solution (total polyphenol dose of 100 mg / kg body weight) or a control solution was administered intragastrically at 10 ml per kg body weight (the time indicated as "administration" in the figure). Rectal temperature was then measured every hour for 3 hours.

[0046] [result] The effect of administration of high molecular weight black tea polyphenols on increasing core body temperature (rectal temperature), as confirmed in Test Example 1 (Figure 5(A)), was not observed in the group administered a non-selective adrenergic β-receptor inhibitor (Figure 5(B)). Furthermore, to identify the adrenergic β-receptor on which the secretion of adrenaline promoted in the adrenal medulla by administration of high molecular weight black tea polyphenols acts, we administered an inhibitor of the adrenergic β-2 receptor, which is involved in skeletal muscle-derived heat production, and an inhibitor of the adrenergic β-3 receptor, which is involved in brown fat cell-derived heat production. The effect of administration of high molecular weight black tea polyphenols on increasing core body temperature (rectal temperature) was not confirmed in the group administered the adrenergic β-2 receptor inhibitor (Figure 5(C)), but was confirmed in the group administered the adrenergic β-3 receptor inhibitor (Figure 5(D)). In other words, it was confirmed that the effect of high molecular weight black tea polyphenols on increasing core body temperature is related to the activation of the adrenergic β-2 receptor, which increases body heat production in skeletal muscle.

[0047] <Test Example 6> Effect of administration of high molecular weight black tea polyphenols on energy metabolism [method] The effects of administration of high molecular weight black tea polyphenols on energy metabolism were examined. The black tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 at a concentration of 13.8 mg / ml (10.0 mg of total polyphenols in 13.8 mg of black tea extract containing 72.3% high molecular weight black tea polyphenols). Saline containing 10% ethanol and 10% Tween 80 was used as a control. Twelve male C57BL / 6J mice were divided into two groups of six. Mice were housed in individual cages specifically designed for exhaled gas analysis. After a 5-hour fast, mice with stable oxygen consumption were given a single intragastric administration of each solution at 10 ml per kg body weight. Oxygen consumption (VO2 / W: ml / min / kg), respiratory quotient (RQ), and spontaneous activity (cross) were measured 30 minutes before and 3 hours after administration, and hourly averages were calculated. Oxygen consumption, respiratory quotient, and spontaneous activity were simultaneously measured using an animal energy metabolism measurement system (ARCO-2000N-RAT, Arco System Co., Ltd.) combined with an infrared beam sensor-based locomotion measurement device (ACTIMO-100N, Shin Factory Co., Ltd.).

[0048] [result] The mean oxygen consumption (VO2) (Figure 6(A)) and respiratory quotient (RQ) (Figure 6(B)) values ​​for the first hour after administration were significantly higher in the high-molecular-weight black tea polyphenols group. However, no significant differences were observed between groups in spontaneous activity (cross) (Figure 6(C)). The significant increase in VO2 indicates improved energy metabolism. Here, the respiratory quotient (RQ) is the volumetric ratio of carbon dioxide emitted to oxygen consumed during the breakdown of nutrients into energy within the body over a given period. Calculating the respiratory quotient allows for estimation of the energy source consumed. Generally, values ​​approaching 0.7 when lipid consumption is high, 0.8 when protein consumption is high, and 1.0 when carbohydrate consumption is high are known. The RQ values ​​for the high-molecular-weight black tea polyphenols group were significantly higher and approached 1.0 within 1 hour after administration compared to the control group (approximately 0.8). This suggests that high-molecular-weight black tea polyphenols enhanced carbohydrate metabolism. These results confirmed that high molecular weight black tea polyphenols transiently increased carbohydrate utilization and improved energy metabolism without any change in exercise volume.

[0049] <Test Example 7> Effect of administration of high molecular weight black tea polyphenols on core body temperature rise in high-fat diet-induced obesity model mice [method] We investigated whether the core body temperature-increasing effect of high-molecular-weight black tea polyphenols, as confirmed in Test Example 1, was also observed in a high-fat diet-induced obesity model mouse. Male C57BL / 6J mice were fed a high-fat diet (HFD) for 33 to 39 weeks under ad libitum feeding conditions to generate a high-fat diet-induced obesity model mouse (DIO mice) (body weight 35 to 60 g, average 50.8 g). The high-fat diet used was HFD32 (dietary fat weight 32%: CLEA Japan, Inc.). The black tea extract was dissolved in saline containing 10% ethanol and 10% Tween 80 to a concentration of 13.8 mg / ml (10.0 mg of total polyphenols in 13.8 mg of black tea extract containing 72.3% high molecular weight black tea polyphenols). Saline containing 10% ethanol and 10% Tween 80 was used as a control. Eleven 40-46 week old DIO mice were acclimated for at least five days and fasted for five hours before measuring their rectal temperature. Based on the rectal temperature measurements, they were divided into two groups: a group of five mice receiving high molecular weight black tea polyphenols and a control group of six mice. Each group received an intragastric administration of 10 ml of each of the above solutions per kg of body weight. Rectal temperatures were then measured every hour for up to three hours.

[0050] [result] In the group administered with high molecular weight black tea polyphenols, core body temperature (rectal temperature) was significantly elevated 1 and 2 hours after administration compared to before administration (Fig. 7(A)), and the cumulative change 3 hours after administration (Fig. 7(B)) was also significantly elevated compared to the control group. In other words, the core body temperature-elevating effect of high molecular weight black tea polyphenols confirmed in Test Example 1 was also observed in DIO mice. It has been reported that diet-induced thermogenesis is lower in obese individuals than in lean individuals (Obes Res. 1997, Vol. 5, No. 6, pp. 622-631). However, the results of Test Example 7 revealed that the effect of high molecular weight black tea polyphenols on increasing core body temperature is also observed in obese individuals.

[0051] The results of the examples revealed that the effect of high molecular weight black tea polyphenols on raising core body temperature follows the steps shown in Figure 8. Specifically, in step 1 of Figure 8, when high molecular weight black tea polyphenols are ingested and reach the digestive tract, a stimulus is transmitted from the intestine to the brain via the afferent vagus nerve, activating the sympathetic nervous system (step 2). The activation of the sympathetic nervous system transmits a stimulus from the brain to the adrenal medulla, causing adrenaline to be secreted into the bloodstream (step 3). After adrenaline reaches muscle tissue throughout the body, it acts on β2-adrenergic receptors (step 4). As a result, energy metabolism in skeletal muscle increases, promoting body heat production (step 5), and raising core body temperature (step 6).

Claims

1. A body heat production promoter whose active ingredient is high molecular weight black tea polyphenols.

2. 2. The body heat production promoter according to claim 1, which is caused by promoting the secretion of adrenaline.

3. The body heat production promoter according to claim 1, which increases the amount of body heat produced in skeletal muscles.

4. An oral composition comprising the body heat production promoter according to any one of claims 1 to 3.

5. The oral composition according to claim 4, which is used for dieting or for improving sensitivity to cold.

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