BACKGROUND OF THE INVENTION
The present invention relates to a ligand for peroxisome proliferator-activated receptor, and a composition for preventing and/or improving Insulin Resistance Syndrome (e.g., type-II diabetes mellitus, hyperinsulinemia, dyslipidemia, obesity, hypertension and arteriosclerotic cardiovascular disease) comprising the ligand for peroxisome proliferator-activated receptor as an active agent.
Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcriptional regulatory factor belonging to the nuclear receptor family, which has been identified as a transcriptional regulatory factor that regulates expression of a group of genes that maintain lipid metabolism. It is known that three subtypes of PPAR, i.e., PPARα, PPARδ (PPARβ, NUC-1, FAAR) and PPARγ, have been identified in mammals. PPARα is mainly expressed in the liver while PPARδ is ubiquitously expressed. PPARγ has two isoforms, PPARγ1 and PPAR65 2. PPARγ1 is expressed not only in adipose tissues but also in immune system organs, adrenals and small intestine. PPARγ2 is specifically expressed in adipose tissues, and is a master regulator which regulates differentiation/maturation of adipocytes (Teruo Kawada, Igaku no Ayumi (Journal of Clinical and Experimental Medicine) 184, 519-523, 1998).
Examples of known PPARγ ligands include: arachidonic acid metabolites such as 15-deoxy-Δ12, 14-prostaglandin J2 and Δ12-prostaglandin J2; unsaturated fatty acids such as ω-3-polyunsaturated fatty acid, α-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and eicosanoids such as 9-hydroxy-octadecadienoic acid and 13-hydroxy-octadecadienoic acid (J. Auwerx, Diabetologia, 42, 1033-1049, 1999). It has been also disclosed that PPARγ ligands include C10-26 conjugated-unsaturated fatty acids having a conjugated-triene or tetraene structure (Japanese Patent Application 2000-355538). It is also known that examples of synthetic PPARγ ligands include thiazolidinediones such as troglitazone, pioglitazone and rosiglitazone.
It has been suggested that thiazolidinediones, which are PPARγ ligands, are associated with improvement of insulin resistance since their agonistic activities correlates with their hypoglycemic actions. Based on these findings, they were developed as drugs for improving insulin resistance against type-II diabetes mellitus (non-insulin dependent diabetes mellitus: NIDDM). Namely, a thiazolidinedione, which is one of PPARγ ligands, can improve insulin resistance by activating PPARγ to increase number of small adipocytes with normal function differentiated from preadipocytes and to decrease number of large adipocytes, which hyperproduce and/or hypersecrete factors causing insulin resistance such as TNFα and free fatty acid, by apoptosis (A. Okuno, et al., Journal of Clinical Investigation, 101, 1354-1361, 1998). PPARγ ligands are also useful for prevention and/or improvement of Insulin Resistance Syndrome, not only for type-II diabetes mellitus but also for hyperinsulinemia, dyslipidemia, obesity, hypertension and arteriosclerotic cardiovascular disease (R. A. DeFronzo, et al., Diabetes Care, 14, 173-194, 1991), due to its ability to improve insulin resistance. As for the effect against obesity, it has been reported that administration of troglitazone to type-II diabetic patients reduces visceral fat in the patients (I. E. Kelly, et al., Diabetes Care, 22, 288-293, 1999; Y. Mori, et al., Diabetes Care, 22, 908-912, 1999). Thus, PPARγ ligands are also useful for prevention and/or improvement of visceral fat obesity.
Curcumin and its derivatives are components contained in tropical or subtropical plants, of which a good representative is perennial Curcuma longa, belonging to Zingiberaceae. Curcuma longa is generally known as turmeric, one of spices which are used in curry, and can be used not only for foods, but also as a colorant in food or clothing, or as a herbal medicine in traditional therapies such as Chinese medicine (Kampo), Indian Ayurveda and Indonesian Jamu due to its hemostatic, stomachic, antibacterial and anti-inflammatory actions.
It has been proved that curcumin has various physiological activities such as anti-oxidative action, cholagogic action, the internal organs (hepatic or pancreatic) function-potentiating action, carcinogenesis-inhibiting action, lipid metabolism-improving action, and whitening action. P. Suresh Babu and K. Srinivasan reported that streptozotocin-induced diabetic rats, which were maintained on diet containing 0.5% curcumin, exhibited reduced cholesterol, triglyceride and phospholipid levels in blood (Molecular and Cellular Biochemistry, 166, 169-175, 1997) and amelioration of renal lesions associated with diabetes mellitus (Molecular and Cellular Biochemistry, 181, 87-96, 1998). Japanese Patent Application Hei-11-246399 discloses that enhanced activity of acyl-CoA oxidase (β-oxidation promotive enzyme) and inhibition of triglyceride accumulation in the liver were observed in rats which received curcumin. However, it has not been known that curcumin and/or its derivatives are PPARγ ligands and have hypoglycemic or visceral fat-reducing action.
As described above, PPARγ ligands can improve insulin resistance and prevent and/or improve Insulin Resistance Syndrome such as type-II diabetes mellitus, hyperinsulinemia, dyslipidemia, obesity (particularly visceral fat obesity) , hypertension and arteriosclerotic cardiovascular disease. Accordingly, the object of the present invention is to provide a PPARγ ligand derived from naturally occurring sources and a composition comprising the PPARγ ligand as an active agent for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity.
SUMMARY OF THE INVENTION
The present inventors found that Curcuma extract has hypoglycemic action and that, after intense studies, particular components contained in Curcuma (curcumin and its derivatives) have PPARγ ligand activities. They also found that these particular components have hypoglycemic action and visceral fat-reducing action. The present invention was developed based on these findings.
In summary, the present invention relates to a ligand for peroxisome proliferator-activated receptor
which comprises curcumin or its derivative.
The present invention also relates to a composition for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, or obesity or visceral fat obesity
which comprises at least one selected from the group consisting of curcumin and its derivatives as an active agent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will be described in more detail referring to the following embodiments. The PPARγ ligand according to the present invention comprises curcumin or its derivative. A composition comprising, as an active agent, at least one selected from the group consisting of curcumin and its derivatives according to the present invention has hypoglycemic action and visceral fat-reducing action, and therefore be useful to prevent and/or improve Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity.
Curcumin to be used in the present invention is 1,7,-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, and curcumin derivatives (curcuminoids) include, for example, demethoxycurcumin, bisdemethoxycurcumin, dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, dihydroxytetrahydrocurcumin, Yakuchinone A and Yakuchinone B, and their salts, oxidants, reductants, glycosides and esters thereof. Those may be purified from plants or chemically synthesized compounds. Plant-derived curcumin and/or its derivatives can be obtained by extraction from plants including Zingiberaceae Curcuma, such as Curcuma longa(turmeric), Curcuma aromatica(wild turmeric), Curcuma zedoaria (zedoary), Curcuma xanthorrhiza, mango ginger, Indonesian arrowroot, yellow zedoary, black zedoary and galangal.
Any conventional method can be used to prepare curcumin and its derivatives to be used in the present invention. For example, turmericoleoresin, a food additive, which essentially contains curcumin, can be produced by extracting from a dry product of rhizome of turmeric with ethanol at an elevated temperature, with hot oil and fat or propylene glycol, or with hexane or acetone at from room temperature to a high temperature. Alternatively, those can be produced by the methods disclosed in Japanese Patent Application 2000-236843, Japanese Patent Application Hei-11-235192 and Japanese Patent Application Hei-6-9479, and Japanese Kohyo Publication Hei-11-502232 and Japanese Kohyo Publication Hei-9-503528. According to the present invention, a purified product of at least one selected from the group consisting of curcumin and its derivatives may be used. Alternatively, a semi-purified or crude product thereof may be used, provided that it does not contain impurities which may not be acceptable as a pharmaceutical or food product.
A composition for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity according to the present invention may comprise a PPARγ ligand, and is the composition comprises, as an active agent, at least one selected from the group consisting of curcumin and its derivatives. The compositions of the invention may be used in, for example, but not limited to, foods and drinks including foods with health claims (e.g., foods for specified health uses or foods for nutrient function claims) or health foods, pharmaceuticals and quasi drugs.
When used as foods and drinks, the inventive compositions may be administered alone, or formulated in combination with any known carrier(s) and/or additive(s) into any suitable dosage form including, for example, capsules, tablets and granules. The PPARγ ligand according to the present invention may be present in such formulations at an amount of 0.1 to 100% by weight, and preferably 10 to 90% by weight. Alternatively, the inventive composition may be added to any kinds of foods and drinks, including: confectionery such as chewing gums, chocolates, candies, jellies, biscuits or crackers; frozen desserts such as an ice cream or ice cube; drinks such as tea, soft drinks, nutritional supplement drinks or beauty supplement drinks; noodles such as udon noodle, Chinese noodle, spaghetti or instant noodle; foods made from fish paste such as boiled fish paste (kamaboko), tube-shaped fish paste cake (chikuwa) or a cake of pounded fish (hanpen); dressing, mayonnaise, sauce or other seasonings; fat foods such as margarine, butter or salad oil; bread; ham; soup; boil-in-bag foods; and frozen foods. A food or drink containing the inventive composition may be given to a human at a dose of 0.1 to 3000 mg/kg body weight/day (based on inventive PPARγ ligand) for an adult, and preferably 1 to 300 mg/kg body weight/day (based on the PPARγ ligand). The inventive composition may be also used as a feed for a domestic animal or pet-food for a pet. In this case, a feed or food containing the inventive composition may be preferably given at a dose of 0.1 to 3000 mg/kg body weight/day (based on the PPARγ ligand).
When used as pharmaceuticals, the inventive compositions may be formulated into any suitable dosage forms for administration including, but not limited to, capsules, tablets, granules, injection solution, suppositories and patches. In preparation of the drugs, such formulations comprising the inventive composition may additionally comprise other pharmaceutically acceptable additive(s) such as an excipient, a disintegrator, a lublicant, a binder, an anti-oxidant, a colorant, an anti-aggregation agent, a sorbefacient, a solubilizer and/or a stabilizer as appropriate. Such a formulation may be administered to a human at a dose of 0.1 to 3000 mg/kg body weight/day (based on inventive PPARγ ligand) for an adult, and preferably 1 to 300 mg/kg body weight/day (based on PPARγ ligand), once or divided into several times a day. The inventive composition may be also administered to a domestic animal or a pet as a pharmaceutical drug. In this case, a formulation containing the inventive composition may be preferably administered at a dose of 0.1 to 3000 mg/kg body weight/day (based on the inventive PPARγ ligand).
According to the present invention, a ligand for peroxisome proliferator-activated receptor γ (PPARγ ) and a composition comprising the same are provided. The composition according to the present invention is useful for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity.