JP2018058832A - Brown fat cell activator containing licorice extract - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation having high activation effect on brown fat cells.SOLUTION: A brown fat cell activator contains licorice (Glycyrrhiza glabra) extract as an active ingredient.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a brown adipocyte activator. More specifically, the present invention relates to a brown adipocyte activator containing a licorice extract.

  In recent years, many people suffer from obesity, which has become a major social problem. Obesity can be a cause of many diseases. For example, it is closely related to lifestyle-related diseases such as metabolic syndrome, dyslipidemia, diabetes, and hypertension, and progresses from lifestyle-related diseases to various diseases such as myocardial infarction, stroke, cirrhosis, pancreatitis, gout, and cancer. Risk is also high. In addition, since the burden on joints and bones increases due to obesity, back pain, knee pain, arthritis, fractures, etc. are likely to occur, and sleep apnea syndrome tends to occur due to pressure on the throat. Obesity is not only a burden on the household, but also increases medical costs, which incurs treatment costs and countermeasure costs in each country, and has a significant impact on the economy.

  Obesity and fat are closely related. Mammalian adipose tissue is roughly classified into two types, white adipose tissue (WAT) and brown adipose tissue (BAT), depending on its function and histological characteristics. In white adipose tissue, white adipocytes present therein store surplus energy in the form of neutral fat (triacylglycerol) to form large monolobular fat droplets. On the other hand, the physiological role of brown adipose tissue is completely opposite, and is a site where energy is consumed and dissipated as heat by stimulation of sympathetic nerves. Brown adipose tissue contains brown adipocytes, which are characterized by having multilocular lipid droplets and abundant mitochondria. UCP1 (uncoupling protein 1, uncoupling protein 1) present in mitochondria of brown adipocytes ) Has the function of dissipating energy as heat (Non-Patent Documents 1 to 3).

  More recent studies have shown that brown adipocytes are either classic brown adipocytes that exist from the fetal stage or inducible brown adipose-like cells (beige adipocytes) that appear in white adipose tissue due to environmental factors such as prolonged cold stimulation. It was found that it was divided into They both have multifat lipid droplets, are rich in mitochondria, and have common features such as the expression of proteins related to heat production such as UCP1, but their developmental characteristics and expressed gene profiles differ greatly. (Non-Patent Documents 1 and 2). Furthermore, it has been reported that BAT detected in human adults has characteristics of beige adipocytes (Non-Patent Documents 4 to 6).

  According to anatomical studies, brown adipocytes are present in humans, but they are difficult to find after adults. Similar trends are seen in other large mammals. On the other hand, brown adipocytes can be seen in rodents such as mice even when they are adults. Therefore, in large mammals such as humans, brown adipocytes disappear as they grow, and there is a theory that adults have no or only trace amounts of brown adipocytes. The negative significance was negative (Non-Patent Documents 7, 8 and 10). However, in recent years, it has become possible to evaluate human BAT using glucose metabolic activity using positron emission tomography (PET) as an index (Non-patent Document 9), so that BAT also has metabolic activity in adults. It contributes to the regulation of heat production, energy consumption and body fat at the time of cold exposure and food intake, and its functional decline contributes to obesity, especially body fat accumulation with aging, etc. It became clear (Non-Patent Document 10). In addition, since aging also reduces cold-induced heat production, not only obesity but also the body is likely to cool down. For example, in a healthy person, BAT activity is detected at about 60% in the 20s in the evaluation combining cold stimulation and PET, but the appearance rate decreases with age, and 10% in the 50s The number is drastically reduced (Non-Patent Document 11).

  Animals need to react to environmental changes to protect their lives. For example, in order to prevent the body temperature from falling to a hypothermic state when the temperature of the outside air decreases, the sympathetic nerve is stimulated to generate heat and maintain the body temperature. Here, it has been reported that brown adipose tissue is deeply involved in such cold stimulated heat production. For example, when the energy consumption of the whole body is measured in a warm condition at room temperature of 27 ° C., it increases in proportion to body weight (especially lean body weight), but cold stimulation (19 ° C., 2 hours), which is a typical stimulus for BAT activation If you add, it will increase further. When the difference between the two conditions is calculated as cold-induced thermogenesis (CIT), there is a high positive correlation with BAT activity regardless of lean body mass, and subjects with higher BAT activity are more cold. There was little decrease in body temperature upon stimulation. From the above, it was revealed that BAT activity can be evaluated by measuring cold-induced heat production (Non-Patent Documents 12 to 14).

  In addition, when eating, the body temperature rises above the amount of heat derived from the temperature of the food itself. This is due to energy consumed when nutrients absorbed in the body are decomposed and stimulation of sensory nerves such as taste and smell. For this reason, after a meal, even if it is resting, the amount of metabolism increases. It is this heat production that makes the body warm after eating (Non-Patent Documents 15 and 16). This heat production due to dietary intake is called diet-induced thermogenesis (DIT) and has been found to be deeply involved with brown adipose tissue (Non-patent Document 16).

  Brown adipose tissue has also been reported to bring about an increase in resting metabolic rate (Non-patent Documents 17 and 18).

  If BAT can be increased or activated in human adults, it is expected that CIT, DIT, and REE can be increased, and systemic energy consumption can be increased (Non-Patent Documents 1, 2, 9 and 10).

  Therefore, it currently prevents obesity by increasing BAT by specifically inducing beige adipocytes (brown adipose-like cells) and / or activating beige adipocytes and brown adipocytes to improve energy metabolism and / or Attempts to control are being made. For example, catechins contained in tea and capsaicins contained in pepper etc. have been reported to have an activating effect on brown adipose tissue (Non-patent Documents 19 and 20). Further, it has been suggested that paradol contained in ginger and the like is associated with the activation of brown adipocytes. It has been suggested that menthol contained in mint, allyl isothiocyanate contained in horseradish, etc., cinnamon aldehyde, etc. contained in cinnamon, etc. are related to the activation of brown adipocytes (Non-patent Document 1). Confirmation has been made. Therefore, a further substance having a high effect of activating brown fat cells is desired.

  On the other hand, licorice (Glycyrrhiza glabra) is a perennial of the genus Licorice that has been used for cooking and medicinal purposes since ancient times. It is said to have detoxification, antioxidant, analgesic and anti-inflammatory effects. In recent years, it has been found that licorice extract has an effect of promoting lipolysis (Patent Document 1). It has also been known that licorice extract increases the amount of brown adipocytes when mixed with forsythia leaf extract, citrus extract, sancin extract and the like (Patent Document 2). However, licorice extract alone induces differentiation of beige adipocytes (brown adipose-like cells) and promotes energy consumption in beige adipocytes and brown adipocytes (hereinafter, activation of brown adipocytes comprehensively) Have never been reported).

International Publication No. 2008/143182 JP 2009-292805 A

Haruo Ono, Shingo Sasamura, History of Medicine Vol. 250 No.9, 2014, 8.30, p811-815 Masayuki Saito, Mami Matsushita, History of Medicine Vol. 250 No.9, 2014, 8.30, p806-810 R. Burcelin et. Al., Biochem. J. (1993) 291, pp. 109-113 Wu J. et.al., Cell, 150, July 20, 2012, pp. 366-376 Sharp LZ et.al., PLos One, November 2012, Volume 7, Issue 11, e49452 Lidell E M. et.al., Nature Medicine (2013), Volume 19, Number 5, May 2012 Ito T, Arch Histol. Cytol. (1991) Mar; 54 (1): 1-39 Heaton J. M. J. Anat. (1972) 112, 1, pp. 35-39 Saito M et.al., Diabetes, July (2009), Vol 58, pp. 1526-1531 The mystery of burning brown fat found so far (2013) Masayuki Saito, NAP Limited Yoneshiro T, Obesity (Silver Spring). 2011 Sep; 19 (9): 1755-60 Yoneshiro T, J Clin Invest. 2013 Aug; 123 (8): 3404-8 Yoneshiro T, Obesity (Silver Spring). 2011 Jan; 19 (1): 13-6. Kajimura S, Saito M., Annu Rev Physiol. 2014; 76: 225-49 Teruo Kawada, Tomoya Sakamoto, History of Medicine 2012; 242 (12): 942-946 Aida Sayuri et al., Obesity Research 2011; 17: 41-48 Bakker LE et.al., Lancet Diabetes Endocrinol. 2014 Mar; 2 (3): 210-7. Vieira-Potter VJ et.al., Am J Physiol Regul Integr Comp Physiol. 2015 Mar 15; 308 (6): R530-42. http://www.kao.com/jp/corp_news/2014/20140826_001.html T. Yoneshiro et.al., The American Journal of Clinical Nutrition 2012; 95: 845-850 Jeukendrup AE et. Al., Obes Rev. 2011; 12 (10) 841-851

  The subject of this invention is providing the brown adipocyte activator containing a licorice extract.

  As a result of intensive studies to obtain a substance having a high activation effect of brown adipocytes, the present inventors have found that the activation effect of brown adipocytes of the licorice extract is very high.

  Glycyrrhiza glabra (English name: Licorice) is a perennial plant of the genus Licorice, which is used for cooking sweeteners, confectionery, spices, and other medicines such as herbal medicines and herbs. As medicinal products, dried roots and rhizomes are used as crude drugs, or decocted, boiled, squeezed, or extracted extracts are taken. It is said to have detoxifying action, analgesic action, anti-inflammatory action and the like.

  Here, it has been known that the licorice extract has an effect of accelerating the degradation of neutral fat accumulated in white fat cells into fatty acids (Patent Document 1). In addition, licorice-derived grabrizine is also known to enhance the action of lipolytic enzymes in the liver and suppress the action of lipogenic enzymes. However, just because it has the effect of accelerating the degradation of neutral fat accumulated in white fat cells, it does not necessarily have an effect of activating human brown fat. For example, forskolin is known to have an effect of accelerating the degradation of neutral fat accumulated in white fat cells, but does not affect human resting metabolic rate (Non-patent Document 21). ), Human brown fat activation effect is not considered.

  In addition, licorice extract has been known to increase the amount of brown adipocytes in the form of a mixture with forsythia leaf extract, citrus extract, sancin extract and the like (Patent Document 2). However, the effect of promoting energy consumption in beige adipocytes and brown adipocytes with a licorice extract alone has not been reported so far.

Accordingly, the present application provides the following inventions.
(1) A brown adipocyte activator containing an extract of licorice (Glycyrrhiza glabra) as an active ingredient.
(2) The brown adipocyte activator according to (1), which promotes energy consumption by heat production.
(3) The brown adipocyte activator according to (2), wherein the heat production is cold-induced heat production or meal-induced heat production.
(4) The brown adipocyte activator according to any one of (1) to (3), which promotes resting metabolism.
(5) The brown adipocyte activator according to any one of (1) to (4), wherein brown adipocytes are activated by enhancing the expression of UCP1.
(6) An energy consumption promoter containing a licorice extract as an active ingredient.
(7) The energy consumption promoter according to (6), which promotes energy consumption by activating brown adipocytes.
(8) A body temperature decrease inhibitor containing a licorice extract as an active ingredient.
(9) The body temperature decrease inhibitor according to (8), which suppresses a decrease in body temperature by activating brown adipocytes.
(10) A UCP1 expression enhancer containing a licorice extract as an active ingredient.
(11) A composition comprising the drug according to any one of (1) to (10).
(12) A composition for activating brown adipocytes containing an extract of licorice as an active ingredient.
(13) The composition according to (12), which promotes energy consumption by heat production.
(14) The composition according to (13), wherein the heat production is cold-induced heat production or meal-induced heat production.
(15) The composition according to any one of (12) to (14), which promotes resting metabolism.
(16) The composition according to any one of (12) to (15), wherein brown adipocytes are activated by enhancing the expression of UCP1.
(17) A composition for promoting energy consumption comprising an extract of licorice as an active ingredient.
(18) The composition according to (17), which promotes energy consumption by activating brown adipocytes.
(19) A composition for suppressing a decrease in body temperature comprising an extract of licorice as an active ingredient.
(20) The composition according to (19), which suppresses a decrease in body temperature by activating brown adipocytes.
(21) The composition according to any one of (11) to (20), wherein the composition is a food composition.

  The brown adipocyte activator of the present invention can activate brown adipocytes to increase cold-induced heat production and meal-induced heat production, promote resting metabolism, and promote systemic energy consumption. If the energy consumption of the whole body increases, obesity can be prevented or suppressed. In addition, licorice, which is an active ingredient of the brown adipocyte activator of the present invention, is an herb that has been conventionally used for food and medicine and is also preferable in terms of safety.

FIG. 1 shows changes in resting energy expenditure (REE = resting energy expenditure) 0 to 120 minutes after intake of licorice extract in Example 2 at the time of test sample intake (time 0) and at each time point. It is shown as ΔREE (kcal / day) which is the difference of REE. The left figure is a graph of the average value of those with low BAT activity, and the right figure is with high BAT activity. ■ is when licorice extract is ingested, ○ is when placebo is ingested. * And ** indicate that there is a significant difference from the 0 time point by the steel test (* p <0.05, ** p <0.01). # Indicates a significant difference with respect to placebo by paired t-test (#p <0.05). FIG. 2 shows the area under the curve (AUC) from 0 to 120 minutes from the intake of the test sample of ΔREE in FIG. The left figure shows the accumulated value at 0 to 60 minutes, the middle figure at 0 to 90 minutes, and the right figure at 0 to 120 minutes. In each figure, the shaded area is when the licorice extract is ingested (right side), and the white area is when the placebo is ingested (left side). * Indicates that there is a significant difference from placebo by paired t-test (* p <0.05).

  The composition comprising the brown adipocyte activator, body temperature decrease inhibitor, energy consumption promoter, UCP1 expression enhancer, and the brown adipocyte activator of the present invention is effective for an extract of licorice (Glycyrrhiza glabra). Contains as a component.

  The licorice (Glycyrrhiza glabra) used in the present invention is a perennial of the licorice genus. Although the place of origin is China, it has long been known as a sweetener and folk medicine not only in China but also in Europe.

  In the present invention, the extract of licorice refers to an extract of roots and / or rhizomes. The extraction method of the extract can be performed by solvent extraction. In the case of solvent extraction, the licorice root and / or rhizome is dried as necessary, and further shredded or ground as necessary, and then an aqueous extractant such as cold water, hot water, or hot water having a boiling point or lower, Alternatively, it is extracted by using a water-containing organic solvent, an organic solvent, a polar solvent such as methanol, ethanol, 1,3-butanediol, ether or the like at normal temperature or by heating. However, the extraction method is not limited to solvent extraction, and may be a conventional method known in the art. As long as the effects of the present invention are not impaired, the form of the extract may be not only the extract itself, but may be appropriately diluted or concentrated by a conventional technique, and further by drying the extract. The obtained powdery or massive solid may be sufficient.

  When the water content is high, the extraction solvent used in the present invention may contain, for example, grillritin, which is a hydrophilic component. When taking a licorice extract for a long period of time, it is preferable that the content of glycyrrhizin is low from the viewpoint of safety. Therefore, an extraction solvent having a low water content may be used.

  In the present invention, brown adipocytes refer to both classic brown adipocytes formed in the fetal period and brown adipose-like cells induced to differentiate into white adipose tissue (sometimes referred to as beige adipocytes or bright cells). Point to. That is, in the present invention, not only the classic brown adipocytes in a narrow sense but also brown-like adipocytes induced in white adipose tissue are called brown adipocytes. In addition, brownish adipocytes induced in white adipose tissue are sometimes called beige adipocytes or brown adipose-like cells.

White adipocytes have large single droplets and small cytoplasm. Brown adipocytes, on the other hand, have small multilocular lipid droplets, and many mitochondria are present around these multilobular lipid droplets, so they have a unique brown color and are rich in sympathetic nerves and blood vessels. It has morphological and histological characteristics. Therefore, white fat cells and brown fat cells can be distinguished by observing cells morphologically and histologically. In addition, white fat stores energy, but brown fat cells consume and dissipate energy as heat. Brown adipocytes have higher energy metabolism than white adipocytes, and glucose uptake increases because energy is released as heat. Therefore, the presence of brown adipocytes can be evaluated, for example, by measuring the accumulation of glucose labeled with 18F by PET (positron emission tomography). Furthermore, in brown adipocytes, a 33 KDa protein called uncoupling protein 1 (UCP1, uncoupling protein 1) is specifically expressed in the inner mitochondrial membrane of cells, so UCP1 mRNA expression and UCP1 protein are measured. Thus, the presence of brown adipocytes can be confirmed. Furthermore, since brown fat cells are activated by cold stimulation, it can also be evaluated by measuring heat production due to cold induction. In addition, the energy consumption can be evaluated by, for example, calculating based on the O ₂ consumption and the CO ₂ emission amount from the measurement values obtained by a metabolic chamber, a simple breath analysis device, and the like. Furthermore, as described above, since the presence of BAT shows a positive correlation with CIT, it can also be evaluated by measuring CIT.

  In this application, the activation of brown adipocytes means the action of promoting the induction of differentiation of brown adipose-like cells (beige cells) in white adipose tissue and / or the energy consumption in beige adipocytes and brown adipocytes. It refers to the promoting action. The activation of brown adipocytes can increase metabolism in beige adipocytes and brown adipocytes, promote energy consumption, and convert fatty acids into heat energy. Conversion from fatty acids to thermal energy may be performed by UCP1.

  The brown adipocyte activator refers to a substance having an action of activating brown adipocytes as described above. As described above, the presence of brown adipocytes and / or the increase in energy metabolism of brown adipocytes can be measured by measuring UCP1 mRNA expression or UCP1 protein, histologically observing cells, and accumulation of 18F-labeled glucose. Can be evaluated by measuring with PET, measuring cold-induced heat production, and the like. In addition, the induction of differentiation of brown adipose-like cells (beige adipocytes) in white adipose tissue is sometimes referred to as brown fat cell reactivation.

  The brown adipocyte activator of the present invention can promote energy metabolism by heat production. Energy metabolism includes basic metabolism, exercise, daily living activities, and heat production. About 60% of daily energy consumption comes from basal metabolism, about 5% from exercise, about 25% from daily living activities, and about 10% from heat production. Many attempts have been made to increase basal metabolism by increasing muscles and increase energy metabolism by actively exercising and daily living activities. On the other hand, energy consumption due to heat production is for the body to cope with a rapid temperature change, and rises due to, for example, a cold stimulus. In addition, it is also known that heat production is increased by eating food, and heat production is performed to generate heat to combat infection and inflammation. Therefore, in this application, energy consumption by heat production refers to metabolic energy consumption consumed for heat production corresponding to cold stimulation, food intake, etc., not based on basal metabolism or muscle exercise. The brown fat cell activator of the present application may promote energy metabolism by increasing heat production in beige fat cells and brown fat cells, in particular, by stimulating sympathetic nerves. Such heat production may occur by converting fatty acid to heat energy, and conversion of fatty acid to heat energy may be performed by UCP1.

  The brown adipocyte activator, energy consuming agent, and the like of the present invention and compositions containing them may increase energy metabolism in brown adipose tissue, not in the liver or muscle, and may increase the expression of UCP1. .

  In this application, cold-induced thermogenesis (CIT) refers to the production of heat when a subject is exposed to the outside air at a reduced temperature. As described above, when the temperature of the outside air decreases, the sympathetic nerve is stimulated to generate heat in order to maintain the temperature in the body. It has been reported that brown adipose tissue has a role of producing heat in response to such cold stimulation (Non-patent Document 12). The brown adipocyte activator of the present application can promote energy metabolism by cold-induced heat production in such brown adipose tissue.

  In the present application, diet-induced thermogenesis (DIT) means that a subject produces heat by eating a meal. Energy is consumed and body temperature rises for reasons such as stimulation of sensory nerves such as taste and digestion and absorption of food due to this meal intake. Here, it has been found that brown adipose tissue is deeply involved with DIT (Non-patent Document 16). The brown adipocyte activator of the present application can promote energy metabolism by diet-induced heat production in such brown adipose tissue.

  In the present application, resting metabolism is energy consumed at resting. Resting energy expenditure (REE) is measured in a resting or supine position. Brown adipose tissue has been reported to cause an increase in resting metabolic rate (Non-patent Documents 17 and 18). The brown adipocyte activator of the present invention can promote resting metabolism.

  The content of the licorice extract in the brown adipocyte activator or UCP1 expression enhancer of the present invention is not particularly limited, but is preferably 10 to 3000 mg per day in terms of dry weight, and is incorporated in an amount to be ingested. Depending on the case, it may be blended in an amount of 10 to 200 mg, 50 to 150 mg, 100 to 200 mg, 100 to 300 mg, 100 to 3000 mg, or 300 to 1000 mg. In order to enhance the effect of the present invention, other brown adipocyte activator, body temperature decrease inhibitor, energy consumption promoter, UCP1 expression promoter, metabolism promoter and the like may be used in combination.

  Although the intake of the licorice extract is not particularly limited, it is preferable to take 10 to 3000 mg in terms of dry weight per day for a human with a body weight of 60 kg. It may also be preferable to ingest an amount such as 10-200 mg, 50-150 mg, 100-200 mg, 100-300 mg, 100-3000 mg, or 300-1000 mg.

  The method for producing a brown adipocyte activator of the present invention may include a step of extracting an extract from licorice root and / or rhizome. The extraction method and the form of the extract used in the present invention are arbitrary as long as the effects of the present invention are not impaired as described above.

  The present invention also provides a composition comprising the above brown adipocyte activator, body temperature decrease inhibitor, energy consumption promoter, or UCP1 expression enhancer. The composition of the present invention can be in various forms such as powder, liquid, solid, granule, tablet, paste, gel, emulsion, cream, sheet, spray, foam and the like.

  The food composition of the present invention may be a powder, a beverage, or a tablet. In addition, the food composition of the present invention includes dry powder, beverages such as tea and soft drinks, tablets and capsules such as supplements, processed foods such as retort foods, luxury products such as desserts, seasonings, dairy products, and fats and oils. It may be a processed product or the like, and may be in various forms such as powder, liquid, solid, granule, granular, paste, and gel. Furthermore, the food composition of the present invention includes not only food for humans and the like but also food for other animals such as livestock.

  The content of the brown adipocyte activator in the composition of the present invention is not particularly limited, but it is preferably blended in an amount of 10 to 3000 mg taken per day in terms of dry weight of the licorice extract. It may be blended in an amount such as 10 to 200 mg, 50 to 150 mg, 100 to 200 mg, 100 to 300 mg, 100 to 3000 mg, or 300 to 1000 mg. In addition, the composition of the present invention has a brown adipocyte activation action, a body temperature decrease suppressing action, an energy consumption promoting action, etc. in order to further enhance the brown fat cell activation action, the body temperature lowering suppressing action, the energy consumption promoting action, etc. Certain other materials may be added.

  Furthermore, in the composition of the present invention, additives can be arbitrarily selected and used as necessary. As additives, excipients and the like can be included.

  The excipient may be anything that is normally used when it is in the desired form, for example, starches such as wheat starch, rice starch, corn starch, potato starch, dextrin, cyclodextrin, crystalline celluloses, Examples thereof include sugars such as lactose, glucose, sugar, reduced maltose, starch syrup, fructooligosaccharide and emulsified oligosaccharide, and sugar alcohols such as sorbitol, erythritol, xylitol, lactitol and mannitol. These excipients can be used alone or in combination of two or more.

  Further, the composition of the present invention may contain other components as necessary, for example, a colorant, a preservative, a thickener, a binder, a disintegrant, a dispersant, a stabilizer, a gelling agent, and an antioxidant. , Surfactant, preservative, pH adjuster, oil, powder, color material, water, alcohols, thickener, chelating agent, silicones, antioxidant, UV absorber, moisturizer, fragrance, various medicinal ingredients Well-known materials such as preservatives, pH adjusters and neutralizers can be appropriately selected and used.

  The brown adipocyte activator of the present invention induces differentiation of brown adipose-like cells (beige cells) in white adipose tissue, and / or activates beige adipocytes and brown adipocytes, and is particularly useful for systemic production by heat production. By promoting metabolism through an approach that promotes energy consumption, obesity can be prevented and / or suppressed. Therefore, it is also effective for treatment and / or prevention of diseases caused by obesity. Moreover, it is possible to prevent browning by activating brown adipocytes and increasing cold-induced heat production, or to increase energy metabolism by meal by increasing meal-induced heat production. Furthermore, licorice, which is an active ingredient of the present invention, is a natural product that has been used since ancient times, and is preferable in terms of safety.

  Next, the present invention will be described in more detail by way of examples. In addition, this invention is not limited by this.

In vivo evaluation of human BAT activity by PET
The activation of brown adipocytes was evaluated using PET (Positron Emission Tomography). When brown adipocytes are activated, glucose is taken up. Therefore, non-metabolizable FDG (fluorodeoxyglucose) labeled with a radioisotope of fluorine (18F) is used to visualize the use of sugar by PET, thereby improving the activity of brown adipose tissue (BAT). The degree can be evaluated (Non-patent Document 9). Cold stimulation also activates brown fat and increases cold-induced heat production. Therefore, the metabolic activity of brown adipose tissue was evaluated by FDG (2-fluoro-2-deoxyglucose) -PET after applying cold stimulation to a healthy adult. Evaluation was performed based on the method described in Non-Patent Document 9.

  Subjects were 19 healthy adult males in their 20s and 30s. Subjects were cold-loaded after 6-12 hours of fasting. In other words, a T-shirt and shorts are lightly worn, sit in a chair in a room controlled at 19 ° C, and place your feet on an ice block that is intermittently wrapped with a towel every 5 to 5 minutes. It was.

After 1 hour under these conditions, ¹⁸ F-FDG (1.7 to 5.4 MBq / kg body weight) was intravenously injected and the same cold exposure was continued. One hour after ¹⁸ F-FDG injection, a full body scan was performed in a room at 24 ° C using a PET / CT system (Aquiduo, Toshiba Medical System, Tochigi) for about 30 minutes. The CT parameters were a tube voltage of 120 kV, a variable tube current control system, and a contrast-free low-dose CT, and parallel images with an axia plane and a slice thickness of 2 mm were obtained.

  Human BAT is localized mainly in the upper part of the clavicle, around the cervical spine, etc., and there are very few brown adipose tissues in the peripheral part distant from these localized parts (Non-patent Documents 11, 12, and 13). Therefore, in order to quantitatively evaluate the FDG accumulation in the shoulder region, which has been reported to have a lot of BAT in humans, SUV (standardized uptake values) was calculated as follows using the shoulder region as a target region. SUV is the relative concentration value when SUV is 1 when the total radioactivity administered is uniformly distributed throughout the body. The intensity of accumulation of radiopharmaceuticals in tumors and organs in PET, etc. It becomes an index to represent. Specifically, SUV is obtained by the following formula.

SUV (tissue radioactivity [Bq / g] / dose [Bq / g body weight]) = organ radioactivity concentration measured in the image (Bq / g) ÷ (radioactivity dose ÷ body weight)

The SUV maximum value in the target area was set as SUV _max . Based on the value of the SUV _max, they were grouped into nine BAT low activity's (average SUV _max 2.1) and 10 people BAT highly active people (average SUV _max 11.7). FDG accumulation around the shoulder was more common in those with high BAT activity, whereas FDG accumulation around the shoulder was below the detection limit in those with low BAT activity.

Effects of licorice extract on metabolic rate of BAT low activity and BAT high activity groups In the BAT low activity group and BAT high activity group divided as described above, the licorice extract was rested by a single crossover test. The effect on metabolic rate was examined.

  In this experiment, as a licorice extract, ethanol was added to the rhizome part of licorice, extracted, filtered, concentrated, mixed with medium-chain fatty acid triglyceride (MCT; C8: C10 = 99: 1 Riken vitamin), and the concentration of grabrizine Of Diana chula gold licorice gravonoids (Asahi Food and Healthcare Co., Ltd.) containing 2% (0.5% ± 0.5%) (Kaneka Gravonoid ™) were used at a time.

  On the day different from the BAT measurement of Example 1, the resting metabolic rate before and after the intake of the licorice extract of each group was measured. The subjects were 19 same males divided into low BAT activity group and high BAT activity group according to Example 1. After fasting for 6 to 12 hours, the subjects were allowed to change into light clothes (T-shirts, short bread), rest in a room at 27 ° C for 30 minutes, and acclimatize to 27 ° C. Thereafter, resting metabolic rate was measured and used as a baseline.

  Baseline resting metabolic rate was measured by breath analysis for 20 minutes using a portable gas monitor AR-10 Type 4 (Arco System) and a dedicated supine hood. This resting metabolism was determined as an average value of a portion where the numerical value was stable for 5 minutes or more after 10 minutes from the start of measurement using the attached software with reference to the previous report (Non-Patent Document 13).

  After the baseline measurement, 100 mg of licorice extract was ingested, and after resting for 10 minutes, resting metabolism was measured for 20 minutes. This measurement was performed 4 times in total, 20 minutes each after 10 minutes to 30 minutes after intake, 40 minutes to 60 minutes after intake, 70 minutes to 90 minutes after intake, and 100 minutes to 120 minutes after intake. After a week of washout, each subject also measured the baseline resting metabolism and changes from 10 to 120 minutes after placebo ingestion in a similar procedure.

  FIG. 1 shows the change in resting energy expenditure (REE = resting energy expenditure) from 0 to 120 minutes after intake of licorice extract as ΔREE. From FIG. 1, it was clarified that licorice extract significantly increased the resting metabolic rate 30 minutes after ingestion compared to placebo intake.

  Further, the area under the time curve (AUC) of ΔREE from 0 to 120 minutes after ingestion was determined. The result is shown in FIG. Comparing the AUC of ΔREE, it can be seen that the intake of licorice extract is significantly higher in AUC of ΔREE, that is, the energy consumption, than the intake of placebo.

  Based on the above results, when licorice extract was administered to individuals with high brown adipocyte activity, energy consumption was promoted at least 30 minutes later than placebo even after a single dose. This suggests that the licorice extract has an immediate effect on energy consumption in brown adipocytes.

  Therefore, by ingesting the brown adipocyte activator of the present application containing licorice extract, brown adipocytes and beige adipocytes are activated to increase cold-induced heat production and meal-induced heat production, It is expected to reduce fat mass and thereby eliminate obesity by promoting whole body energy consumption. In general, aging causes a decrease in metabolism and makes the body feel cold, but the intake of licorice extract is also expected to prevent and improve coldness by increasing energy metabolism (heat production). . Furthermore, it is also expected that brownish adipocytes (beige adipocytes) are induced to differentiate in white adipose tissue by activating the brown adipocytes of licorice extract.

Claims (17)

  Brown adipocyte activator containing an extract of licorice (Glycyrrhiza glabra) as an active ingredient.   The brown adipocyte activator according to claim 1 for promoting energy consumption by heat production.   The brown adipocyte activator according to claim 2, wherein the heat production is cold-induced heat production or meal-induced heat production.   The brown adipocyte activator according to any one of claims 1 to 3, which promotes resting metabolism.   The brown adipocyte activator according to any one of claims 1 to 4, which activates brown adipocytes by enhancing the expression of UCP1.   Energy consumption promoter containing licorice extract as an active ingredient.   The energy consumption promoter according to claim 6, which promotes energy consumption by activating brown adipocytes.   UCP1 expression enhancer containing licorice extract as an active ingredient.   The composition containing the chemical | medical agent of any one of Claims 1-8.   A composition for activating brown adipocytes, comprising a licorice extract as an active ingredient.   11. A composition according to claim 10 for promoting energy consumption by heat production.   The composition according to claim 11, wherein the heat production is cold-induced heat production or meal-induced heat production.   The composition according to any one of claims 10 to 12, which promotes resting metabolism.   The composition according to any one of claims 10 to 13, which activates brown adipocytes by enhancing the expression of UCP1.   A composition for promoting energy consumption, comprising an extract of licorice as an active ingredient.   16. The composition of claim 15, wherein the composition promotes energy consumption by activating brown adipocytes.   The composition according to any one of claims 9 to 16, wherein the composition is a food composition.

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