JP6245867B2 - PPARγ activity improving agent and oral composition using the same - Google Patents

Description

  The present invention relates to an oral composition using a PPARγ activity improver and a PPARγ activity improver.

  Metabolic syndrome (visceral fat syndrome), which is a combination of obesity with visceral fat accumulation (visceral fat-type obesity) and any combination of hyperglycemia, hypertension, and lipid abnormalities, is greatly related to lifestyle-related diseases. I know that. Obesity is a condition in which fat accumulates and cells are enlarged, and so far fat cells have been thought to be a tissue that accumulates excess energy. However, it has been found that adipocytes secrete physiologically active substances and play an important role in sugar and lipid metabolism.

  When fat accumulates in the fat cells, a physiologically active substance called adipocytokine is secreted from the fat cells. Specific examples of adipocytokines include adiponectin, leptin, TNF-α, PAI-1, HB-EGF, resistin and the like. In particular, adiponectin is a protein that is secreted specifically from adipocytes, and it is known that adiponectin is secreted in a large amount in small adipocytes and that the amount of secretion is reduced in enlarged fat cells. And it is also present in the blood at a high concentration, and a decrease in the blood adiponectin concentration is considered to cause insulin resistance and cause lifestyle-related diseases such as cardiovascular disease, diabetes and obesity. Insulin resistance is a state in which insulin sensitivity is reduced. That is, insulin is ineffective, and blood glucose control is not normal, which is a major cause of hyperglycemia.

  A protein that affects the secretion of this adipocytokine is a peroxisome proliferator-activated receptor (PPAR). This PPAR is one of nuclear receptors that regulate transcription depending on a substance (ligand) that binds to a specific receptor. In mammals, three types of PPARα, PPARδ, and PPARγ are known. PPARα is expressed in the liver, kidney, heart, small intestine, etc., and PPARδ is not expressed in a tissue-specific manner and has a universal expression. Is recognized. PPARγ has at least three isoforms, is deeply involved in insulin sensitivity, and plays a role in controlling adipocyte differentiation and lipid uptake (Non-patent Document 1).

  In particular, PPARγ is an indispensable molecule for adipocyte differentiation. Specific examples of the PPARγ ligand include arachidonic acid metabolites such as 15-dioxy-Δ12,14-prostaglandin J2 and Δ12-prostaglandin J2, α-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid ( Eicosanoids such as unsaturated fatty acids such as DHA) and 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid are known (Non-patent Document 2). Further, conjugated unsaturated fatty acids having 10 to 26 carbon atoms having a conjugated triene structure or a conjugated tetraene structure (Patent Document 1) are known synthetic compounds such as thiazolidine derivatives such as troglitazone, pioglitazone, and rosiglitazone. Yes.

  A thiazolidine derivative, which is a PPARγ ligand, activates PPARγ to increase small adipocytes having normal functions differentiated from preadipocytes. And the insulin resistance is improved by reducing the hypertrophic fat cells in which the production and secretion of TNF-α, which is an adipocytokine that brings about insulin resistance, is increased by cell death (apoptosis) (Non-patent Document 3). ). By improving insulin resistance, it is effective for prevention and improvement of symptoms such as hyperlipidemia, hypertension, type 2 diabetes, visceral fat obesity and fatty liver. Therefore, the PPARγ ligand is effective in preventing and ameliorating a pathological group caused by insulin resistance, that is, metabolic syndrome.

  Thus, PPAR is involved in adipocytokines. In particular, PPARγ ligand leads to downsizing of adipocytes by induction of differentiation from preadipocytes into small adipocytes capable of producing adiponectin and apoptosis of enlarged adipocytes. In small adipocytes, in addition to an increase in the production of adiponectin, the production of TNF-α, which is an inflammatory cytokine, decreases, resulting in an increase in insulin sensitivity. On the other hand, hypertrophic large fat cells increase the production amount of TNF-α, decrease insulin sensitivity, and increase blood glucose level. Thus, the improvement of PPARγ activity promotes the secretion of adipocytokines, particularly adiponectin which affects the improvement of insulin sensitivity, and further reduces the production of TNF-α. Therefore, thiazolidine derivatives, which are PPARγ ligands, increase blood adiponectin levels in patients with impaired glucose tolerance (Non-Patent Document 4).

  Moreover, as a method for promoting the secretion of adiponectin, triterpenes extracted from rice bran, rahan fruit, shimeji, chrysanthemum, rye, birch and moon peach (Patent Document 2), specific aminoalkoxybibenzyls (Patent Document 3) A method of administering curcumin (patent document 4) and fermented tea extract (patent document 5) extracted from rhizomes of ginger family turmeric is proposed. In addition, a technique in which an extract of a Labiatae plant promotes secretion of adiponectin has been proposed (Patent Document 6).

  Furthermore, there is a PPARγ ligand agent comprising at least one compound selected from the group consisting of dehydrodioigenol A, dehydrodioigenol B, magnolol, oleanolic acid, betulinic acid and salts of these compounds (Patent Document 7). Proposed.

JP 2000-355538 A JP-A-2005-068132 JP 2005-053890 A JP 2005-060308 A JP 2004-315379 A JP 2007-106718 A Japanese Patent Laying-Open No. 2005-097216

“Ayumi of Medicine”, Ishiyaku Publishing Co., Ltd., 1998, Vol. 184, p. 519-523 “Diabetologia” (UK), European Diabetes Society, 1999, Vol. 42, p. 1033-1049 "The Journal of Clinical Investigation" (USA), American Society for Clinical Investigation, 1998, Vol. 101, p. 1353-1361 “Diabetes” (USA), American Diabetes Society, 2001, 50, p. 2094-2099

  The present invention was made to provide an oral composition using a PPARγ activity enhancer and a PPARγ activity enhancer that promote secretion of adipocytokines and improve sugar and lipid metabolism.

As a result of intensive studies to solve the above problems, the present inventors have found that an extract of legumes and an extract of Lamiaceae have a PPARγ activity, and have completed the present invention. It was.
That is, the present invention is as follows.

  (1) A PPARγ activity improver comprising an extract of a leguminous plant and an extract of a Labiatae plant.

  (2) The PPARγ activity enhancer according to claim 1, wherein the legume is rooibos.

  (3) The PPARγ activity improver according to claim 1, wherein the Labiatae plant is basil.

  (4) An oral composition comprising the PPARγ activity improving agent according to any one of (1) to (3).

  The present invention is a PPARγ activity enhancer and an oral composition using the same, and by ingesting it, PPARγ can be activated, secretion of adipocytokines from adipocytes can be promoted, and insulin sensitivity can be improved It becomes. Therefore, it is effective in preventing or improving diabetes, arteriosclerosis, hypertension, hyperlipidemia, metabolic syndrome and the like.

  The PPARγ activity improver of the present invention contains an extract extracted from a leguminous plant and an extract extracted from a Lamiaceae plant.

  Specific examples of the legume extract include soybeans, peas, peanuts, rooibos, enju, licorice and the like. The state of the leguminous plant may be the same as in the case of the Lamiaceae plant or may be in a dry state, but it is preferable to use a dried one in terms of handling and availability. In the present invention, an extract of rooibos is used because it can act on cells before being differentiated from precursor cells into mast cells, thereby improving PPARγ activity and in particular, promoting the secretion of adiponectin. It is preferable.

  The Lamiaceae plant is specifically selected from one or more plants selected from perilla such as blue perilla and red perilla, egoma, basil, mint, sage, marjoram, oregano, thyme and lemon balm. Use the same thing. The state of the Lamiaceae plant may be a raw state or a dried state, but it is preferable to use a dried one from the viewpoint of storage stability as raw materials, handling of extract components and availability. In the present invention, an extract of basil is used because it acts on cells before being differentiated from precursor cells into mast cells, improves PPARγ activity, and particularly promotes adiponectin secretion. It is preferable.

  The blending ratio of the leguminous plant extract and the Lamiaceae plant extract is more preferably 0.1 or more, preferably the extract of the Lamiaceae plant is 10 when the extract of the leguminous plant is 10 by mass ratio. Is 1 or more, particularly preferably 2.5 or more. Moreover, when the leguminous plant extract is 10 in terms of mass ratio, the extract of Lamiaceae plant is 10 or less, more preferably 9.0 or less, and particularly preferably 8.0 or less. By blending leguminous plant extract and Lamiaceae plant extract in this range, the effect of improving PPAR activity, particularly PPARγ activity, for each cell leading to differentiation from precursor cells to mast cells is sufficiently obtained. be able to.

  The method for extracting the leguminous plant extract and the Lamiaceae plant extract is not particularly limited, and may be a method usually used when extracting each component including an extract from a plant or the like. As specific examples, one or two or more parts selected from whole plants, flowers, sepals, seeds, fruits, leaves, branches, bark, root barks, rhizomes, roots, etc. are used without being processed, Or processing, such as cutting, grinding | pulverization, or a fine powder, is followed by extraction or extraction with a solvent. In addition, although there is no restriction | limiting in particular in the site | part of the plant to be used, it is good to use a leaf from the point of handling and acquisition. When using seeds or fruits, it is desirable to degrease in advance to reduce the oil content. In the case of heat extraction, the obtained filtrate can be dried under reduced pressure or freeze-dried.

  In this invention, when using the extraction method using the said solvent, it does not specifically limit as a solvent, Arbitrary things can be selected suitably. Specific examples include water, lower alcohols having 1 to 4 carbon atoms, hydrous polyhydric alcohols, other organic solvents, acids and alkalis. When extraction is performed using a highly volatile solvent, the solvent can be removed and then dissolved in water. In the present invention, these may be used alone or in combination of two or more. In particular, when it is difficult to use an organic solvent such as a food or cosmetic material, it is preferable to select water or ethanol. When a dried product of the leguminous plant and Lamiaceae plant is extracted with water, the operation is easy and can be used as a food for beverages without being processed.

  Solvent extraction method uses the leguminous plant and Lamiaceae plant in the raw or dry state as they are without processing, or cuts, grinds or processes fine powder, and the extraction solvent is 5 to 100 times the amount. Add. Subsequently, it is left to stand at normal pressure and normal temperature for 1 to 72 hours or shaken. The temperature condition is appropriately set depending on the boiling point of the solvent to be used, but is preferably set in the range of −4 to 100 ° C. Moreover, it can filter, after setting temperature conditions before and behind the boiling point of an extraction solvent, and extracting for 10 to 30 minutes. Furthermore, pressurization conditions can be set arbitrarily. The extraction time is appropriately set in the range of 10 minutes to 72 hours. During extraction, the extraction may be promoted by applying vibrations such as ultrasonic waves or low frequencies, or shaking the container.

  In the present invention, the PPARγ activity enhancing action can be further enhanced by solvent extraction or concentration of the obtained extract rather than exploitation.

  Moreover, the extract which added the solvent to the pressing liquid obtained by squeezing by methods, such as a pressing process, and / or the residue, and extracted can also be used as an extract in this invention. Further, a supercritical extraction method using a supercritical fluid using carbon dioxide, carbon dioxide gas, or the like can be used.

  In the present invention, each plant for obtaining an extract can be extracted either alone or in combination.

  The extract obtained by the solvent extraction method can be used without being processed, but if necessary, purification treatment such as deodorization and decolorization can be added within a range not affecting the effect. As such a purification treatment, a normal means can be arbitrarily selected. Specific examples include filtration, ion exchange resin, activated carbon column and the like. Furthermore, a purified product in the form of a solution, solid, paste, gel, or powder can be obtained by lyophilization or concentration treatment.

  Furthermore, the present invention relates to an oral composition using the PPARγ activity improver. Specific examples of the oral composition include foods, beverages, pharmaceuticals, quasi drugs, foods for specified health use, functional nutritional foods, health foods, and the like. In particular, a health food in a form that can be ingested as a normal meal is preferred. Furthermore, feed for animals other than humans, such as domestic animals and pets, diet foods for animals, beverages, and the like. The oral composition of the present invention can achieve its effect even with the PPARγ activity improver alone, but can contain known ingredients used in foods and pharmaceuticals for facilitating oral intake, and can be processed by an appropriate method. can do. The shape of the food and drink composition of the present invention is not particularly limited, and specific examples include beverages, powders, granules, tablets, capsules, ampoules, pills, powders, granules, solids, liquids, gels, bubbles, and emulsions. , Sheets, mists, sprays, and other forms that are generally ingestible as food or drugs. An optimum shape can be appropriately selected according to the use conditions.

  The content of the PPARγ activity enhancer contained in the oral composition is appropriately adjusted according to the type, purpose, form, intake method, etc., but the intake amount of the PPARγ activity enhancer converted per day is 0. .1 to 500 mg / kg body weight is desirable.

  Examples of foods and beverages as the oral composition include oral compositions such as gums and candy, processed fishery products such as kamaboko, livestock products such as sausages and hams, Western confectionery, Japanese confectionery, Chinese noodles Noodles such as soba and buckwheat, seasonings such as sauce and soy sauce, spices such as mustard and pepper powder, processed vegetables and fruits such as jam, marmalade, chocolate spread, pickles, prepared dishes, sprinkles, canned foods, cheese and yogurt, etc. Dairy products, miso soup, soup, fruit juice, vegetable juice, whey beverages, soft drinks and liquor beverages such as liquors, nutritional supplements, health supplements and the like.

  Next, the present invention will be described in more detail with reference to examples.

(Preparation of extract)
(Extract 1)
Under normal pressure at 23 ° C., 5 g of a dried product of basil (produced in South Africa) was immersed in 95 ml of water, and stirred for 1 hour using a stirrer whose rotation speed was set to 800 to 1200 rpm. Subsequently, the obtained extract was filtered with a filter paper No. 2 (Advantech Toyo Co., Ltd.) was used for filtration to obtain an extract.

(Extract 2)
Extracts were obtained in the same manner as Extract 1 except that garlic (from South Africa) was used as a plant for obtaining the extract.

(Extract 3)
Extracts were obtained in the same manner as Extract 1 except that Rooibos (from South Africa) was used as a plant for obtaining the extract.

Example 1
Extracts 1 and 3 were each weighed in 15 μl to prepare 30 μl of mixed extract, which was used as a PPARγ activity improver.

(Comparative Examples 1-5)
Extracts 1 to 3 were mixed at a blending ratio shown in Table 1, and the extract was used as a PPARγ activity improver.

(Measurement of adiponectin and PPARγ gene expression levels)
Using Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, fat precursor cells 3T3-L1 were added to a 6-well plate at 2 × 10 ⁴ cells / ml at 37 ° C. in a 5% carbon dioxide atmosphere. Dispensing and culturing for 24 hours. Subsequently, 2 μmol / l of a recombinant low-concentration insulin differentiation inducer was added and cultured for 144 hours, and then the extract used as a PPARγ activity improver was added. From the cells collected after the addition, total RNA was extracted using Fast pure RNA Kit (manufactured by Takara Bio Inc.), cDNA was synthesized using PrimeScript RT reagent Kit (manufactured by Takara Bio Inc.), and then adiponectin and The PPARγ gene expression level was measured using a real-time PCR apparatus (manufactured by Takara Bio Inc.). The obtained measurement results are shown in Tables 2 and 3. In addition, the obtained numerical value makes adiponectin and a PPARγ gene expression level 1 when a PPARγ activity improving agent is not added, and shows a relative value with respect to it.

As is apparent from the results of Tables 2 and 3, in Example 1, when the PPARγ activity improver was added, both the adiponectin expression level and the PPARγ expression level were larger than Comparative Examples 1 to 5. Yes. This indicates that basil, ie an extract of Lamiaceae and rooibos, ie an extract of legumes, have significantly improved PPARγ activity. In particular, when Example 1 is compared with Comparative Example 5, the numerical value is remarkably increased by using a mixed component rather than a single component. Furthermore, when Example 1 is compared with Comparative Example 1 and Comparative Example 3, it can be seen that each of the mixed components has an activity improving effect that cannot be obtained with a single component. Therefore, the PPARγ activity improver of the present invention can be expected to have a remarkable effect by using a combination of components.
From this, oral compositions such as foods, beverages, pharmaceuticals, pet animal feed and the like containing the PPARγ activity improver of the present invention improve PPARγ activity by ingesting them, and promote the secretion of adiponectin, Insulin resistance can be effectively improved. In addition, diabetes, arteriosclerosis, hypertension, hyperlipidemia, obesity, metabolic syndrome, type 2 diabetes, visceral fat obesity, and fatty liver can be prevented or improved.

  It is effective for the prevention or improvement of diabetes, arteriosclerosis, hypertension, hyperlipidemia, metabolic syndrome, etc. by processing into foods and beverages as oral compositions and taking them.

Claims (5)

Legume water containing leaves, lower alcohol having 1 to 4 carbon atoms, or leguminous plant extract with water-containing polyhydric alcohol, and water of Lamiaceae plants containing leaves, lower alcohol having 1 to 4 carbon atoms, Or a Lamiaceae plant extract with hydrous polyhydric alcohol,
The legume is rooibos,
A PPARγ activity improver, wherein the Labiatae plant is basil.   The PPARγ activity enhancer according to claim 1, wherein the leguminous plant extract is a water extract, and the Labiatae plant extract is also a water extract. An oral composition for activating PPARγ, comprising the PPARγ activity improving agent according to claim 1. A method for producing a PPARγ activity enhancer comprising an extract of legumes and an extract of Lamiaceae,
Extracting leguminous plants containing leaves with water, lower alcohols having 1 to 4 carbon atoms, or hydrous polyhydric alcohols to obtain leguminous plant extracts;
Extracting a Labiatae plant containing leaves with water, a lower alcohol having 1 to 4 carbon atoms, or a hydrous polyhydric alcohol to obtain a Labiatae plant extract; and
Mixing said legume extract and said Labiatae plant extract;
Including
The production method in which the legume is Rooibos and the Labiatae is basil . A method for producing a PPARγ activity enhancer comprising an extract of legumes and an extract of Lamiaceae,
Extracting a mixture of legumes containing leaves and Lamiaceae plants containing leaves with water, a lower alcohol having 1 to 4 carbon atoms, or a hydrous polyhydric alcohol, a mixed extract of legumes and Lamiaceae Including obtaining
The production method in which the legume is Rooibos and the Labiatae is basil .