JP2006213657A - HUMAN beta3-ADRENALIN RECEPTOR AGONIST AGENT - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a human β3-adrenalin receptor agonist agent derived from a safe natural raw material having been eaten, and to provide a composition containing the same and used for preventing or treating life-style related diseases such as overweight, obesity, diabetes, hyperlipemia, hypertension, and gout. <P>SOLUTION: This human β3-adrenalin receptor agonist agent contains at least one extract selected from the group consisting of a Pulsatilla chinensis (Bunge) Regel extract and a Thuja orientalis L extract which are obtained by extractions using water-soluble solvents, as an active ingredient. The human β3-adrenalin receptor agonist agent is effective as a composition for preventing or treating life-style related diseases such as overweight, obesity, diabetes, hyperlipemia, hypertension, and gout. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a human β3 adrenergic receptor agonist agent, and a composition for preventing or treating lifestyle-related diseases such as obesity, obesity, diabetes, hyperlipidemia, hypertension, gout and the like comprising the same Related to things.

  The obese population is steadily increasing due to overeating, overnutrition and lack of exercise. Obese people, particularly those with visceral fat obesity with visceral fat accumulation, are complicated with lifestyle-related diseases such as diabetes, hyperlipidemia, hypertension, gout, and so on, which is a major social problem. In addition, when obese people reduce their body weight by 5 to 10%, the symptoms of comorbid lifestyle-related diseases are reduced or improved, so obesity prevention and / or improvement is prevention and / or improvement of lifestyle-related diseases. It leads to.

  Adrenergic receptors are receptors that bind to catecholamine agonists such as adrenaline and noradrenaline released from sympathetic nerves, and are classified into two types, α receptors and β receptors, depending on the sensitivity to catecholamine agonists. That is, α-adrenergic receptors are sensitive in the order of noradrenaline ≧ adrenergic> dopamine> isopreterenol, and β-adrenergic receptors are sensitive in the order of isopreterenol> adrenergic noradrenaline> dopamine.

  β-adrenergic receptors include β1, β2, and β3 receptors, and the presence of β4 receptors has recently been suggested. As an agonist (agonist) action for each receptor, β1 adrenergic receptor agonists increase heart rate, β2 adrenergic receptor agonists bronchial smooth muscle relaxation, β3 adrenergic receptor agonists activate heat production, and It is known to have an action of promoting lipolysis. Therefore, β3 adrenergic receptor agonists are effective in preventing and / or improving lifestyle-related diseases such as obesity.

  A β3 adrenergic receptor agonist was first discovered in 1984, and anti-obesity action and anti-diabetic action by heat production and lipolysis were recognized in animal experiments. However, these effects were weak in humans. The cause of this effect difference was 1989, and it became clear that there was a species difference in the chemical structure of rodents such as mice and rats and human β3 adrenergic receptors (see Non-Patent Documents 1 and 2). ). From these, an agonist having higher selectivity for β3 adrenergic receptors than β1 and β2 and high selectivity for human β3 adrenergic receptors, ie, a selective human β3 adrenergic receptor agonist, It is effective in preventing and / or improving lifestyle-related diseases such as obesity and diabetes, and its development is desired.

  Recently, several compounds are known as selective human β3 adrenergic receptor agonists (see Non-Patent Document 1), and their effects as anti-obesity drugs or anti-diabetic drugs have been confirmed in clinical trials. However, a human β3 adrenergic receptor agonist derived from a natural material with dietary experience is not yet known.

  The bald beetle is a plant belonging to the genus Pulsatilla (Pulsatilla), which is a regular product of the broad-leaved Pulsatilla chinensis (Bunge) Regel (medium) distributed from northeastern China to Shaanxi in the north and Jiangsu in the east. About the kind is used as a substitute, and its root has an effect on detoxification action, anti-inflammation, abdominal pain, and the like, and is used by decoction (see Non-Patent Document 3).

  Sakuhakuyo is a plant of the cypress family Thuja, and its leaves including young leaves are used in the private sector for astringency, hemostasis, stasis, and the like (see Non-Patent Document 4).

However, Pulsatilla chinensis for bald bean and Thuja orientalis L. for Sakuhaku have human β3 adrenergic receptor action, and are effective in preventing and / or improving lifestyle-related diseases such as obesity and diabetes in humans. It is not yet known.
Japanese Patent Application Laid-Open No. 2004-168766 discloses an α-glucosidase inhibitor containing Sakuhakuyo, an agent for preventing or improving diabetes, and an agent for preventing or improving obesity. However, JP 2004-168766 does not disclose or suggest a human β3 adrenergic receptor agonist agent.
JP2004-168766 Yasutaka Takakura, Toshihide Yoshida, Japanese Pharmacology Journal, 118, 315-320, 2001 C. Weyer, et al., Diabetes & Metabolism, 25, 11-21, 1999 Koichi Kimura, Kaoru Kimura, primary color Japanese medicinal plant picture book, nursery school Hiroshi Mitsuhashi, Primary Color Makino Wakuhan Daikankan, Hokuryukan

  The present invention relates to a human β3 adrenergic receptor agonist agent derived from a safe natural material with dietary experience, and obesity, obesity, diabetes, hyperlipidemia, hypertension, gout characterized by containing the same It is an object to provide a composition for preventing or treating lifestyle-related diseases such as the above.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that an extract obtained by extracting bald eagle and sakuhakuyo with a water-soluble solvent is a hakuto extract and a sakuyakuyo extract that are capable of accepting human β3 adrenaline. It has been found that it has a body agonistic action, and the present invention has been completed.

In other words, the present invention provides the following.
(1)
A human β3 adrenergic receptor agonist comprising as an active ingredient at least one selected from the group consisting of a bald eagle extract and a Saku Hakuyo extract.
(2)
The human β3 adrenergic receptor agonist agent according to (1), wherein the bald eagle extract is an extract obtained by extracting bald eagle with a water-soluble solvent.
(3)
The human β3 adrenergic receptor agonist agent according to (1), wherein the extract of Sakuhakuyo is an extract obtained by extracting Sakuhakuyo with a water-soluble solvent.
(4)
The human β3 adrenergic receptor agonist agent according to any one of (2) to (5), wherein the water-soluble solvent is a lower alcohol having 1 to 3 carbon atoms and having 10% by volume or more.
(5)
The human β3 adrenergic receptor agonist agent according to any one of (2) to (4), wherein the water-soluble solvent is an ethanol aqueous solution of 10% by volume or more.
(6)
A composition for the prevention or treatment of lifestyle-related diseases, comprising the human β3 adrenergic receptor agonist agent according to any one of (1) to (5) as an active ingredient.
(7)
The composition for preventing or treating a lifestyle-related disease according to (6), wherein the lifestyle-related disease is at least one disease selected from the group consisting of obesity, obesity, diabetes, hyperlipidemia, hypertension, and gout.
(8)
The lifestyle-related disease according to (6), wherein the lifestyle-related disease is selected from the group consisting of high body fat percentage, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, and hyperuricemia Or a composition for treatment.
(9)
A method for preventing or treating lifestyle-related diseases, comprising administering the composition according to any one of (6) to (8) to a mammal.
(10)
The method for preventing or treating a lifestyle-related disease according to (9), wherein the lifestyle-related disease is at least one disease selected from the group consisting of obesity, obesity, diabetes, hyperlipidemia, hypertension and gout.
(11)
The lifestyle-related disease according to (9), wherein the lifestyle-related disease is selected from the group consisting of high body fat percentage, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, and hyperuricemia Or treatment method.

  According to the present invention, a human β3 adrenergic receptor agonist agent derived from a safe natural material with experience of eating can be obtained. The composition containing the composition is useful as a composition for preventing or treating lifestyle-related diseases such as obesity, obesity, diabetes, hyperlipidemia, hypertension, gout and the like.

  Hereinafter, embodiments of the present invention will be described in detail.

  According to one aspect, the human β3 adrenergic receptor agonist of the present invention comprises at least one selected from the group consisting of a bald eagle extract and a Saku Hakuyo extract, and may be the extract itself.

  The bald eagle used in the present invention is the root of the broad-leaved clover, a plant of the genus Pulsatilla. In the present invention, any varieties of the genus Oxalis can be used, but the root of Pulsailla chinensis (Bge.) Regel. Is preferred.

  The Sakuhakuyo (acupuncture leaves) used in the present invention is a leaf of Konotegasiwa which is a plant of the cypress family Thuja, and is used that has been sun-dried after washing with water. In the present invention, any variety of the genus Kurobe can be used, but leaves of Thuja orientalis L. are preferred.

  In order to produce the human β3 adrenergic receptor agonist of the present invention, the bald eagle extract and / or the Astragalus extract used in the present invention can be obtained by solvent extraction or the like from the above-mentioned Bald eagle or Astragalus extract. In addition, the extract can be used in the present invention as an extract, or as a crude extract or a semi-purified extract, as long as it does not contain impurities inappropriate for beverages and pharmaceuticals. Hereinafter, when the amount of the human β-adrenergic receptor agonist agent is defined in the present specification, the amount means the dry matter amount of the extract unless otherwise specified.

  In the case of solvent extraction, for example, boiled beetle roots, leaves of Sakuhakuyo are kept in their original form, or pulverized or powdered, usually immersed in 1 to 20 times the amount of the following extraction solvent, and extracted by stirring and / or standing. Then, an extract can be obtained by filtration or centrifugation. Next, the extract can be obtained by removing the solvent from the resulting extract by concentration and / or concentration to dryness, if desired. The extraction solvent is preferably a water-soluble solvent from the viewpoint of efficiently extracting active ingredients. As far as this specification is concerned, the water-soluble solvent refers to water, a solvent miscible with water, or an aqueous solution thereof. Water, a water-miscible solvent or an aqueous solution thereof may contain other components such as sodium chloride, hydrogen ions, surfactants, saccharides and the like as long as the extraction efficiency is not adversely affected. When the water-soluble solvent is an aqueous solution, the concentration of the water-soluble solvent in the aqueous solution is not particularly limited. From the viewpoint of efficiently extracting active ingredients, the concentration of the water-soluble solvent is preferably an aqueous solution of 10% by volume to 100% by volume, more preferably 50% by volume to 100% by volume, and more preferably 70% by volume to 100% by volume. % Or less is still more preferable, and 90 volume% or more and 100 volume% or less is especially preferable. Of the water-soluble solvents, lower alcohols having 1 to 3 carbon atoms such as methanol, ethanol, and propanol are more preferable from the viewpoint of extraction efficiency, and ethanol is particularly preferable from the viewpoint of safety of the residual solvent. The extraction temperature of the water-soluble solvent is not particularly limited, and can generally be suitably carried out at -20 to 100 ° C, 1 to 80 ° C, preferably 20 to 60 ° C. The extraction time is not particularly limited, and it can be suitably carried out usually from 0.1 hour to 1 month, preferably from 0.5 hour to 7 days.

  In the present invention, the method for evaluating the action of a human β3 adrenergic receptor agonist is not particularly limited, and for example, it can be evaluated by using a cell expressing a human β3 adrenergic receptor. That is, in an in vitro experimental system, human β3 adrenergic receptor is stably expressed in animal cells such as CHO (cultured cells derived from Chinese hamster ovary), the extract is added to the cells, and intracellular cyclic It can be evaluated by measuring the increase in AMP concentration (AA Konkar, et al., J. Pharmacol. Exp. Ther., 291, 875-883, 1999; T. Kiso, et al., Biol. Pharm. Bull. , 22, 1073-1078, 1999). In addition, it can be evaluated by transfection of CRE-LUC reporter gene into cells stably expressing the human β3 adrenergic receptor, adding the extract and measuring luciferase activity (W. Zheng , et al., J. Med. Chem., 42, 2287-2994, 1999; SS Vansal & DR Feller, Biochem. Phaemacol., 58, 807-810, 1999). CRE-LUC is a reporter gene in which a luciferase (LUC) gene is bound to a cyclic AMP response element (CRE), and luciferase is expressed by increasing the intracellular cyclic AMP concentration. Specifically, according to the assay described in Example 3, those in which an increase in luciferase specific activity was significantly observed were evaluated as having human β3 adrenergic receptor agonist activity.

  Alternatively, in the above experimental system, instead of human β3 adrenergic receptor, cells expressing human β1 or β2 adrenergic receptor can be used to compare differences in β1, β2, and β3, and the selectivity can be compared. Can be evaluated.

  The human β3 adrenergic receptor agonist of the present invention can treat or prevent lifestyle-related diseases. Thus, in one aspect, the invention relates to a composition for treating or preventing lifestyle-related diseases.

  The lifestyle-related diseases referred to here are based on the opinion statement “Basic direction of disease countermeasures focusing on lifestyle” published by the Public Health Council (December 18, 1996). It refers to a group of diseases in which lifestyle habits such as eating habits, weekly exercise, rest, smoking, and drinking are related to the onset and progression. Examples of lifestyle-related diseases include, but are not limited to, at least one disease selected from the group consisting of obesity, obesity, diabetes, hyperlipidemia, hypertension and gout.

  The lifestyle diseases include obesity, obesity, diabetes, hyperlipidemia, hypertension, gout, high body fat percentage, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, and Examples include hyperuricemia.

Obesity and obesity here refer to obesity diagnostic criteria of the Japanese Society of Obesity. That is, obesity is defined as having a BMI (Body Mass Index: body weight (kg) / height (m) ² ) of 25 or more. Obesity is defined as obesity and health impairment due to obesity or visceral obesity fat obesity. The determination of visceral fat type obesity is a waist (diameter around the umbilicus) of 85 cm or more for men, 90 cm or more for women, or a visceral fat area by abdominal CT examination is 100 cm ² or more. Health disorders due to obesity are 1) type 2 diabetes, impaired glucose tolerance, 2) abnormal lipid metabolism, 3) hypertension, 4) hyperuricemia, gout, 5) coronary artery disease (myocardial infarction, angina) 6) Cerebral infarction (cerebral thrombosis / transient ischemic attack), 7) Sleep apnea syndrome / Pickwick syndrome, 8) Fatty liver, 9) Orthopedic disease (osteoarthritis / lumbar spondylosis), 10) At least one selected from the group consisting of menstrual abnormalities.

  In addition, the obesity includes a high body fat percentage state in which the body fat percentage is 25% or more for men and 30% or more for women. Examples of the type 2 diabetes / glucose-resistant brain disorder include conditions such as hyperglycemia and hyperinsulinemia. Examples of the type 2 diabetes / impaired glucose tolerance include conditions such as hypercholesterolemia, hypertriglyceridemia, high LDL-cholesterolemia, and low HDL-cholesterolemia.

As used herein, the high body fat percentage conforms to the obesity diagnostic criteria of the Japanese Society of Obesity. BMI (Body Mass Index: body weight (kg) / height (m) ² ) is 25 or more.

  As used herein, hyperinsulinemia follows the criteria of 75 g GTT (glucose tolerance test) of the Japanese Diabetes Society. A fasting blood glucose level is 126 mg / dl or more, and a GTT2 time value is 200 mg / dl or more.

  Hypercholesterolemia here refers to the criteria based on the guidelines of the Japanese Atherosclerosis Society. The serum total cholesterol concentration is 220 mg / dl or more, and the LDL-cholesterol concentration is 140 mg / dl or more.

  Hypertriglyceridemia referred to here follows the criteria based on the guidelines of the Japanese Atherosclerosis Society. The triglyceride (TG) value is 150 mg / dl or more.

  The term “hypertension” as used herein follows the criteria for determining hypertension of the World Health Organization / International Hypertension Society (WHO / ISH). The systolic blood pressure is 140 mmHg or more, or the diastolic blood pressure is 90 mmHg or more as occasional blood pressure measured multiple times.

  As used herein, hyperuricemia refers to the amount of total uric acid in the body (reflected by the serum uric acid level), which is determined by the balance between the amount of uric acid produced and the amount of excretion. A state in which the amount of uric acid is increased is hyperuricemia. Since the toxicity of hyperuricemia is mainly caused by uric acid (salt) crystals precipitated in the tissue, the serum uric acid level is 7.0 mg / dl or more regardless of gender due to the solubility of uric acid in body fluids.

  The composition for treating or preventing lifestyle-related diseases containing the human β3 adrenergic receptor agonist agent of the present invention can be used for food and drink and for medicine. In order to produce the composition of the present invention, the human β3 adrenergic receptor agonist agent of the present invention is mixed with other pharmaceutically acceptable formulation materials such as excipients, disintegrants, lubricants, binders, An antioxidant, a colorant, an anti-aggregation agent, an absorption accelerator, a solubilizing agent, a stabilizer and the like can be appropriately added and prepared. The form is not limited. For example, foods and drinks such as health functional foods (special health foods, nutritional functional foods), health foods, nutritional supplements, functional foods, or easily available pharmaceuticals or pharmaceuticals such as OTC It can be used as an outside product.

  When used as a food or drink, it can be taken directly as it is, or it can be ingested in a form that is easy to take, such as capsules, tablets, granules, using additives such as known carriers and auxiliaries. be able to. The content of the human β3 adrenergic receptor agonist of the present invention in these preparations is not particularly limited, but is preferably 0.1 to 100% by weight, more preferably 2 to 95% by weight, and still more preferably 10 to 90% by weight. It is. Furthermore, mixed with food and drink ingredients, confectionery such as chewing gum, chocolate, candy, jelly, biscuits and crackers; frozen confectionery such as ice cream and ice confectionery; beverages such as tea, soft drinks, energy drinks and beauty drinks; udon Noodles such as Chinese noodles, spaghetti and instant noodles; kneaded products such as salmon, bamboo rings and half pieces; seasonings such as dressings, mayonnaise and sauces; fats and oils such as margarine, butter and salad oil; bread, ham, soup, retort food, It can be used for all foods and drinks such as frozen foods. When ingesting the preventive / ameliorating agent of the present invention for eating and drinking, the intake is preferably 0.01 to 1000 mg / kg weight, more preferably 0.1 to 100 mg / kg weight per adult day as the extract. is there.

  When used as a pharmaceutical, the dosage form is not particularly limited, and examples thereof include capsules, tablets, granules, injections, suppositories, and patches. In formulation, other pharmaceutically acceptable formulation materials such as excipients, disintegrants, lubricants, binders, antioxidants, colorants, anti-aggregation agents, absorption enhancers, solubilizers An agent, a stabilizer and the like can be added as appropriate. The dosage of these preparations is preferably 0.01 to 1000 mg / kg body weight, more preferably 0.1 to 100 mg / kg body weight per adult day per day in terms of the extract, divided into 1 to several times. Administer.

  When used as a quasi-drug, other additives are added as necessary, for example, ointments, liniments, aerosols, creams, soaps, facial cleansers, whole body cleansers, lotions, lotions, baths It can be used for agents and the like, and can be used locally.

  In the method for preventing or treating lifestyle-related diseases, which is one aspect of the present invention and characterized by administering the above composition to a mammal, the mammal is not particularly limited, but a human is preferable. Administration here is not particularly limited, but includes enteral administration such as oral and sublingual administration: parenteral administration such as transdermal, intravenous, intraperitoneal, nasal, and intraocular administration. Oral administration is preferred.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1
(Preparation method of baldness extract)
The baldness root (Shinwa product) is cut into small pieces and pulverized with a pulverizer, and 2 g of the pulverized product is extracted with 10 ml of 99.5 vol% ethanol / water (room temperature (23-24 ° C.), dark place, 3 days. The solution was filtered and concentrated to dryness to obtain 113.6 mg of Hakuto extract.

(Example 2)
(Method for preparing Sakuhakuyo extract)
Extract 2g powder of Sakuhakuyo leaf (Shinwa product) with 10ml 99.5 vol% ethanol / water (room temperature (23-24 ° C), left in the dark for 3 days), filter and concentrate to dryness , 83.6 mg of sanjak extract was obtained.

(Example 3)
(Method for measuring human β3 adrenergic receptor agonist activity)
CHO-K1 cells (cultured cells derived from Chinese hamster ovary) were transfected with a human β3 adrenergic receptor gene expression plasmid using Lipofectamine ^™ 2000 (Invitrogen), which is a gene introduction reagent, and human. Cells expressing the β3 adrenergic receptor (hereinafter referred to as β3 / CHO cells) were obtained.

Day 1 of experiment: β3 / CHO cells were seeded in a 96-well culture plate at 3 × 10 ⁴ cells / well and cultured under conditions of 37 ° C. and 5% CO ₂ for about 24 hours. As the medium, an HD medium containing 5% FBS (fetal bovine serum) was used. HD medium is Ham F-12 (SIGMA) 5.35 g / L, DMEM (GIBCO) 4.75 g / L, L-glutamine (Wako Pure Chemical Industries) 0.59 g / L, CaCl ₂ · 2H ₂ O (Wako Pure Chemical Industries) was prepared with a composition of 0.044 g / L and sodium bicarbonate (GIBCO) 1.27 g / L.

Experiment Day 2: Cells were transfected with pCRE-luc (STRATAGENE) using Lipofectamine ^™ 2000 (Invitrogen). After 6 hours, the medium was changed to a new medium and cultured overnight. PCRE-luc is a reporter plasmid in which a luciferase gene is bound to a cyclic AMP response element (CRE).

Experiment Day 3: The medium was replaced with the sample and cultured for 6 hours. Samples dissolved in dimethyl sulfoxide (DMSO) were added to the medium at 1/1000 volume to obtain the concentrations shown in Table 1. DMSO was used as an untreated control, and BRL37344 (TOCRIS), which is a selective β3 adrenergic receptor agonist, was used as a positive control. After washing the cells with Ca, Mg-containing phosphate buffered saline (PBS +), Looklite ^™ (Perkin Elmer), a luminescence measurement reagent with luciferase, was added, and TopCount ^™ micro scintillation / luminescence counter (Perkin Elmer) The luminescence intensity of luciferase was measured. The ratio to the luciferase luminescence intensity of the untreated control was taken as the luciferase specific activity of the sample.

  Table 1 shows the results of measurement on the bald eagle extract obtained in Example 1 and the Alaska extract obtained in Example 2.

陽性対照のＢＲＬ３７３４４では、ルシフェラーゼ比活性の上昇が認めたれた。つまり、ＢＲＬ３７３４４はヒトβ３アドレナリン受容体を介して細胞内サイクリックＡＭＰ濃度を上昇させルシフェラーゼを発現させていることから、ＢＲＬ３７３４４のヒトβ３アドレナリン受容体アゴニスト作用が確認された。

In the positive control BRL37344, an increase in luciferase specific activity was observed. That is, BRL37344 increased the intracellular cyclic AMP concentration via the human β3 adrenergic receptor and expressed luciferase, confirming the action of BRL37344 on the human β3 adrenergic receptor agonist.

  Both the bald eagle extract of Example 1 and the Sakuhakuo extract of Example 2 have an increase in luciferase specific activity as in the positive control BRL37344, and have human β3 adrenergic receptor agonist activity. There was found.

Example 4
25 parts by weight of a bald pea extract obtained in the same manner as in Example 1, 150 parts by weight of coconut oil, 70 parts by weight of grape seed oil, and 5 parts by weight of vitamin E are mixed to contain a bald pea extract. A soft capsule for food and drink was prepared.

(Example 5)
2 parts by weight of Sakuhakuyo extract obtained in the same manner as in Example 2, 20 parts by weight of squalane, 10 parts by weight of olive oil, 5 parts by weight of purified beeswax, 3 parts by weight of glycerin monosaleate, and 2 parts of cetoste alcohol A skin cream containing an extract of Sakuhakuyo, mixed and emulsified in a composition of 3 parts by weight, 3 parts by weight of polyoxyethylene hydrogenated castor oil, 10 parts by weight of glycerin, 3 parts by weight of vitamin C and 42 parts by weight of purified water Prepared.

Claims (11)

  A human β3 adrenergic receptor agonist comprising as an active ingredient at least one selected from the group consisting of a bald eagle extract and a Saku Hakuyo extract.   The human β3 adrenergic receptor agonist agent according to claim 1, wherein the bald eagle extract is an extract obtained by extracting bald eagle with a water-soluble solvent.   The human β3 adrenergic receptor agonist agent according to claim 1, wherein the extract is obtained by extracting Sakusakuyo with a water-soluble solvent.   The human β3 adrenergic receptor agonist agent according to any one of claims 2 to 5, wherein the water-soluble solvent is a lower alcohol having 1 to 3 carbon atoms and having 10% by volume or more.   The human β3 adrenergic receptor agonist agent according to any one of claims 2 to 4, wherein the water-soluble solvent is an ethanol aqueous solution of 10% by volume or more.   A composition for the prevention or treatment of lifestyle-related diseases comprising the human β3 adrenergic receptor agonist agent according to any one of claims 1 to 5 as an active ingredient.   The composition for preventing or treating a lifestyle-related disease according to claim 6, wherein the lifestyle-related disease is at least one disease selected from the group consisting of obesity, obesity, diabetes, hyperlipidemia, hypertension, and gout.   The prevention of lifestyle-related diseases according to claim 6, wherein the lifestyle-related diseases are selected from the group consisting of high body fat percentage, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, and hyperuricemia. Or a composition for treatment.   A method for preventing or treating lifestyle-related diseases, comprising administering the composition according to any one of claims 6 to 8 to a mammal.   The method for preventing or treating a lifestyle-related disease according to claim 9, wherein the lifestyle-related disease is at least one disease selected from the group consisting of obesity, obesity, diabetes, hyperlipidemia, hypertension and gout.   The lifestyle-related disease according to claim 9, wherein the lifestyle-related disease is selected from the group consisting of high body fat percentage, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, and hyperuricemia. Or treatment method.