JP2008273938A - Adiponectin production-promoting agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a food, a pharmaceutical formulation and an animal food useful for therapy and prophylaxis of various disorders originated from low adiponectinemia, insulin resistance sthenia or the like (for example, metabolic syndrome, diabetes and its complication, non-alcoholic fat hepatitis (NASH) and hepatic disease origined from it, and cancers such as endometrial carcinoma, breast carcinoma after menopause, leukemia, colon cancer, stomach cancer and prostatic cancer). <P>SOLUTION: This agent relates to adiponectin with Olea europaea leaf extracts as an active ingredient and particularly a high-molecular weight adiponectin production-promoting agent. The agent includes the food, the pharmaceutical formulation or the animal food. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an adiponectin production promoter containing olive leaf extract as an active ingredient, and more particularly to an adiponectin production promoter that promotes the production of high molecular weight adiponectin. The present invention is suitably applied to foods, pharmaceutical preparations, feeds and the like.

  Adiponectin is a protein that is specifically produced and secreted from adipocytes, and is known to be closely related to lifestyle-related diseases such as cardiovascular diseases, diabetes, and obesity. Hypoadiponectinemia, which is a pathological condition in which the blood adiponectin concentration is reduced, is considered to be one of the root causes of the above-mentioned diseases, and the treatment / prevention of hypoadiponectinemia is caused by the above-mentioned hypoadiponectinemia Useful for prevention and treatment of diseases and lifestyle-related diseases. In addition, since insulin resistance increases under hypoadiponectinemia, increased insulin resistance is considered to be one of the causes of the above diseases and lifestyle-related diseases. Therefore, improving insulin resistance is also useful for the prevention and treatment of the above diseases and lifestyle-related diseases.

  More recently, adiponectin plays a central role in the development and development of metabolic syndrome, a decrease in blood adiponectin concentration promotes the development of nonalcoholic steatohepatitis (NASH), liver fibrosis, and The pathological conditions of metabolic syndrome include visceral fat accumulation, insulin resistance, arteriosclerosis-induced lipoprotein abnormality, high blood pressure, hyperuricemia, etc.In addition, metabolic syndrome is mild but systemic inflammatory condition, It has been reported that attention has been paid in association with the onset of carcinogenesis and inflammatory diseases (see, for example, Non-Patent Documents 1 and 2). Carcinogenesis related to obesity and insulin resistance includes uterine cancer, postmenopausal breast cancer, leukemia, colon cancer, gastric cancer, prostate cancer, etc., and reports that these are closely related to hypoadiponectinemia Has been. Therefore, treatment / prevention of hypoadiponectinemia and improvement of insulin resistance are useful for prevention / treatment of the above-mentioned diseases such as metabolic syndrome.

  Under the above circumstances, research and development of components that promote the production of adiponectin in blood are being promoted. So far, with respect to adiponectin, Patent Document 1 has proposed an adiponectin secretion-promoting composition containing soybean saponin as an active ingredient, and Patent Document 2 has proposed a blood adiponectin amount increasing agent containing proanthocyanidin as an active ingredient. Proposes an adiponectin production enhancer containing an HMG-CoA reductase inhibitor as an active ingredient.

  Furthermore, it has been reported that, among adiponectins, high molecular weight adiponectin is particularly highly related to the above diseases (for example, see Non-Patent Documents 3 to 4).

  Adiponectin is a low molecular weight (LMW) of 67 kDa or less, 136 kDa middle molecular weight (MMW), a high molecular weight multimeric adiponectin (HMW) of 300 kDa or higher. weight), which has three types of multimeric structures. Low molecular weight adiponectin is mainly composed of a trimeric adiponectin, and the trimeric adiponectin has a high molecular weight adiponectin of 6-mer or higher (12-18-mer) due to a disulfide bond between cysteine residues at the amino terminal position 39. A molecular weight multimeric adiponectin (= high molecular weight adiponectin) is formed.

  Among human adiponectin gene mutations, G84R in which the 84th amino acid glycine is replaced with arginine and G90S in which the 90th amino acid glycine is replaced with serine inhibit only the formation of HMW and form MMW and LMW. Is not inhibited. A human having a G84R or G90S adiponectin gene mutation has diabetes in addition to hypoadiponectinemia, and it has been revealed that HMW adiponectin is important for the insulin resistance improving action. In addition, it has been reported that HMW adiponectin is particularly decreased in insulin resistance, which is the basis of obesity and metabolic syndrome.

  The high molecular weight multimeric adiponectin is more correlated with the improvement of insulin resistance by administration of the thiazolidine derivative than the total adiponectin. In addition, each factor of metabolic syndrome is significantly correlated with high molecular weight multimeric adiponectin and insulin sensitivity, reduction of visceral fat, and glycolipid metabolism.

  As described above, it has been clarified that high molecular weight multimeric adiponectin plays the most important role in the pathogenesis of diabetes and metabolic syndrome, but it increases the amount of high molecular weight multimeric adiponectin in the blood. As such, there are no reports on food ingredients that can be safely ingested daily with only pharmaceutical ingredients such as thiazolidine derivatives and fibrates.

  On the other hand, it is conventionally known that olive leaf extract contains phenol components such as oleuropein and hydroxytyrosol. The action of the olive leaf extract includes hypoglycemic action (alpha amylase inhibition, alpha glucosidase inhibition) (see, for example, Patent Document 4), blood neutral fat lowering action, blood cholesterol lowering action (see, for example, Patent Document 5). , Suppression of blood sugar level increase, diabetes onset suppression (see, for example, Patent Document 6), blood pressure lowering action and anti-arteriosclerotic action, etc. have been reported, but the report on the olive leaf extract has an adiponectin production promoting effect, To the best of the inventors' knowledge, nothing has been done so far.

Tamura et al., “Adiponectin and Carcinogenesis”, Adiposcience, Fuji Medical Publishing, 2005, Vol. 2, No. 2, p. 122-127 Kawada, 3 others, “Gastrointestinal pathology based on visceral fat accumulation and its onset mechanism: focusing on adipocytokines, especially adiponectin”, Nissho, Japan Gastroenterology Society, November 2005, Vol. 102, No. 11, p. 1384-1391 Kumada, et al., “Diagnosis of Metabolic Syndrome-High Molecular Weight Adiponectin”, Nippon Clinic, Nippon Clinic, 2006, Vol. 64, Special Issue 9, p. 536-539 Horikoshi, “High Molecular Weight Adiponectin”, Ayumi of Medicine, Ishiyaku Shuppan Publishing Co., Ltd., April 2006, Vol. 217, No. 1, p. 156-162 JP 2006-143609 A JP 2006-182706 A JP-A-2005-232150 Japanese Patent Laid-Open No. 2002-010753 JP 2004-352626 A JP 2005-176770 A

  In view of the above-described conventional circumstances, if a substance capable of more strongly promoting adiponectin production can be elucidated, various diseases caused by decreased adiponectin blood concentration, increased insulin resistance, etc., such as metabolic syndrome, diabetes and its combination Possibility is opened to the development of pharmaceutical preparations that can treat and prevent various pathological conditions such as infectious diseases, arteriosclerosis, gastrointestinal diseases, for example, fatty liver improving agents, foods and feeds.

  That is, an object of the present invention is to elucidate a substance that can promote the production of adiponectin and to develop pharmaceutical preparations, foods, and feeds that are useful for the treatment and prevention of various diseases based on the adiponectin production promoting substance.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive research. As a result, they have found that olive leaf extract has an adiponectin production promoting effect, and have completed the present invention.

  That is, the present invention provides an adiponectin production promoter containing olive leaf extract as an active ingredient.

  The present invention also provides the above adiponectin production promoter, which is a food, pharmaceutical preparation, or feed.

  Moreover, this invention provides the said adiponectin production promoter which is the foodstuff which attached | subjected the function display based on the adiponectin production promotion effect.

  The present invention also provides the above adiponectin production promoter, wherein the production of adiponectin is promoted to produce high molecular weight adiponectin having a molecular weight of 300 kDa or more.

  The present invention also provides the adiponectin production promoter, which is a preventive or therapeutic agent for hypoadiponectinemia.

  The present invention also provides the adiponectin production promoter, which is an insulin resistance improving agent.

  The present invention also provides the adiponectin production promoter, which is a preventive or therapeutic agent for metabolic syndrome.

  The present invention also provides the above adiponectin production promoter, which is a preventive or therapeutic agent for diabetes and its complications.

  The present invention also provides the adiponectin production promoter, which is a preventive or therapeutic agent for nonalcoholic steatohepatitis (NASH) and liver disease derived therefrom.

  Since the present invention has a high effect of promoting adiponectin production, it is possible to provide functional agents and foods and drinks using the same. By improving various insulin resistances involving adiponectin and improving blood adiponectin concentration, metabolic syndrome It is also useful for the treatment and prevention of various pathological conditions such as diabetes and its complications, arteriosclerosis, digestive system diseases, etc., and is also expected to be effective as a therapeutic and preventive agent for fatty liver.

  Hereinafter, the present invention will be described in detail.

  The olive leaf extract used in the present invention refers to an extract obtained by extracting leaves of plants belonging to the genus Olea. Examples of plants belonging to the genus Olive include olive (O. europaea) and chrysophia species (O. chrysophylla). In the present invention, olive (O. europaea) is preferably used.

  The olive leaf extract can be obtained by drying the olive leaf as necessary, then immersing it in an extraction solvent for a certain period of time, or bringing it into contact with an extraction solvent heated to reflux, followed by filtration and concentration. As the extraction solvent, any solvent that is usually used for extraction can be used. For example, water, methanol, ethanol, propylene glycol, 1,3-butylene glycol, glycerol and other alcohols, chloroform, dichloroethane, four Organic solvents such as carbon chloride, acetone and ethyl acetate can be used alone or in combination. The extract obtained by extraction with the above solvent is used as it is, or concentrated extracts are used, or these extracts are removed by using an adsorption method, for example, ion exchange resin, or a porous polymer (for example, Amberlite XAD- After adsorbing on the column of 2), elution with methanol or ethanol and concentration can also be used. Further, a partitioning method, for example, an extract extracted with water / ethyl acetate can be used.

  The olive leaf extract is commercially available as “Opiace”, “Oralis” (all of which are manufactured by Eisai Food Chemical Co., Ltd.), etc., and these commercially available products can also be used.

  The adiponectin production promoter of the present invention can be administered to humans and animals as a pharmaceutical preparation, and can be ingested by being mixed with various foods and drinks, feeds (pet foods, etc.).

  When the adiponectin production promoter of the present invention is used as a pharmaceutical preparation, a preventive or therapeutic agent for hypoadiponectinemia, an agent for improving insulin resistance, a preventive or therapeutic agent for metabolic syndrome, a preventive or therapeutic agent for diabetes and its complications, cancer (Including endometrial cancer, postmenopausal breast cancer, leukemia, colon cancer, gastric cancer, prostate cancer, etc.), non-alcoholic steatohepatitis (NASH) and liver diseases derived therefrom (for example, fatty liver) It is preferably used as a preventive agent and the like.

  The pharmaceutical preparation is appropriately used orally or parenterally (intravenous administration, intraperitoneal administration, etc.). The dosage form is also arbitrary, for example, oral solid preparations such as tablets, granules, powders and capsules, oral liquid preparations such as internal liquids and syrups, and parenteral liquid preparations such as injections. These forms can also be appropriately prepared by known methods. For these pharmaceutical preparations, commonly used binders, disintegrants, thickeners, dispersants, reabsorption accelerators, corrigents, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonicity Excipients such as agents, stabilizers and pH adjusters may be used as appropriate.

  In the pharmaceutical preparation of the present invention, the dose (actual portion) of the olive leaf extract, which is an active ingredient, varies depending on the type, dosage form thereof, age of the patient, body weight, indication symptoms, etc. Adults are preferably administered once to several times a day, and are preferably administered at a dose of about 10 mg to 1000 mg per day, or olive leaf extract 300 mg / day (102.6 mg / day as oleuropein).

  When the adiponectin production promoter of the present invention is used as food or drink, feed, etc., in addition to general food and drink, prevention and treatment of hypoadiponectinemia, improvement of insulin resistance, prevention and treatment of metabolic syndrome, diabetes and its complications Preventive and therapeutic agents for cancer, including cancer (including endometrial cancer, postmenopausal breast cancer, leukemia, colon cancer, gastric cancer, prostate cancer, etc.), nonalcoholic steatohepatitis (NASH) and liver diseases derived therefrom It can be applied to functional foods and beverages, foods for sick people, foods for specified insurance, etc., which are based on the concept of physiological functions such as.

  As a form of food-drinks, it can shape | mold arbitrarily, for example in the shape of a granule, a granular form, a paste form, a gel form, solid form, or a liquid. These include various known substances that are recognized to be contained in foods, such as binders, disintegrants, thickeners, dispersants, reabsorption accelerators, flavoring agents, buffers, surfactants, Excipients such as solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers and pH adjusters can be contained as appropriate.

  The content (actual portion) of the olive leaf extract, which is an active ingredient contained in the food and drink of the present invention, can be appropriately determined according to the type, purpose, form, method of use and the like. It can be set to about 03 to 0.1% by mass. In particular, when used as a health food or drink, it is preferable to contain the active ingredient of the present invention in such an amount that a predetermined effect is sufficiently exhibited. Therefore, in such a case, the food / beverage product of the present invention contains an olive leaf extract and is labeled as being used to increase the amount of adiponectin in the blood or to prevent or improve metabolic syndrome. It can be a food and drink.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to a following example.

Example 1
Ingestion of a high-fat diet in KK-Ay mice that genetically develop type 2 diabetes reduces obesity and type 2 diabetes as well as blood adiponectin levels (Tsuchida A et al, Diabetes. 2005: 3358-3370). Therefore, using 12 KK-Ay / TaJcl mice (male, 5 weeks old, manufactured by CLEA Japan), a control group (6 mice) was prepared so that the average body weight between groups was almost equal after one week of preliminary breeding. And olive leaf extract intake group (6 animals).

  In the control group, a high fat diet (solid feed, manufactured by Oriental Yeast Co., Ltd.) containing about 30% by weight of fat was freely ingested (Maeda N et al, Nat Med. 2002: 731-737). In the olive leaf extract ingestion group, olive leaf extract (“Opiace”; manufactured by Eisai Food Chemical Co., Ltd.) is 0.57% by mass with respect to the high fat diet (Oriental Yeast Co., Ltd.). The olive leaf extract added high fat diet (solid feed) added so that it might become the mixing | blending ratio of (w / w) (actual part) was made to ingest freely.

  After feeding each of the above feeds freely for 2 weeks in each group, blood was collected from the tail vein in both groups under ether anesthesia, and serum was prepared according to a conventional method. The adiponectin concentration in the serum was measured using an adiponectin measurement ELISA kit (manufactured by Otsuka Pharmaceutical). The results are shown in FIG. As is clear from the results of FIG. 1, the blood adiponectin concentration was significantly increased (P <0.05) in the olive leaf extract ingested group compared with the control group. From this result, it is considered that by ingesting the olive leaf extract, adiponectin production was promoted, the decrease in insulin sensitivity due to the intake of a high fat diet was suppressed, and the blood glucose level was decreased.

  In other words, olive leaf extract is used in various diseases such as metabolic syndrome, diabetes and its complications, arteriosclerosis, gastrointestinal diseases, etc. due to decreased blood levels of adiponectin and increased insulin resistance. On the other hand, it was confirmed that it has excellent preventive and therapeutic effects.

Example 2
The blood adiponectin concentration is inversely correlated with the body mass index (BMI), which is an index representing the degree of obesity in humans. The average value is reported to be about 6 μg / ml for Japanese men and about 9 μg / ml for women. ing. According to the Japanese Society of Obesity, standard weight is given when the BMI is 22, and obesity is given when the BMI is 25 or more.

  Therefore, in 21 males and females with a BMI of 25 or more whose blood adiponectin level is below average, the serum after taking an olive leaf extract-containing supplement (test sample) three times a day for 8 weeks before meals The total adiponectin concentration and the high molecular weight multimer adiponectin concentration were measured.

(subject)
According to the configuration shown in Table 1 below.

(Test sample)
The following olive leaf extract-containing supplement was used. In addition, content shows content in 3 tablets.
(Compound component) (mg / 3 tablets)
Olive leaf extract 300 (pure)
Seaweed polyphenol ^{(Note 1)} 100
Red ginger extract 15
(Note 1): A type of polyphenol called phlorotannin extracted from a brown alga of the family Hibamatidae called Ascophilum Nodsum from France.

(Test method)
Take the test sample (supplement) 3 times a day, 1 tablet before meal, orally for 8 weeks, collect blood at the start of the test (week 0), 4 weeks, and 8 weeks, and prepare serum according to the standard method, Serum total adiponectin concentration and high molecular weight multimer adiponectin concentration were measured. For the measurement, a human multimeric adiponectin fractionation measurement kit (Daiichi Kagaku) was used. The results are shown in FIG.

  FIG. 2 (a) shows the total amount of adiponectin in blood, and FIG. 2 (b) shows the amount of high molecular polymer adiponectin in blood. In the figure, the horizontal axis indicates the week. As is clear from these figures, the blood total adiponectin concentration was significantly increased after 8 weeks of ingestion, and the high molecular weight multimeric adiponectin concentration was significantly increased at both of 4 weeks and 8 weeks after ingestion.

  This Example 2 confirmed for the first time an increase in blood adiponectin concentration, particularly a high molecular weight multimeric adiponectin concentration, due to ingestion of olive leaf extract in humans, in addition to pharmaceuticals. From this, the adiponectin production promoter of the present invention can be used as food and the like, and by ingesting these foods, it is possible to increase high molecular multimeric adiponectin in the blood, metabolic syndrome, diabetes and Excellent preventive / therapeutic effects are expected for various pathologies such as complications, arteriosclerosis, and digestive diseases.

  Further formulation examples are shown below. In addition, in each prescription example, an extract compounding quantity shows a pure part (actual part).

Example 3: Supplement (in 3 tablets)
(Mixed component) (mg)
Olive leaf extract 300
Resveratrol ^{(Note 2)} 2
Red ginger 15
(Note 2): A type of polyphenol that is abundant in grape skins, shoots, red wine, and peanut skins.

Example 4: Supplement (in 3 tablets)
(Mixed component) (mg)
Olive leaf extract 300
Fresh coffee extract ^{(Note 3)} 100
Red ginger 15
(Note 3): An extract extracted with water-containing ethanol from the seeds of coffee beans and Rubiaceae coffee tree.

Example 5: Supplement (in 3 soft capsules)
(Mixed component) (mg)
Coenzyme Q10 100
Black pepper extract 4
L-carnitine tartrate 100
Isoflavone aglycon 30
Vitamin B ₁ 20
Vitamin B ₂ 12
Isoleucine 10
Leucine 20
Valine 10
Olive leaf extract 10

2 is a graph showing blood adiponectin concentrations in a control group and an olive leaf extract ingestion group in Example 1. 3 is a graph showing the blood adiponectin concentration in humans in Example 2. FIG. 2 (a) shows the blood total adiponectin concentration, and FIG. 2 (b) shows the polymer multimeric adiponectin concentration.

Claims (9)

  Adiponectin production promoter containing olive leaf extract as an active ingredient.   The adiponectin production promoter according to claim 1, which is a food, a pharmaceutical preparation or a feed.   The adiponectin production promoter according to claim 1 or 2, which is a food with a function indication based on the adiponectin production promoting effect.   The adiponectin production promoter according to any one of claims 1 to 3, wherein the production promotion of adiponectin is the production promotion of high molecular weight adiponectin having a molecular weight of 300 kDa or more.   The adiponectin production promoter according to any one of claims 1 to 4, which is a preventive or therapeutic agent for hypoadiponectinemia.   The adiponectin production promoter according to any one of claims 1 to 4, which is an insulin resistance improving agent.   The adiponectin production promoter according to any one of claims 1 to 4, which is a preventive or therapeutic agent for metabolic syndrome.   The adiponectin production promoter according to any one of claims 1 to 4, which is a preventive or therapeutic agent for diabetes and its complications.   The adiponectin production promoter according to any one of claims 1 to 4, which is a preventive or therapeutic agent for nonalcoholic steatohepatitis (NASH) and liver disease derived therefrom.

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