WO2004045632A1

WO2004045632A1 - Peroxisome proliferator-activated recetor ligand

Info

Publication number: WO2004045632A1
Application number: PCT/JP2003/014295
Authority: WO
Inventors: Tozo Nishiyama; Misuzu Tsukagawa; Tatsumasa Mae
Original assignee: Kaneka Corporation
Priority date: 2002-11-12
Filing date: 2003-11-11
Publication date: 2004-06-03
Also published as: JPWO2004045632A1; TW200507865A; AU2003277665A1

Abstract

A peroxisome proliferator-activated receptor (PPAR) ligand containing as the active ingredient a fennel extract, which is a safe food material, has a highly excellent PPAR ligand activity and is useful as a preventive and/or an improving agent for hyperlipemia, diabetes, obesity and inflammation. As the fennel, at least one member selected from among sweet fennel, bronze fennel, Florence fennel, bitter fennel and German fennel is preferable. As the extract, one obtained by extracting fennel with a solvent (preferably ethanol) is preferable. One extracted from a dry fennel powder is still preferable.

Description

Description Peroxisome proliferator-activated receptor ligand agent

The present invention relates to a ligand for a peroxisome proliferator-activated receptor (peroxisomeprolyf-e-r-at-or-acti-v-at-t-d-e-rec: PPAR) ligand agent. Further, the present invention provides a prophylactic and / or Z- or ameliorating agent for human or animal hyperlipidemia, diabetes, obesity, inflammation, etc., which comprises a PPAR ligand agent as an active ingredient, and a PPAR ligand agent The present invention relates to a method for preventing and improving or ameliorating hyperlipidemia, diabetes, obesity, inflammation and the like in a human or animal using the same. Background art

P PAR is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, like steroid receptors, retinoid receptors and thyroid receptors. Forms (type, δ (or β), type A) have been identified in various animal species, including humans (Proceedings of the National Academic of Sciences, 1992, 89, p. 4653—46 57). Among the isoforms of PPAR, PPAR is expressed in the liver, kidney, skeletal muscle, etc., which have high fatty acid catabolism, and is particularly highly expressed in the liver (En docrinology, 1996). 137, p. 354-366), genes related to fatty acid metabolism and intracellular transport (eg, acyl-CoA synthetase, fatty acid binding protein ゃ lipoprotein lipase, etc.) and cholesterol and neutral lipids. It positively or negatively regulates the expression of apolipoprotein (AI, AII, CIII) genes associated with Xie. P PAR <5 is ubiquitously expressed in various tissues in the body, mainly in nerve cells. At this time, the physiological significance of P PAR δ is unknown. PPARa is highly expressed in adipocytes and is involved in adipocyte differentiation (J ournalof Lipid Research, 1995, Volume 37, p. 907-925). Thus, each isoform of PPAR performs a specific function in a particular organ or tissue.

On the other hand, fibrate-based hyperlipidemia therapeutic agents (such as Clofi'brate and Bezafibrate) that have already been clinically applied have a PPARα ligand effect, and are considered to be one of the mechanisms of pharmacological effects. (Bio C 1 inica, 2001, Volume 16, p. 65-68). In addition, PPARa ligands improve not only lipid metabolism but also glucose metabolism, and have shown effects such as lowering blood lipids, lowering blood glucose levels, and improving insulin sensitivity (Diabetes, 2001 , Volume 50, p. 41 1-41 7), which is considered to be effective also in a state where two or more symptoms such as hyperlipidemia, diabetes mellitus, hyperglycemia, insulin resistance, and obesity occur simultaneously. . In addition, thiazolidine-based insulin sensitizers are said to exhibit a hypoglycemic effect via PPARr activation (Ayumi, 2001, 198, 747-754). In addition, PPARr ligands have been thought to regulate adipocyte differentiation and improve insulin resistance.

In addition, both P PARo! And P PARr have become known to be involved in a wide range of inflammatory cells in addition to the previously considered involvement in lipid metabolism and sugar metabolism (History of Medicine, 1999 , 190, p. 928-932), and application to new anti-inflammatory drugs based on a new mechanism is also expected.

In addition to the above-mentioned drugs, polyphenols such as monoacylglycerol (Japanese Patent Application Laid-Open No. 2001-354558), gallic acid esters, galloyltannins, quercetin, flavone, isoflavones, catechin and epipicatechin ( Japanese Patent Application Publication No. 2002-80362) is known to have PPAR ligand activity.

As described above, the PPAR ligand agent is expected to have a preventive and / or Z- or ameliorating effect on many symptoms as mentioned above. However, the drugs shown above are expensive and have disadvantages such as side effects due to long-term administration. Polyphenols such as monoacylglycerol, gallic acid esters, galloyltannins, quercetin, flavone, isoflavones, catechins and epicatechins have sufficient PPARs. There were inconveniences such as the inability to obtain a gand effect. Therefore, a material having high safety and high PPAR ligand action is desired.

In view of the above, the present invention provides a PPAR ligand agent which is derived from natural foods, has no side effects or safety and has high PPAR ligand activity, and a hyperlipidemia comprising the same. It is intended to provide a preventive and / or ameliorating agent for diseases, diabetes, obesity, inflammation and the like. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that an extract of fennel of a plant of the genus Apiaceae has a PPAR ligand activity, and completed the present invention. Reached.

That is, the present invention relates to a PPAR ligand agent containing a fennel extract as an active ingredient.

In addition, the present invention relates to a method for positively or negatively controlling the expression of various genes via human or animal PPAR using the above-mentioned PPAR ligand agent. Further, the present invention provides a method for preventing or preventing one or more symptoms selected from the group consisting of human or animal hyperlipidemia, diabetes, obesity, and inflammation, which comprises the above-mentioned PPAR ligand agent. Or an ameliorating agent, and a method for preventing and / or ameliorating one or more symptoms selected from the group consisting of human or animal hyperlipidemia, diabetes, obesity, and inflammation.

Fennel is a perennial herb belonging to the genus Apiaceae, and is one of the herbs commonly used in fish dishes. The Japanese name is ikiyo, which is used as a diuretic, expectorant, carminative, and stomachic. In addition, the water extract and the 50% ethanol extract have a blood pressure lowering effect (Proceedings of the National Academic of Sciences, 1999, Vol. 89, p. 4653-4657, Japanese patent application publication) 200 1—335494), the ethanol extract has antioxidant activity (see Japanese Patent Application Publication No. 299151, 1994), and is used as a water or water-soluble polar organic solvent extract. Has the effect of suppressing liver injury (Japanese Patent Application Publication No. 2001-72599) And so on). In addition, fennel extract is known to have an anti-inflammatory effect due to inhibition of 3-hydroxysteride dehydrogenase or hyaluronidase (see Japanese Patent Application Publication No. 318887/1999). However, it has never been known to have PPAR ligand activity in fennel extracts. Furthermore, it was not known at all that the present action has a preventive and / or ameliorating effect on hyperlipidemia, diabetes, obesity, and inflammation. BEST MODE FOR CARRYING OUT THE INVENTION

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

The PPAR ligand agent of the present invention contains a fennel extract as an active ingredient. Examples of the extract of fennel of the present invention include sweet fennel (Sweet Fennel 1), bronze fennel (Bronze Fennell), Florence Fennenel, and bitter fennel (Bitter Fennell). ), An extract of German Fennell 1 can be used. Among them, the extract of fennel used in the present invention is preferably a plant extract of sweet fennel, bronze fennel or Florence fennel from the viewpoint of availability.

The PPAR ligand agent referred to in the present invention is a substance containing a compound having an ability to bind to a PPAR ligand binding region, that is, a PPAR ligand activity. The PPAR ligand agent of the present invention becomes an important regulator of many physiological functions including glucose and lipid metabolism via PPAR, and prevents and / or ameliorates hyperlipidemia, diabetes, obesity, inflammation, etc. be able to. That is, the PPAR ligand agent of the present invention can positively or negatively regulate the expression of various genes related to hyperlipidemia, diabetes, obesity, inflammation and the like. Examples of the various genes include, but are not limited to, acyl CoA synthase, fatty acid binding protein, lipoprotein lipase, and apolipoprotein.

PPAR ligand activity can be measured, for example, by using a reporter to evaluate the binding of the PPAR ligand-binding domain to the GAL4 fusion protein by luciferase expression. Competition binding using a protein containing a PPAR ligand binding region (Cell, 1995, vol. 83, p. 803-812), and Atssei (Cell, 1995) , Pp. 83, p. 81 3—8 19). In these assays, the activity of the sample is generally higher than that of the solvent control, and the sample that shows higher activity than the solvent control and is dose-dependent is evaluated as having “PPAR ligand activity”.

The method for obtaining the extract of the present invention from fennel includes, for example, a method by solvent extraction. The extraction operation is not limited to the solvent extraction, but may be an extraction operation such as steam distillation or extraction with carbon dioxide using a supercritical extraction technique. Furthermore, 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 that are unsuitable for foods and drinks and pharmaceuticals.

The solvent used for the extraction is preferably a safe solvent that can be used for the production and processing of foods, food additives, pharmaceuticals, etc., for example, water, ethanol, acetone, glycerin, ethyl acetate, propylene glycol, hexane, edible oils, etc. And two or more of these may be used as a mixture. Among them, organic solvents such as ethanol, acetone, ethyl acetate, and hexane are preferable in terms of easy removal of the solvent after extraction, and ethanol is more preferable in terms of safety of the residual solvent.

In the case of solvent extraction, for example, fennel is immersed in 1 to 20 times the amount of the above solvent, stirred or left, and filtered or centrifuged to obtain an extract. Next, the solvent may be removed from the obtained extract. The fennel for extraction may be raw or dried, but preferably dried from the viewpoint of storage. The form of the fennel may be any of a prototype, pulverized, cut, or powder. The extraction temperature is generally -20 to 100 ° C, usually 1 to 80 ° C, preferably 20 to 60 ° C. The extraction time is usually 0.1 hour to 1 month, preferably 0.5 hour to 7 days.

In the present invention, the plant parts used for obtaining the fennel extract are not particularly limited, and any of whole plants, leaves, stems, roots, flowers, seeds and the like may be used. The form of the extract of the present invention may be in the form of an extract or may be a form from which the solvent has been removed. Further, it may be dissolved and suspended in a suitable solvent. These extracts have PPAR ligand activity, and can be subjected to deodorization, purification, and other operations within a range not losing PPAR ligand activity.

The PPAR ligand agent of the present invention contains the above-mentioned fennel extract as an active ingredient, and may contain an effective amount in a range that can exhibit PPAR ligand activity. The hyperlipidemia, diabetes, obesity, inflammation prevention and Z or ameliorating agent of the human or animal of the present invention comprises a PPAR ligand agent as described above. A prophylactic and / or ameliorating agent for one or more symptoms selected from the group consisting of hyperlipidemia, diabetes, obesity, and inflammation is used as a prophylactic and / or ameliorating agent for each of these symptoms alone. It may be used, or may be used as a preventive and / or ameliorating agent for a condition in which two or more of these symptoms occur simultaneously.

In the present invention, the prevention of hyperlipidemia is defined as the 髙 lipidemia state or boundary defined by the Japan Atherosclerosis Society in the guidelines for the management of atherosclerotic diseases (issued in September 2002). To prevent or delay the state of the territory. The improvement of hyperlipidemia means that the hyperlipidemia state or the boundary area state described above is brought closer to the state defined as the normal area in the above-mentioned guidelines.

In the present invention, the prevention of diabetes is defined as the diabetes condition or boundary area defined by the Diabetes Society of Japan in the Diabetes Treatment Guidebook 202-202 (issued in May 2002). Refers to preventing or delaying a condition. In addition, the improvement of diabetes refers to bringing the hyperlipidemia state or the boundary area state closer to the state defined as a normal area in the above guide.

In the present invention, prevention of obesity is defined as obesity or obesity in the Obesity Society of Japan Obesity Guidance Manual 2nd Edition (issued in July 2001) by the Japan Obesity Society. Refers to preventing or delaying a condition. Further, the improvement of obesity refers to a situation in which the above-mentioned society defines obesity or obesity to approach a state where the above-mentioned society defines a normal range. In the present invention, the inflammation, PPAR is involved, inflammation via Roikotoryen B _4, inflammatory cytokines Ya protein in cells such as macrophages (e.g., TNF-a, IL one l j3, IL one 6, NO synthase , Gelatinase B, Scavenger Recept (Yuichi) refers to inflammation and the like. And prevention of inflammation refers to preventing or delaying the above-mentioned symptoms of inflammation. In addition, amelioration of inflammation refers to recovering or reducing the above-mentioned symptoms of inflammation. The PPAR ligand agent of the present invention, and the agent for preventing and / or ameliorating hyperlipidemia, diabetes, obesity, and inflammation in humans or animals containing the same can be used for eating and drinking and for medicine. The form is not limited. For example, health foods (special health foods, nutritional foods), nutritional foods, foods and drinks such as dietary supplements, or easily available drugs such as over-the-counter drugs (OTC) or pharmaceutical departments It can be used as a foreign product.

When the PPAR ligand agent of the present invention or the agent for preventing and / or ameliorating hyperlipidemia, diabetes, obesity, and inflammation in humans or animals containing the same is used as a food or drink, it can be directly taken as it is. In addition, using known additives such as carriers and auxiliaries, capsules, tablets, granules and the like can be ingested and ingested. The content of the preventive and / or ameliorating agent for hyperlipidemia, diabetes, obesity, and inflammation of the present invention in these molding agents is preferably calculated as an extract of fennel, which is an active ingredient (dry weight, the same applies hereinafter). 0.1 to 100% by weight, more preferably 10 to 90% by weight. Furthermore, mixed with food and drink ingredients, confectionery such as chewing gum, chocolate, candy, jelly, biscuit, cracker, etc .; ice confectionery such as ice cream, ice confectionery; tea, soft drink, nutritional drink, beauty Beverages such as drinks; Udon, Chinese food, spaghetti, instant foods, etc .; kneaded products such as kama, bamboo rings, and hanpon; seasonings, such as dressings, mayonnaise, and sauces; It can be used for all foods and drinks such as bread, ham, soup, retort food, frozen food. When these preventive and / or ameliorating agents for eating and drinking hyperlipidemia, diabetes, obesity, and inflammation are taken, the amount of the extract is preferably 0.01 to 100 OmgZkg body weight per adult per day as the extract. , More preferably 0.1 to 1 00 mg / kg body weight.

When the PPAR ligand agent of the present invention or an agent for preventing and / or improving hyperlipidemia, diabetes, obesity, and inflammation in humans or animals containing the same or a Z or ameliorating agent is used as a pharmaceutical, the dosage form is not particularly limited. For example, capsules, tablets, granules, injections, suppositories, patches and the like can be mentioned. In the formulation, other pharmaceutically acceptable pharmaceutical ingredients, such as excipients, disintegrants, lubricants, binders, antioxidants, coloring agents, antiaggregants, absorption promoters, dissolution aids It can be prepared by appropriately adding agents, stabilizers and the like. The dosage of these preparations is preferably 0.01 to: LOO OmgZkg body weight, more preferably 0.1 to 10 Omg / kg body weight per day per adult in terms of the extract, divided into one or several doses. Administration.

When the PPAR ligand agent of the present invention and the agent for preventing and improving Z or amelioration of hyperlipidemia, diabetes, obesity, and inflammation in humans or animals containing the same are used as quasi-drugs, if necessary, Additives such as ointments, liniments, aerosols, creams, stones, facial cleansers, body cleansers, lotions, lotions, baths, etc. Can be used. 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 of ethanol extract of fennel

1 kg of sweet fennel whole plant powder (Kaneki Sun Spice, Japan) was immersed in 5 L of ethanol, extracted at room temperature and protected from light for 7 days, and then an extract was obtained by filtration. The extract was concentrated under reduced pressure to remove the solvent, and 139.93 g of an oily extract was obtained. (Example 2) Preparation of ethyl acetate extract of fennel

2.0 g of sweet fennel whole plant powder (Kaneki Sun Spice Co., Ltd.) was immersed in 10 ml of ethyl acetate, extracted at room temperature and protected from light for 7 days, and then an extract was obtained by filtration. The extract was concentrated under reduced pressure to remove the solvent, and 416 mg of an oily extract was obtained. (Example 3) Measurement of ligand activity of PPAR

CV-1 cells (cultured cells from male African green monkey kidney (ATCC CCL 70 obtained from American Evening Culture Collection) should be placed in a 96-well culture plate at 6 × 10 ³ ce 11 s / we 11 the implantation, were cultured for 24 hours at 37 ° C, 5% C_〇 ₂ under conditions in. the culture medium, 1 0% FB S (© shea calf serum), 1 0 m l ZL Benishirin-stress but-mycin solution (each 500 0 DMEM (Dulbecco's Modified E) containing IU / m1, 5000 Mg / m1, GIB CO; US (now Invitrogen)), 37 mg ZL ascorbic acid (Wako Pure Chemical Industries, Ltd .; Japan) After washing the CV-1 cells cultured as above with OPT I-MEM (registered trademark, GI BCO), pM-PPARa and 4xUAS were used. g-luc was transfected using Lipofect AMINE-PLUS (registered trademark, GI BCO). A chimeric protein in which yeast-derived transcription factor GAL4 gene (amino acid sequence 1 to 147) and human PPARα ligand binding site gene (amino acid sequence 167 to 468) are linked to expression plasmid pM (C ontech, USA). 4xUAS g-luc is a reporter 'plasmid in which the GAL4 response element (UAS g) is incorporated four times upstream of the luciferase gene (Ce11, 1995 Year, Volume 83, ρ · 8033-812, etc.) About 24 hours after transfection, replace the medium with the fennel extract of Example 1 or 2 (η = 4 ) And cultured for 24 hours DMSO was used as a solvent control (untreated control), and the medium was added in an amount of 1 to 1000. The cells were washed with phosphate buffered saline (PBS +) containing Ca and Mg. Thereafter, 1 uc 1 ite (registered trademark, Packard, USA) was added and To the above measurement group to measure the emission intensity of the luciferase in Pukaunto Microplate Scintillation / Ruminessen scan counter (P ackard Co.), as a control group pm- P PAR Hino Instead p M was measured. For each sample, the ratio of the average value (n = 4) of the luminescence intensities of the measurement group and the control group (measurement group no control group) was calculated, and the solvent control

The specific activity relative to (untreated control) was defined as the PPAR-ligand activity of the sample. In addition, PPAR o! Ligand activity of each compound was compared using bezafibrate (Sigma; USA) as a positive control. Table 1 shows the results. table 1

(mean ± SD) As is clear from Table 1, each of the fennel extracts showed a dose-dependent P PAR -ligand activity.

(Example 4) Measurement of PPARr ligand activity

The procedure was performed in the same manner as in Example 3 except that pM-PPARτ was used instead of pM-PPARo! In the method described in Example 3. PM-PPARr is a plasmid in which the chimeric protein gene in which the yeast-derived transcription factor GAL4 gene (amino acid sequence 1-147) and the human PPART ligand binding site gene (amino acid sequence 174-475) are linked to pM is inserted. It is. Troglitazone (Sankyo Co., Ltd .; Japan) was used as a positive control. Table 2 shows the results. Table 2

(mean soil SD) As is clear from Table 2, each of the fennel extracts showed a dose-dependent PPAR r ligand activity.

(Example 5) Preparation of capsule for eating and drinking

40 parts by weight of the ethanol extract of fennel obtained in Example 1, 30 parts by weight of sodium carboxymethylcellulose, 20 parts by weight of crystalline cellulose, and 10 parts by weight of vitamin C were mixed and ground. Then, the mixture was filled into gelatin capsules (size: No. 02, Riki Busgel Japan K.K.) to prepare capsules for eating and drinking containing the extract at 40% by weight.

(Example 6) Effect on rat model of hyperlipidemia

The effect of the fennel extract of Example 1 was evaluated as follows using a hyperlipidemia (hyperneutral lipemia) model / rat that develops when fructose water is given to SD lad. Bezafibrate, a drug for treating hyperlipidemia, was used as a positive control.

SD rats (oss, 6 weeks old) were divided into three groups (six in each group), and each was given 25% (w / v) fructose water as drinking water. The experimental animal powder feed (CE-2, CLEA Japan; Japan) was used as a basic feed, and a non-supplemented group (control group), a bezafibrate-added group, and a fennel extract-added group were fed freely for one week. Bezafibrate is obtained by pulverizing Bezator 20 Omg tablets (containing 20 Omg of bezafibrate per tablet, Kitssei Pharmaceutical Co., Ltd .; Japan) and adding bezafibrate It was added to the powdered feed so that the added amount was 0.01% (w / w). The fennel extract was added to the powdered feed so that the amount added was 0.2 (w / w).

One week after feeding, the animals were fasted for 5 hours, and blood was collected from the jugular vein under anesthesia for approximately 1 m1 under neutral anesthesia, and the neutral fat in plasma was measured. The results are shown in Table 3. Table 3

As is clear from Table 3, the neutral fat value was significantly reduced in the bezafiltrate-added group and the fennel-added group compared to the neutral fat value in the non-added group (control group). Industrial applicability

The PPAR ligand agent of the present invention has excellent PPAR ligand activity. In addition, it is highly safe because it is derived from food materials, is useful for preventing and / or improving hyperlipidemia, diabetes, obesity, and inflammation, and has functional health foods (specified health foods, nutritional foods), and health. It can be used as foods and drinks such as dietary supplements, or easily available drugs or quasi-drugs such as OTC.

Claims

The scope of the claims

1. A loxoxin-proliferating agent-responsive receptor ligand agent comprising as an active ingredient an extract of fennel belonging to the genus Apiaceae.

2. The peroxisome proliferator-activated receptor ligand agent according to claim 1, wherein the peroxisome proliferator-activated receptor is a peroxisome proliferator-activated receptor and / or a peroxisome proliferator-activated receptor.

3. The peroxisome proliferator-activated receptor ligand according to claim 1, wherein the peroxisome proliferator-activated receptor is a peroxisome proliferator-activated receptor α.

4. The peroxisome proliferator-activated receptor ligand according to claim 1, wherein the peroxisome proliferator-activated receptor is a peroxisome proliferator-activated receptor.

5. The extract of fennel is sweet fennel (Sweet Fennel 1), bronze fennel (Bronze Fennel), Florence Fennell (Florence Fennel 1), Bitter Fennel (Bitter Fennel), German The peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4, which is an extract of at least one fennel selected from fennel (German F ennel).

6. The peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4, wherein the extract of fennel is a solvent extract.

7. The peroxisome proliferator-responsive receptor ligand agent according to claim 6, wherein the solvent is ethanol.

8. The peroxisome proliferator-activated receptor ligand agent according to claim 6, wherein the extract of fennel is solvent-extracted from dried fennel.

9. The peroxisome proliferator-activated receptor ligand agent according to claim 6, wherein the fennel extract is extracted from powdered fennel.

10. Using a fennel extract belonging to the genus Apiaceae as a ligand, administer a prophylactically and therapeutically effective amount to humans or animals to peroxisome activity. A method for positively or negatively controlling the expression of various genes via a sex agent-responsive receptor.

11. The method according to claim 10, wherein the peroxisome proliferator-activated receptor is a peroxisome proliferator-activated receptor.

12. The method according to claim 10, wherein the peroxisome proliferator-activated receptor is peroxisome proliferator-activated receptor α.

13. The method according to claim 10, wherein the peroxisome proliferator-responsive receptor is a peroxisome proliferator-responsive receptor.

14. A group consisting of human or animal hyperlipidemia, diabetes, obesity, and inflammation, which comprises the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4. A preventive and / or ameliorating agent for one or more symptoms selected from the group consisting of:

15. An agent for preventing and / or ameliorating hyperlipidemia in a human or animal, comprising the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4.

16. A preventive and / or ameliorating agent for diabetes in humans or animals, which comprises the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4.

17. An agent for preventing and improving obesity in humans or animals, comprising the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4.

18. A preventive and / or ameliorating agent for human or animal inflammation, which comprises the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4.

19. The preventive and / or ameliorating agent for hyperlipidemia, diabetes, obesity, and inflammation according to claim 14, which is used for eating and drinking.

20. The agent for preventing and / or ameliorating hyperlipidemia, diabetes, obesity and inflammation according to claim 14, which is for use in medicine.

21. A prophylactic / therapeutically effective amount of the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4 to a human or animal. A method for preventing and / or ameliorating one or more symptoms selected from the group consisting of human or animal hyperlipidemia, diabetes, obesity, and inflammation.

22. A human, comprising administering to a human or animal an effective prophylactic / therapeutic amount of the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1-4. Or a method of preventing and / or ameliorating hyperlipidemia in an animal.

23. A human or animal, comprising administering to a human or animal a prophylactically and therapeutically effective amount of the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4. A method of preventing and / or ameliorating diabetes in animals.

24. A human, which comprises administering to the human or animal a prophylactic / therapeutically effective amount of the peroxisome proliferator-activated receptor ligand agent according to any one of claims 1 to 4. Or a method for preventing and / or ameliorating obesity in an animal. 25. The prophylactically / therapeutically effective amount of a peroxisome proliferator-activated receptor ligand agent as described in any one of claims 1-4. A method for preventing and / or ameliorating inflammation in a human or animal, comprising administering to a human or animal.