JPWO2007040005A1 - Peroxisome proliferator-responsive receptor PPARα activator, and composition for preventing or ameliorating specific symptoms containing the activator - Google Patents

Abstract

It contains at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ8-dihydroabietic acid and 12-sulfodehydroabietic acid or a pharmaceutically acceptable salt thereof as an active ingredient. A peroxisome proliferator-responsive receptor α activator. The activator is useful for preventing or ameliorating at least one symptom selected from the group consisting of insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver.

Description

  The present invention relates to a peroxisome proliferator-responsive receptor α activator and a composition for preventing or ameliorating specific symptoms containing the activator. More specifically, it acts as a peroxisome proliferator-responsive receptor α activator and is at least one selected from the group consisting of insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver The present invention relates to a composition having an action of preventing or improving symptoms.

  Peroxisome proliferator-responsive receptors (PPARs) are activator-dependent transcriptional regulators belonging to the nuclear receptor family responsible for controlling the expression of genes involved in lipid and sugar metabolizing sugars. Three types of PPARs are known: PPAR-α, PPAR-δ, and PPAR-γ. PPAR-γ is mainly expressed in adipose tissue, immune cells, adrenal gland, spleen and small intestine, PPAR-α is expressed mainly in adipose tissue, liver, kidney and skeletal muscle, and PPAR-δ is mainly observed in tissue specificity. It is known that it is expressed universally (Non-Patent Document 1).

Among these PPAR subtypes, PPAR-α has been reported to be activated by drugs such as long chain fatty acids, clofibrate, fenofibrate, bezafibrate, gemfibrozil (see Non-Patent Documents 2 and 3). PPAR-α activators are known to increase fatty acid metabolism and lower blood triglyceride levels, and are useful as preventive or therapeutic agents for hyperlipidemia and the like. Furthermore, it has been reported that PPAR-α activator improves not only lipid metabolism but also glucose metabolism, and exhibits effects such as lowering blood lipid, lowering blood glucose level, improving insulin resistance, etc. (See Patent Documents 4, 5, 6, 7, and 8), and is effective as an agent for preventing and / or improving hyperlipidemia, type 2 diabetes, hyperglycemia, insulin resistance, obesity and the like. However, these compounds have problems such as side effects due to long-term use, and development of safer preventive or therapeutic drugs is desired.
Ayumi of Medicine, 1998, 184, 519-523 Journal of the National Cancer Institute, 1998, 90, 1702-1709 Current Opinion in Lipidology, 1999, 10, 245-257 Japan Clinical, 2005, 63, 4, 539-548 Japan Clinical, 2005, 63, 4, 549-555 Japanese Clinical, 2005, 63, 4, 557-564 Japan Clinical, 2005, 63, 4, 631-642 Diabetes, 2001, 50, 411-417

  The present invention provides a highly safe and useful peroxisome proliferator-responsive receptor α activator, and insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, hyperlipidemia, hypertension, etc. It aims at providing the composition which has the effect | action which prevents or improves this.

As a result of diligently examining the relationship with activation of the peroxisome proliferator-responsive receptor α, focusing on the resin acid component contained in the natural product rosin, which has not been studied previously, A specific resin acid or a derivative thereof in rosin, that is, at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid, or pharmaceutically It was found that an acceptable salt has an excellent peroxisome proliferator-responsive receptor α activating action, and further research has been made based on this finding to complete the present invention.

That is, the present invention
(1) Contains at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydrobietic acid or a pharmaceutically acceptable salt thereof as an active ingredient A peroxisome proliferator-responsive receptor α activator, characterized by
(2) The peroxisome proliferator-responsive receptor α activator according to (1) above for preventing or ameliorating a disease or symptom mediated by peroxisome proliferator-responsive receptor α,
(3) The peroxisome proliferation according to (2) above, wherein the disease or symptom mediated by the peroxisome proliferator-responsive receptor α is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver Agent-responsive receptor α activator,
(4) The peroxisome proliferator-responsive receptor α activator according to (1) above, which is a composition for preventing or improving insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver ,
(5) Insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver characterized by containing the peroxisome proliferator-responsive receptor α activator according to (1) Preventive or ameliorating composition,
(6) The composition for prevention or improvement according to the above (5), which is a pharmaceutical composition,
(7) The composition for prevention or improvement according to (5), which is a food,
(8) at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid, or a pharmaceutically acceptable salt thereof, and peroxisome A food characterized by displaying that a disease or symptom mediated by a proliferative drug responsive receptor α is prevented or ameliorated,
(9) The food according to (8) above, wherein the disease or symptom mediated by the peroxisome proliferator-responsive receptor α is insulin resistant type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver,
(10) The patient having a disease or symptom mediated by the peroxisome proliferator-responsive receptor α is selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid A method for preventing or ameliorating a disease or symptom mediated by a peroxisome proliferator-responsive receptor α, comprising administering at least one compound or a pharmaceutically acceptable salt thereof, and (11) a peroxisome proliferator responsiveness at least one selected from the group consisting of dihydroabietic acid and 12 sulfodehydroabietic acid - receptor α is dehydroabietic acid for the manufacture of a medicament for preventing or ameliorating a disease or condition mediated, Merukushi acid, 13β-Δ ⁸ Or a pharmaceutically acceptable salt thereof ,
About.

Which is the active ingredient dehydroabietic acid in the peroxisome proliferator-activated receptor α activator of the present invention, Merukushi acid, 13β-Δ ⁸ - dihydroabietic acid and 12 sulfodehydroabietic acid or a pharmaceutically acceptable salt thereof All have an excellent peroxisome proliferator-activated receptor α activation action and are highly safe because they are derived from natural products. Therefore, the peroxisome proliferator-responsive receptor α activator of the present invention or a composition containing the same is a group consisting of insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver It is useful for preventing or ameliorating at least one symptom selected from more, and can be applied to medicines or foods.

Hereinafter, the present invention will be described in detail.
The peroxisome proliferator-responsive receptor α activator of the present invention is at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid, or a compound thereof It contains a pharmacologically acceptable salt as an active ingredient.

The structural formula of the active ingredient (free acid) in the peroxisome proliferator-responsive receptor α activator of the present invention is as follows.

Among the active ingredients, dehydroabietic acid and mercucic acid are generally called resin acids, and are amber transparent glassy resin having a softening point of about 70 to 80 ° C. obtained by refining pine resin produced from pine trees ( Rosin). 13β-Δ ⁸ -dihydroabietic acid is a component of hydrogenated rosin obtained by hydrogenating rosin. 12-Sulfodehydroabietic acid is a sulfonated product of dehydroabietic acid. Each of these is a known compound, but it has never been known as an active ingredient of the peroxisome proliferator-responsive receptor α activator before this application.

The compound as the active ingredient can be easily isolated, purified or synthesized by a known method. For example, in the case of mercuric acid, the method described in JP-A No. 51-131899, and in the case of dehydroabietic acid, the method described in Journal of Organic Chemistry, 1966, Vol. 31, pages 4246-4247, Merck In the case of acid, the method described in Holzforshung, 1974, Vol. 28, pages 186-188, and in the case of 13β-Δ ⁸ -dihydroabietic acid, it is described in JP-A-51-149256. In the case of 12-sulfodehydroabietic acid, the method described in JP-A-58-77814 can be adopted. In the peroxisome proliferator-responsive receptor α activator of the present invention, at least one resin acid purified or isolated by the above method or a pharmaceutically acceptable salt thereof is used alone or in appropriate combination. Also good.

  When the active ingredient of the present invention is a salt, the salt includes all pharmacologically acceptable ones. A pharmacologically acceptable salt is preferably a less toxic salt. Suitable salts include, for example, alkali metal (potassium, sodium, lithium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts (tetramethylammonium salts, tetrabutylammonium salts, etc.) or organic amines ( And salts of triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D-glutamine, etc. It is done.

The PPARα activation action (PPARα agonist activity) of these active ingredients can be measured, for example, by a method such as FB Letters, 2002, 514, 315-322. That is, a plasmid (pM-PPARα) that produces a chimeric protein of a ligand binding site of PPAR-α and a DNA binding site of GAL4 (yeast DNA-binding transcription factor activator), and upstream of a luciferase gene that is a reporter gene A plasmid (4 × UASg-luc) in which four response elements (UASg) of GAL4 are incorporated was cotransfected into cultured cells of African green monkey kidney (CV-1) by the lipofection method, and the resulting transformant was obtained. After culturing for a certain period, the PPARα-GAL4 chimeric protein is activated by contacting with a test compound, and the binding to UASg upstream of 4 × UASg-luc is enhanced, thereby increasing the production of luciferase. The PPARα activation effect can be evaluated by measuring the activity of the produced luciferase.
In the above measurement method, the ligand binding site of PPAR-α is the amino acid sequence 201- in the human PPAR-α amino acid sequence (see http://www.genome.jp/dbget-bin/www_bget?sp:PPAT_HUMAN). This corresponds to 463. The protein at the DNA binding site of GAL4 (yeast DNA-binding transcription factor activator) is the amino acid sequence of GAL4 (see http://www.genome.jp/dbget-bin/www_bget?sp:GAL4_YEAST). Corresponds to the amino acid sequence 1-147.

  The active ingredient of the present invention exhibits a glucose metabolism improving action, a lipid metabolism improving action, a hypoglycemic action, a body fat accumulation inhibiting action, a visceral fat accumulation inhibiting action, an insulin reducing action, etc. based on the PPARα activation action. The active ingredient of the present invention has an action of reducing cytokines (for example, MCP-1), which is an inflammatory factor associated with obesity. Therefore, the peroxisome proliferator-responsive receptor α activator of the present invention is useful as an agent for preventing and improving lifestyle-related diseases and metabolic syndrome associated with obesity, and more specifically, insulin resistance, type 2 It is useful as a preventive / ameliorating agent for diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver.

  When the peroxisome proliferator-responsive receptor α activator of the present invention and a composition comprising the same (hereinafter, both are also referred to as a preparation) as a medicine, an oral preparation, an injection, an external preparation, Suppositories or inhalants. Examples of oral preparations include dosage forms such as tablets, granules, fine granules, powders, capsules, solutions, emulsions, suspensions, and syrups. These preparations can be produced by a method known per se. For example, in the case of granules, fine granules, powders and tablets, the active ingredient of the present invention and pharmaceutically acceptable additives such as excipients (eg lactose, starch, sucrose, glucose, mannitol) , Starch, inorganic salts, etc.), lubricants (eg, talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, etc.), disintegrants (eg, carmellose, carmellose) Calcium, starch, crystalline cellulose, low-substituted hydroxypropylcellulose, etc.), binder (eg starch, dextrin, gum arabic powder, hydroxypropyl starch, crystalline cellulose, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl Mix by known methods, etc.) together with such pyrrolidone, granulation, it can be produced by tabletting or grinding. For granules and tablets, suitable coating agents (eg, gelatin, sucrose, gum arabic, carnauba wax, etc.), enteric coating agents (eg, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylcellulose phthalate, carboxy) The coating may be applied with methyl ethyl cellulose or the like.

  When manufactured as a capsule, the active ingredient of the present invention is mixed evenly with known excipients, or granulated or granulated, and if necessary, coated with an appropriate coating agent, and then capsules Or may be encapsulated with a capsule base that has increased plasticity by adding glycerin or sorbitol to a suitable capsule base (eg gelatin). Examples of the excipient include magnesium stearate, calcium stearate, talc or light anhydrous silicic acid for improving fluidity and lubricity, crystalline cellulose and lactose for pressurized fluidity, or the above disintegrant. Etc.

  When manufactured as an emulsion, suspension, or syrup, for example, a stabilizer (eg, sodium edetate), a suspending agent (eg, gum arabic, carmellose, etc.), a corrigent (eg, simple syrup, glucose) Etc.), fragrance, purified water, ethanol, vegetable oil, emulsifier and the like can be appropriately selected and used.

  The injection may be either an aqueous injection or an oily injection. In the case of an aqueous injection, according to a known method, for example, an aqueous solvent (eg, distilled water for injection, physiological saline, aqueous glucose solution, etc.) and a pharmaceutically acceptable additive such as an isotonic agent (eg, Sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, glucose, propylene glycol, etc.), buffer (eg phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, Epsilon aminocaproic acid buffer, etc.), preservative (eg, chlorobutanol, etc.), thickener (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.), stabilizer (eg, sodium bisulfite, thio) Sodium sulfate, sodium edetate, sodium citrate, ascorbic acid, etc. , Suspension agents (eg, gum arabic, tragacanth, dextrin, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium alginate, carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, bentonite, bee gum, silicic anhydride, etc.) A solution to which an emulsifier (sodium lauryl sulfate, sorbitan, fatty acid ester, polyoxyethylene sorbitan, polyoxyethylene fatty acid ester, monoglyceride, etc.) or a pH adjuster (eg hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.) is appropriately added In addition, after dissolving the active ingredient of the present invention, it can be prepared by sterilizing by filtration through a filter or the like and then filling in an aseptic container. Further, suitable solubilizers such as alcohol (ethanol, etc.), polyalcohol (propylene glycol, polyethylene glycol, etc.), nonionic surfactants (polysorbate 80, polyoxyethylene hydrogenated castor oil 50, etc.) may be used. . In the case of an oily injection, examples of the oily solvent include sesame oil, peanut oil, soybean oil, corn oil and the like, and benzyl benzoate, benzyl alcohol and the like may be used as a solubilizing agent. The prepared injection solution is usually filled in an appropriate ampoule or vial. The concentration of the active ingredient of the present invention in the injection is usually adjusted to about 0.001 to 10.0 w / v%, preferably about 0.005 to 5.0 w / v%.

  Examples of external preparations include ointments, creams, lotions, and the like. In the case of ointments and creams, for example, water-absorbing ointments, hydrophilic ointments, simple ointments, white ointments or macrogol ointments, stearyl alcohol, It can be prepared by a conventional method such as mixing with a known base such as cetanol, paraffin, liquid paraffin, beeswax and coconut oil.

  Lotion agents may contain commonly used additives. For example, such additives include suspending agents, emulsifiers, wetting agents (eg glycerin, propylene glycol, sorbitol, 1,3-butylene glycol). , Dl-pyrrolidone carboxylic acid, sodium lactate, etc.) or preservatives (eg paraoxybenzoates, benzalkonium chloride, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sodium edetate, boric acid, borax, etc.) Is mentioned. Using these additives, a lotion preparation can be prepared according to a conventional method.

  Suppositories can also be prepared in a conventional manner using a conventional base (for example, cacao butter, laurin butter, glycerogelatin, macrogol, witepsol).

  Inhalants can also be adjusted by conventional means on formulations. When manufactured as an inhalant, the additive may be any additive as long as it is generally used in inhalable preparations. For example, in addition to a propellant, the above-described excipients and binders. , Lubricants, preservatives, stabilizers, tonicity agents, pH adjusters or flavoring agents (citric acid, menthol, glycyrrhizin ammonium salt, glycine, fragrance, etc.) and the like are used. As the propellant, a liquefied gas propellant, a compressed gas, or the like is used. Examples of the liquefied gas propellant include fluorinated hydrocarbons (alternative chlorofluorocarbons such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, dimethyl ether, and the like. Examples of the compressed gas include soluble gas (carbon dioxide gas, nitrous oxide gas, etc.), insoluble gas (nitrogen gas, etc.), and the like.

  When the preparation of the present invention is used as a pharmaceutical, the dose of the active ingredient varies depending on the age, body weight, degree of disease, and dosage form of the patient. For example, in the case of an injection, the dose for an adult is usually about 0 by weight. 0.01 mg to 1 g / day, and in the case of oral preparations, the weight is usually about 0.01 mg to 1 g / day.

  When the preparation of the present invention is used as a food, additives that are acceptable as food additives (eg, glucose, fructose, sucrose, maltose, sorbitol, stevioside, rubusoside, corn syrup, lactose, citric acid, tartaric acid, malic acid Succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, Arabia Gum, carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, fragrances or preservatives, etc.) by known methods Tablets, granules, can be a capsule or the like.

  Moreover, the formulation of this invention can also be mixed with another food ingredient, and can also be used as a foodstuff. In this case, other food ingredients are not particularly limited and can be used for various foods. Examples of foods that can be used include soy sauce, powdered soy sauce, miso, powdered miso, moromi, horsetail, fried potatoes, mayonnaise, dressing, vinegar, three cups of vinegar, powdered sushi vinegar, tentsuyu, noodle soup, sauce, ketchup, grilled meat sauce, Curry roux, Chinese element, Stew element, Soup element, Dashi element, Compound seasoning, Seasoning such as mirin, new mirin, table sugar or coffee sugar, rice cracker, hari, okono, flower forest sugar, fertilizer, salmon, manju , Japanese confectionery such as Uiro, An-an, Yokan, Mizuhama, Nishidama, Jelly, Castella or Jasper, biscuits, crackers, cookies, pie, pudding, cream puffs, waffles, sponge cake, donuts, chocolate, chewing gum, caramel, Candy such as candy or gummy jelly, ice cream, ice cream Ice confectionery such as day or sherbet, syrup such as ice honey, spread and paste such as butter cream, custard cream, flower paste, peanut paste or fruit paste, processed fruit and processed vegetables such as jam, marmalade, syrup pickles or confectionery, bread Processed cereal foods such as noodles, cooked rice or artificial meat, fat and oil foods such as salad oil or margarine, pickles such as Fukujinzuke, bedara-zuke, Senkage-zuke or ryakyou-zuke, pickled elements such as takuanzuke or Chinese cabbage, ham Or meat products such as sausage, fish meat ham, fish sausage, fish products such as sea cucumber, chikuwa or hampen, sea salt of sea urchin, squid salt, vinegar kumbu, vinegar kumbu, sardine or puffer fish Boiled, grilled, and fried food produced from marine products Foods, fried foods, steamed foods, fried foods, shrimp fries, croquettes, shumai, gyoza, spring rolls, hamburger steaks, meatballs, fish hamburgers or fish balls, frozen cooked foods, hamburgers, meatballs, red rice, beef meals, Tori-Kamameshi, Brown rice soup, Curry, Meat sauce, Domigrassa sauce, Potage soup, Consomme soup, Stew, Oden, Happo greens, Boiled beans, Yakitori, Chawanmushi or Boiled vegetables, Boiled egg, Milk drink, Butter Or egg products such as cheese and dairy products, bottled and canned fish, livestock meat, fruits or vegetables, alcoholic beverages such as synthetic liquor, brewed liquor, fruit liquor or Western liquor, coffee, cocoa, juice, tea, tea, oolong tea, minerals Soft drinks such as beverages, carbonated beverages, lactic acid beverages or lactic acid bacteria beverages, And instant food such as instant cakes, hot cake mixes, instant juice, instant shirako or instant soup.

  The content of the preparation of the present invention in the food varies depending on the type of food, but the content of the active ingredient is usually about 0.001 to 0.1% by mass.

  Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.

[Example 1]
(Method for measuring PPAR-α ligand activity)
CV-1 cells (cultured cells derived from male African green monkey kidney) were implanted in a 96-well culture plate at 6 × 10 ³ cells per well, and cultured at 37 ° C. under 5% CO ₂ for 24 hours. 10% FBS (fetal bovine serum), 10 ml / L penicillin / streptomycin solution (each 5000 IU / ml, 5000 μg / ml, manufactured by GIBCO), 37 mg / L ascorbic acid (manufactured by Wako Pure Chemical Industries, Ltd.) DMEM (Dulbeccos Modified Eagle Medium: manufactured by GIBCO) was used. After the cells were washed with OPTI-MEM (GIBCO), pM-PPARα and 4 × UASg-luc were transfected using Lipofectamine Plus (GIBCO). PM-PPARα is a plasmid in which a gene for a chimeric protein linked with a human PPAR-α ligand binding site gene (amino acid sequence 201-463) is inserted, and 4 × UASg-luc is a response of GAL4 upstream of the luciferase gene. It is a reporter plasmid in which the sequence (UASg) is incorporated four times (can be prepared by the method described in Cell, 1995, 83, 803-812). About 24 hours after transfection, the medium was replaced with a medium containing each test compound (n = 4) and cultured for 24 hours. The test compound was dissolved in dimethyl sulfoxide (DMSO), DMSO was used as an untreated control, and 1/1000 amount was added to the medium. After washing the cells with Ca, Mg-containing phosphate buffered saline (PBS +), Looklite (Packard) was added, and luciferase luminescence was performed using a top-count microplate scintillation / luminescence counter (Packard). The strength was measured.
As in the measurement group, measurement was performed using pM instead of pM-PPARα as a control group. For each test compound, the ratio (measurement group / control group) of the average value (n = 4) of the luminescence intensity of the measurement group and the control group was calculated, and the specific activity relative to the untreated control was determined as the PPAR-α ligand activity of each test compound. It was. The results are shown in Table 1.

[Example 2]
(Animal experiments for improving carbohydrate metabolism and lipid metabolism of compositions having PPARα activity)
Four weeks old male KKAy hereditary obese / diabetic mice (manufactured by CLEA Japan) were preliminarily raised for 6 days with commercially available solid feed (manufactured by CLEA Japan), divided into 4 groups as 6-7 animals per group, and basic purification A predetermined amount of a test compound shown in Table 2 below was added to a high-fat diet (protein energy ratio 20%, carbohydrate energy ratio 20%, fat energy ratio 60%, D12492 manufactured by Research Diet) or a basic purified high-fat diet. The samples were reared for 5 weeks by pair feeding.

During the test period, blood glucose level was measured, and after 5 weeks, body weight was measured, sacrificed, intraperitoneal fat weight and blood parameters were measured, blood glucose level, leptin, insulin and MCP-1 secretion, abdominal cavity The ratio of internal fat mass to body weight was determined. The results are as shown in Tables 3-7. Statistical analysis is performed with a paired t-test, and an asterisk ( ^{*) in} the table indicates that there is a significant difference at a risk rate of less than 5% compared to the control.

上記表から、デヒドロアビエチン酸投与群は、コントロール群に比べ有意に血糖値上昇を抑制すると共に、レプチン、インスリン、ＭＣＰ−１の濃度および腹腔内脂肪量／体重が有意に低下したことがわかる。この結果より、デヒドロアビエチン酸は、糖・脂質の代謝改善作用、内臓脂肪蓄積抑制作用、高インスリン血症の改善作用を有することが明らかである。

From the above table, it can be seen that the dehydroabietic acid administration group significantly suppressed the increase in blood glucose level as compared with the control group, and the concentrations of leptin, insulin, MCP-1 and intraperitoneal fat mass / body weight significantly decreased. From these results, it is clear that dehydroabietic acid has an action to improve sugar / lipid metabolism, an inhibitory action on visceral fat accumulation, and an action to improve hyperinsulinemia.

[Example 3]
(Measurement of anti-inflammatory activity of a composition having PPARα activity in vitro)
Inhibition of the inflammatory cytokine MCP-1 secreted from RAW264.7 cells (mouse-derived macrophage-like cell line) was evaluated.
That is, RAW264.7 cells were suspended in the DMEM medium described in Example 1, and the suspension (1 × 10 ⁶ cells / ml) was dispensed into a 12-well culture plate at 2000 μl per well, followed by 37 ° C. CO _2. After culturing for 2 hours in an incubator, 2 μl of lipopolysaccharide (LPS, 100 ng / ml, Sigma) per well and a predetermined amount of dehydroabietic acid were added and stimulated for 16 hours in a 37 ° C. CO ₂ incubator. Subsequently, the culture supernatant was recovered, and the production amount of MCP-1 in the supernatant was quantified by ELISA using a conventional method, and the mRNA expression level was quantified by real-time PCR using a conventional method. MCP-1 secretion amount and MCP-1 mRNA expression level were expressed as relative values when the control was 100%. The results are shown in Tables 8 and 9. Statistical analysis is performed with a paired t-test. In the table, asterisk ( ^*) indicates that there is a significant difference with a risk rate of less than 5% compared to the control, and ^** indicates a significant difference with respect to the risk rate of less than 1%.

  From the above table, in each RAW264.7 cell to which dehydroabietic acid was added after LPS stimulation, the secretion of MCP-1 at the protein level was significantly suppressed as compared to the control, and the expression was also significantly suppressed at the mRNA level. You can see that From this result, it is clear that dehydroabietic acid has an anti-inflammatory activity, that is, an anti-inflammatory activity related to obesity due to a decrease in MCP-1, which is an inflammatory factor.

[Formulation Example 1]
(tablet)
Dehydroabietic acid 5.0g
Corn starch 12.0g
Lactose 22.6g
Magnesium stearate 0.4g
Add each of the above ingredients and mix well to make tablets for tableting according to the wet tablet preparation method. Tablet with magnesium stearate added to give 400 tablets. Tablets may be sugar-coated as necessary.

[Formulation Example 2]
(Food)
300 g of starch syrup was heated and melted at 150 ° C. in 650 g of sugar, cooled to 120 ° C., 10 g of citric acid was added, 3 g of 13β-Δ ⁸ -dihydroabietic acid and 10 g of fragrance were added, and the mixture was stirred and homogenized. Later, it is molded and cooled to obtain a candy.

  The peroxisome proliferator-responsive receptor α activator according to the present invention is used in medicines or foods for suppressing or preventing insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, etc., hyperlipidemia, hypertension, etc. be able to.

Claims (11)

It contains at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid or a pharmaceutically acceptable salt thereof as an active ingredient. A peroxisome proliferator-responsive receptor α activator.   The peroxisome proliferator-responsive receptor α activator according to claim 1 for preventing or ameliorating a disease or condition mediated by peroxisome proliferator-responsive receptor α.   The peroxisome proliferator according to claim 2, wherein the disease or symptom mediated by the peroxisome proliferator-responsive receptor α is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver. Responsive receptor α activator.   The peroxisome proliferator-responsive receptor α activator according to claim 1, which is a composition for preventing or improving insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver.   Insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver prevention, comprising the peroxisome proliferator-responsive receptor α activator according to claim 1 Or an improving composition.   The composition for prevention or improvement according to claim 5, which is a pharmaceutical composition.   The composition for prevention or improvement according to claim 5, which is a food. A peroxisome proliferator response containing at least one compound selected from the group consisting of dehydroabietic acid, mercucic acid, 13β-Δ ⁸ -dihydroabietic acid and 12-sulfodehydroabietic acid or a pharmaceutically acceptable salt thereof A food characterized by showing that a disease or symptom mediated by sex receptor α is prevented or ameliorated.   The food according to claim 8, wherein the disease or symptom mediated by the peroxisome proliferator-responsive receptor α is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver. To a patient having a disease or condition peroxisome proliferator-activated receptor α mediated, dehydroabietic acid, Merukushi acid, 13β-Δ ⁸ - of at least one selected from the group consisting of dihydroabietic acid and 12 sulfodehydroabietic acid A method for preventing or ameliorating a disease or symptom mediated by a peroxisome proliferator-responsive receptor α, which comprises administering a compound or a pharmaceutically acceptable salt thereof. Dehydroabietic acid, Merukushi acid for the manufacture of a medicament for peroxisome proliferator-activated receptor α is preventing or ameliorating a disease or condition mediated, 13β-Δ ⁸ - the group consisting of dihydroabietic acid and 12 sulfodehydroabietic acid Use of at least one compound selected from the above or a pharmaceutically acceptable salt thereof.