JP2021107400A - Obesity suppressant - Google Patents

Abstract

To provide an obesity-suppressing product that promotes the differentiation of white adipose precursor cells to brown adipocytes and activates UCP1 in brown adipocytes to increase energy consumption in brown adipose cells; and/or activates the brown adipose tissue via inflammation suppression in the adipose tissue to increase energy consumption in the brown adipose tissue, thereby suppressing accumulation of excess fat in the body and suppressing obesity, effective for prevention and treatment of lifestyle diseases, such as diabetes, dyslipidemia, and arteriosclerosis, and metabolic syndromes, in which these lifestyle diseases and obesity, especially visceral fat type obesity, are accumulated in one individual.SOLUTION: According to the present invention, an obesity suppressant comprises as an active ingredient at least one of succinic acid, gluconic acid, 2-keto-D-gluconic acid, parathyroid hormone-related peptide (PTHrP).SELECTED DRAWING: None

Description

The present invention promotes the differentiation of white adipose tissue into brown adipose tissue, activates uncoupling protein 1: UCP1 in brown adipose tissue, and increases energy consumption in brown adipose tissue. , And / or, through suppression of inflammation in adipose tissue, activates brown adipose tissue and increases energy consumption in brown adipose tissue, thereby suppressing fat accumulation in the living body and suppressing obesity. It relates to an adipose inhibitor that is excellent, effective in the prevention and treatment of lifestyle diseases and metabolic syndrome, and has excellent stability and safety. The present invention also relates to obesity-suppressing foods and drinks, obesity-suppressing nutritional compositions, obesity-suppressing feeds, and obesity-suppressing pharmaceuticals containing the obesity-suppressing agent.

With recent changes in eating habits and lifestyles, the number of patients with lifestyle-related diseases such as diabetes, dyslipidemia, and arteriosclerosis is increasing, mainly in developed countries. In addition, the proportion of obese people in Japan, which is directly linked to the increase in medical expenses, is as high as 28% for men and 20% for women, which has become a major social problem (Non-Patent Document 1). On the other hand, these lifestyle-related diseases and obesity, especially the state in which visceral fat obesity is accumulated in one individual, is called metabolic syndrome, and it is known that it leads to serious diseases such as stroke. Recently, visceral fat-type obesity has frequently occurred in mammals other than humans, for example, pets kept at home, which has become a big problem from the viewpoint of animal protection.

The main cause of obesity is the enlargement of fat cells. In addition, the enlarged adipocytes secrete inflammatory cytokines such as Tumor Necrosis Factor α (TNFα) and free fatty acids, induce insulin resistance from a chronic inflammatory state, and develop lifestyle-related diseases including diabetes. It is believed to cause. On the other hand, it is known that non-hypertrophied adipocytes secrete anti-inflammatory cytokines such as adiponectin and leptin to enhance islin sensitivity. Therefore, it is very important to prevent the hypertrophy of adipocytes and suppress inflammation in order to prevent obesity, lifestyle-related diseases associated with obesity, and various diseases such as metabolic syndrome (Patent Document 1). 2, 2).

In general, it has been reported that there are two types of adipocytes, white adipocytes and brown adipocytes (Non-Patent Document 2). White adipocytes store fat in the cells in the form of triglycerides and store energy. On the other hand, brown adipocytes, like white adipocytes, accumulate fat inside the cells, but due to the action of UCP1 existing on the mitochondrial membrane, the proton gradient generated by the electron transport chain is not converted to ATP. Convert to heat energy. That is, in the living body, the balance of systemic energy and body fat is adjusted by the energy storage by white adipocytes and the energy consumption by heat production of brown adipocytes. In recent studies, brown adipocytes are of the "existing type" in which the cell fate is already determined at the early stage of embryogenesis and the "induced type" in which differentiation is induced from white adipocytes due to various environmental factors in adults. It is known that there are two types (Non-Patent Document 2). In humans, existing brown adipocytes are present in small amounts around the scapula, behind the neck, and under the armpits, and decrease with age. On the other hand, it has been reported that long-term cold stimulation and administration of PPARγ agonist activate the existing brown adipose tissue in adults, and that white adipose tissue progenitor cells existing in white adipose tissue differentiate into brown adipose tissue. .. Therefore, it promotes the differentiation of white adipose progenitor cells into brown adipocytes and activates brown adipocytes to promote energy metabolism, suppress excessive fat accumulation and obesity in the living body, and suppress metabolic syndrome and the like. Can be prevented or ameliorated.

Furthermore, recently, when a diet with a high fat content is consumed, the function of UCP1 in brown adipocytes is reduced and obesity is exhibited. It has been reported that even if it does not become obese. Therefore, there is an active search for drugs and foods that can be expected to have the effect of enhancing the function of UCP1 and suppressing obesity. In addition, since the inflammatory state causes dysfunction of UCP1 existing in brown adipocytes, the search for drugs and foods that can be expected to have the effect of enhancing the function of UCP1 through anti-inflammatory action and suppressing obesity is also being conducted. .. However, in this case, in order to suppress excessive fat accumulation and obesity in the living body, it is important to review lifestyle habits, especially eating habits, so that it can be safely ingested on a daily basis. It is important that there is no safety problem even if it is ingested for a long period of time.

Since milk and dairy products have been eaten since ancient times, they are foods that can be safely and safely ingested for a long period of time on a daily basis, and epidemiological studies have reported that their intake suppresses obesity. Further, it is known that κ-casein and lactoferrin, which are proteins contained in milk, suppress fat accumulation in adipocytes and improve lipid metabolism, respectively (Patent Documents 3 and 4). However, succinic acid and gluconic acid, 2-keto-D-gluconic acid, parathyroid hormone-related Peptide (PTHrP), especially succinic acid and gluconic acid contained in milk and dairy products, 2-keto -D-gluconic acid and PTHrP promote the differentiation of white adipose precursor cells into brown adipose cells and enhance the function of UCP1 present in brown adipose cells, thereby suppressing fat accumulation in the living body, which is excellent. It is not known to exert an anti-obesity effect.

Japanese Unexamined Patent Publication No. 2006-28049 Japanese Unexamined Patent Publication No. 2011-153093 Japanese Unexamined Patent Publication No. 2009-190980 International Publication No. 2003/057245

Ministry of Health, Labor and Welfare, 2013 National Health and Nutrition Survey Report Kazimura, S. et. al. : Cell Metab. , 2010, 11: 257-262, 2010

The present invention promotes the differentiation of white adipose tissue into brown adipose tissue, activates UCP1 in brown adipose tissue, increases energy consumption in brown adipose tissue, and / or suppresses inflammation in adipose tissue. By activating brown adipose tissue and increasing energy consumption in brown adipose tissue, it suppresses fat accumulation in the body and has an excellent effect of suppressing obesity, and prevents lifestyle diseases and metabolic syndrome. It relates to an obesity inhibitor that is effective for treatment and has excellent stability and safety. Another object of the present invention is to provide an obesity-suppressing food or drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug containing the obesity-suppressing agent.

As a result of diligent studies to solve the above problems, the present inventors promoted the differentiation of white adipose precursor cells into brown adipose cells by succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP. Or activate UCP1 in brown adipose tissue to increase energy consumption in brown adipose tissue and / or activate brown adipose tissue through suppression of inflammation in adipose tissue and energy in brown adipose tissue. It was found that increasing consumption has a remarkable effect of suppressing obesity.
That is, the present invention includes the following aspects.
(1) An obesity suppressant containing succinic acid, gluconic acid, 2-keto-D-gluconic acid and / or PTHrP as active ingredients.
(2) The obesity inhibitor according to (1) above, wherein the succinic acid, gluconic acid, 2-keto-D-gluconic acid and / or PTHrP are derived from milk.
(3) The obesity-suppressing agent according to (1) to (2) above, wherein the obesity-suppressing effect enhances energy metabolism.
(4) The obesity-suppressing agent according to (1) to (3) above, wherein the obesity-suppressing effect promotes the differentiation of white adipose progenitor cells into brown adipocytes.
(5) The obesity-suppressing agent according to (1) to (3) above, wherein the obesity-suppressing effect activates brown adipose tissue.
(6) The obesity-suppressing agent according to (1) to (3) or (5) above, wherein the obesity-suppressing effect suppresses inflammation in adipose tissue.
(7) An obesity-suppressing food or drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug, which comprises the obesity-suppressing agent according to any one of (1) to (6) above.
(8) The food or drink for obesity control according to (7), wherein the food or drink is milk powder, milk drink, lactic acid bacteria drink, fermented milk, soft drink, cheese, margarine, cream, pudding, jelly, or wafer. 9) A method for suppressing obesity by orally ingesting the obesity suppressant according to any one of (1) to (8).

The anti-obesity agent of the present invention promotes the differentiation of white adipose tissue precursor cells into brown adipose tissue, activates UCP1 in brown adipose tissue, increases energy consumption in brown adipose tissue, and / or fat. Through suppression of inflammation in tissues, the action of activating brown adipose tissue and increasing energy consumption in brown adipose tissue is remarkable, suppressing excessive fat accumulation and obesity in the body, and causing diabetes and lipid abnormalities. It is effective for the prevention and treatment of lifestyle diseases such as illness and arteriosclerosis and those lifestyle diseases and obesity, especially metabolic syndrome in which visceral fat type obesity is accumulated in one individual. In addition, since the obesity suppressant of the present invention contains a substance contained in mammalian milk as an active ingredient, it can be safely and safely ingested for a long period of time on a daily basis.

As the active ingredients of the obesity suppressant of the present invention, succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, those prepared by a known method can be used. For example, those prepared from the milk of mammals such as humans, cows, buffaloes, goats, sheep, camels, horses, ryamas, and yaks, those prepared from foods such as shellfish, scallops, shell juice, grains, and honey, and microorganisms. Those produced by, chemically synthesized, produced by genetic engineering techniques, purified from blood and organs, etc. can be used. It is also possible to use purified and commercially available reagents.

The active ingredients of the obesity suppressant of the present invention, succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, may be used as they are as the obesity suppressant, but if necessary, they are powdered according to a conventional method. , Granules, tablets, capsules, drinks, etc. can be formulated and used. In addition, foods and drinks such as nutritional supplements, milk powder, milk drinks, lactic acid bacteria drinks, fermented milk, soft drinks, cheese, margarine, cream, pudding, jelly, and wafers, nutritional compositions, feeds, and pharmaceuticals as they are or after formulation. It is also possible to blend in.

The obesity-suppressing food and drink, the obesity-suppressing nutritional composition, the obesity-suppressing feed, and the obesity-suppressing drug of the present invention are succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, which are used alone or arbitrarily. It is possible to contain the stabilizers and sugars, lipids, flavors, vitamins, minerals, flavonoids, polyphenols and other raw materials usually contained in other foods and drinks, feeds and medicines. Further, the food and drink for obesity control, the nutritional composition for obesity control, the feed for obesity control and the drug for obesity control of the present invention include succinic acid, gluconic acid, 2-keto-D-gluconic acid and PTHrP which are active ingredients. In addition, other components having an obesity-suppressing effect, such as κ-casein and lactoferrin, can also be used. Further, such foods and drinks for obesity control, nutritional compositions for obesity control, feeds for obesity control or pharmaceuticals for obesity control may be used as raw materials, and raw materials and the like usually contained in other foods and drinks may be blended and prepared. It is possible.

In the amount of succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP in the obesity suppressant, the food and drink for obesity control, the nutritional composition for obesity control, the feed for obesity control, and the drug for obesity control of the present invention. Is not particularly limited, but in order to promote the differentiation of white adipose precursor cells into brown adipose cells and activate brown adipose cells, 10 to 100 mg of succinic acid per adult per day. It is preferably 100 mg or more, 80 to 800 mg for gluconic acid, preferably 800 mg or more, 0.8 to 8 mg for 2-keto-D-gluconic acid, preferably 8 mg or more, and 20 to 200 mg for PTHrP, preferably. It is preferable to adjust the blending amount in foods and drinks, nutritional compositions, feeds, medicines, etc. so that 200 mg or more of obesity can be taken orally.

The milk powder, which is a food and drink for suppressing obesity of the present invention, refers to raw milk, milk, special milk, or milk powder processed into powder by spray-drying or freeze-drying using these as raw materials. Includes powder, full milk powder, whey powder, milk mineral concentrate, dried cheese powder, WPI, WPC, formula milk powder or special milk powder and the like. As auxiliary raw materials, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shell juices, scallops, grains, sugars, spices, flavors or nutritional substances, etc., which are generally used in the production of milk powder, are all used. It is possible. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The milk beverage, which is a food and drink for obesity control of the present invention, refers to raw milk, milk, special milk, or a beverage produced from these as a raw material, and has a milk solid content of 3.0% or more. As an auxiliary ingredient, vegetable juice, fruit juice, stabilizers, emulsifiers, starch, modified starch, vegetable fat, shell juice, scallops, grains, sugars, spices, fragrances, nutrients, etc. are generally used in the production of milk beverages. Any of the auxiliary raw materials used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The lactic acid bacteria beverage, which is a food and drink for suppressing obesity of the present invention, refers to raw milk, milk, special milk, or a beverage obtained by fermenting these with lactic acid bacteria or yeast as a raw material, or using the lactic acid bacteria as a main raw material. The number or the number of yeasts is 10 million pieces / ml or more. As auxiliary ingredients, vegetable juice, fruit juice, stabilizers, emulsifiers, starch, processed starch, vegetable fat, shell juice, scallops, grains, sugars, spices, fragrances, nutrients, etc., generally for the production of lactic acid bacteria beverages Any of the auxiliary raw materials used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The fermented milk, which is a food and drink for suppressing obesity of the present invention, is raw milk, milk or special milk, or fermented with lactic acid bacteria or yeast using these as raw materials. Non-fat milk solid content of 8.0% or more and the number of lactic acid bacteria or yeast. 10 million pieces / ml or more, hard type with a pudding-like structure that is filled and fermented in a retail container, soft type that crushes fermented cards and fills them in a container, cards Includes liquid fermented milk, which is homogenized and liquefied after crushing. As an auxiliary ingredient, vegetable juice, fruit juice, stabilizers, emulsifiers, starch, modified starch, vegetable fat, shell juice, scallops, grains, sugars, spices, fragrances or nutrients, etc., generally for the production of fermented milk. Any of the auxiliary raw materials used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The refreshing drinking water, which is a food and drink for suppressing obesity of the present invention, refers to a beverage containing less than 1% by volume of alcoholic beverage excluding lactic acid bacteria beverage, milk and dairy products, and is a carbonated beverage, fruit beverage, coffee beverage, tea-based beverage, etc. Includes sports beverages, dairy beverages, functional beverages, nutritional beverages, soy milk beverages and the like. Stabilizers, emulsifiers, starches, modified starches, vegetable fats, shell juices, scallops, grains, sugars, spices, flavors or nutrients, etc., which are commonly used in the production of soft drinks, are used as auxiliary ingredients. It is possible. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The cheese which is a food and drink for suppressing obesity of the present invention may be natural cheese or processed cheese, and for example, fresh cheese such as cream cheese, mozzarella, ricotta, mascarpone, fromage blanc, camembert, bree and the like. White mold cheese, blue mold cheese such as Gorgonzora, Stillton, Rockfall, wash cheese such as Rivalo, semi-hard cheese such as Probolone, Goda, natural cheese such as hard cheese such as Grana, Emmental, and cheddar, process cheese, cheese food, milk, etc. Includes all cheeses such as foods whose main ingredient is. The raw material cheese for processed cheese is not particularly limited as long as it is used in the production of ordinary processed cheese, and for example, either hard or semi-hard natural cheese or a combination of such cheese is used. Even the one can be used. It is also possible to use processed cheese as a part of the raw material. The molten salt and emulsifier of processed cheese are not particularly limited as long as they are used in the production of ordinary processed cheese, and for example, any of citrate, phosphate, sucrose fatty acid ester and the like, or Even a combination of such a molten salt and an emulsifier can be used. For the production of processed cheeses such as dairy products such as skim milk powder, milk components, stabilizers, emulsifiers, starches, processed starches, vegetable fats, shell juices, shells, grains, sugars, spices, fragrances, etc. Any of the auxiliary materials used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The margarines, which are foods and drinks for obesity control of the present invention, refer to water-in-oil emulsified compositions such as margarine and fat spread, and are prepared by using one or more kinds of fats and oils, milk components, emulsifiers and the like as main raw materials. NS. The oil and fat raw material is not particularly limited as long as it is used in the production of a water-in-oil emulsified composition such as ordinary margarine or spread, and for example, rapeseed oil, soybean oil, palm oil, corn oil, and saflower oil. , Vegetable oils and fats such as coconut oil and olive oil, animal oils and fats such as milk fat, fish oil, beef oil and pork oil, hardened oils thereof, ester exchange oils, fractionated oils, etc., or a combination of such oils and fats. You can use it even if you have it. As an auxiliary material, it is generally used for the production of dairy products such as skim milk powder, milk components, stabilizers, emulsifiers, starch, processed starch, vegetable fat, shell juice, shells, grains, sugars, spices or fragrances, etc. Any of the auxiliary raw materials to be used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The cream, which is a food or drink for suppressing obesity of the present invention, refers to an oil-in-water emulsified composition such as whipped cream or coffee cream, and is prepared by using one or more kinds of fats and oils, milk components, emulsifiers and the like as main raw materials. .. The oil and fat raw material is not particularly limited as long as it is used in the production of an oil-in-water emulsified composition such as ordinary whipped cream and coffee cream, and for example, rapeseed oil, soybean oil, palm oil, corn oil, and saflower. Vegetable oils and fats such as oils, palm oils and olive oils or animal oils and fats such as milk fats, fish oils, beef oils and pig fats, hardened oils thereof, ester exchange oils, fractionated oils, etc., or a combination of such oils and fats. Can still be used. As an auxiliary ingredient, it is generally used in the production of creams such as dairy products such as skim milk powder, milk components, stabilizers, emulsifiers, starch, processed starch, vegetable fat, shell juice, shells, grains, sugars, spices or fragrances. Any of the auxiliary raw materials to be used can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The pudding, which is a food and drink for suppressing obesity of the present invention, refers to a pudding that utilizes the thermal coagulation of egg protein and a pudding that uses a gelling agent, and contains one or more of eggs, milk components, sugars, and the like. Prepared as the main ingredient. The gelling agent is not particularly limited as long as it is used in ordinary pudding production, and for example, agar, gelatin, locust bean gum, xanthan gum, gellan gum, carrageenan, sodium alginate, starch, guar gum, tamarind seed gum, and karaya gum. , Pectin, carboxymethyl cellulose, psyllium seed gum, purulan, curdlan, etc., or a combination of such gelling agents can be used.
As auxiliary raw materials, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shell juices, scallops, grains, sugars, spices, flavors and the like, which are generally used in the production of pudding, can be used. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The jelly which is a food and drink for obesity control of the present invention refers to a jelly hardened by using a gelling agent, and is prepared by using one or more kinds of fruit juice, vegetable juice and sugar as a main raw material. The jelly may contain one or more of instant coffee, fruit juice, pulp, flavoring or coloring. Further, as the jelly, one that has been whipped or has air bubbles retained can be used. The gelling agent is not particularly limited as long as it is used in ordinary jelly production, and for example, agar, gelatin, locust bean gum, xanthan gum, gellan gum, carrageenan, sodium alginate, starch, guar gum, tamarind seed gum, and karaya gum. , Pectin, carboxymethyl cellulose, psyllium seed gum, purulan, curdlan and the like, or a combination of such gelling agents can be used.

The wafer, which is a food and drink for suppressing obesity of the present invention, is prepared by mixing one or more raw materials such as flour, milk powder, egg yolk, swelling agent, salt, fragrance, and fat, and adding water to adjust the concentration of the dough. Then, it is poured into two upper and lower baking plates and baked into a thin plate, and one or more kinds of cream, chocolate, caramel, jelly, etc. are sandwiched between the wafer sheets. As an auxiliary material, dairy products such as skim milk powder, milk components, stabilizers, emulsifiers, starch, processed starch, vegetable fat, shell juice, shells, grains, sugars, spices or fragrances, etc. are generally used in the production of wafers. Any auxiliary material can be used. Further, for the purpose of fortification, vitamins, minerals, vegetable powder, wheat germ, oligosaccharides and the like can be added. These auxiliary raw materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless there is a particular need.

The obesity suppressant of the present invention can be orally administered by adding an appropriate auxiliary agent to the above-mentioned active ingredients such as succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP to form an arbitrary form. It can be a possible obesity-suppressing composition. For formulation, commonly used diluents or excipients such as fillers, bulking agents, binders, disintegrants, surfactants and lubricants can be used. Excipients include, for example, sucrose, lactose, starch, crystalline cellulose, mannit, light anhydrous silicic acid, magnesium aluminate, synthetic aluminum silicate, magnesium aluminometasilicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate. , Calcium carboxylmethylcellulose, etc., or a combination of two or more.

Examples and test examples are shown below, and the present invention will be described in detail, but these are merely examples, and the present invention is not limited thereto.

(Method of preparing succinic acid)
Skim milk was obtained from 200 kg of raw milk using a cream separator. This skim milk was applied to a UF membrane having a molecular weight cut off of 10 kDa (HFK131 (manufactured by KOCH Membrane System)) to remove proteins. A solution from which this protein has been removed is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) to release an organic acid, and then the eluate is a strong basic anion exchange resin. The organic acid was adsorbed on the resin by passing the solution through a column packed with (IR400 (manufactured by Organo)). After cleaning the resin, the organic acid adsorbed on the resin is eluted with 1N ammonium carbonate in the form of an ammonium salt, and the solution is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) again. After removing the ammonia, the mixture was concentrated under reduced pressure. This concentrated solution is passed through a column packed with Diaion HP20SS (manufactured by Mitsubishi Chemical Corporation) to adsorb the organic acid on the resin, and then methanol with a concentration of 0-100% is passed in steps. Fractions containing succinic acid were recovered. This fraction was vacuum dried to give 100 g of succinic acid (Example Product 1). When this succinic acid was analyzed by HPLC, the purity was 90% or more. The succinic acid thus obtained can be used as it is as the obesity suppressant of the present invention.

(Preparation method of gluconic acid)
Skim milk was obtained from 400 kg of raw milk using a cream separator. This skim milk was applied to a UF membrane having a molecular weight cut off of 10 kDa (HFK131 (manufactured by KOCH Membrane System)) to remove proteins. A solution from which this protein has been removed is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) to release an organic acid, and then the eluate is a strong basic anion exchange resin. The organic acid was adsorbed on the resin by passing the solution through a column packed with (IR400 (manufactured by Organo)). After cleaning the resin, the organic acid adsorbed on the resin is eluted with 1N ammonium carbonate in the form of an ammonium salt, and the solution is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) again. After removing the ammonia, the mixture was concentrated under reduced pressure. This concentrated solution is passed through a column packed with Diaion HP20SS (manufactured by Mitsubishi Chemical Corporation) to adsorb the organic acid on the resin, and then methanol with a concentration of 0-100% is passed in steps. Fractions containing gluconic acid were recovered. This fraction was vacuum dried to give 100 g of gluconic acid (Example 2). When this gluconic acid was analyzed by HPLC, the purity was 90% or more. The gluconic acid thus obtained can be used as it is as the obesity suppressant of the present invention.

(Method for preparing 2-keto-D-gluconic acid)
Skim milk was obtained from 200 kg of raw milk using a cream separator. This skim milk was applied to a UF membrane having a molecular weight cut off of 10 kDa (HFK131 (manufactured by KOCH Membrane System)) to remove proteins. A solution from which this protein has been removed is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) to release an organic acid, and then the eluate is a strong basic anion exchange resin. The organic acid was adsorbed on the resin by passing the solution through a column packed with (IR400 (manufactured by Organo)). After cleaning the resin, the organic acid adsorbed on the resin is eluted with 1N ammonium carbonate in the form of an ammonium salt, and the solution is passed through a column packed with a strong acid cation exchange resin (IR120B (manufactured by Organo)) again. After removing the ammonia, the mixture was concentrated under reduced pressure. This concentrate was applied to a μBondopak C18 column (manufactured by Waters) and passed through a 20% acetonitrile / 3 mM phosphate buffer to recover a fraction containing 2-keto-D-gluconic acid. This fraction was lyophilized to give 80 g of 2-keto-D-gluconic acid (Example 3). When this 2-keto-D-gluconic acid was analyzed by HPLC, the purity was 90% or more. The 2-keto-D-gluconic acid thus obtained can be used as it is as the obesity suppressant of the present invention.

(Method for preparing PTHrP)
Skim milk was obtained from 80,000 kg of raw milk using a cream separator. This skim milk was passed through a UF membrane having a molecular weight cut off of 10 kDa to remove proteins, concentrated under reduced pressure, and then freeze-dried. This lyophilized product was applied to a column packed with Sephadex G-25 (GE Healthcare Japan Co., Ltd.), and a sodium chloride solution having a concentration of 0 to 1 M was passed stepwise to recover a fraction containing PTHrP. Next, acetone was added to this fraction to precipitate the protein, which was redissolved in a 70% formic acid solution containing 20 g / L cyanogen bromide, allowed to stand overnight, concentrated under reduced pressure, and then combined with a 7.5 M urea solution. A 0.1% trifluoroacetic acid solution was added. This solution was applied to a GRACE Vydac C18 column (manufactured by GRACE VYDAC) and passed through a 20% acetonitrile / 3 mM phosphate buffer containing 1% trifluoroacetic acid to recover the fraction containing PTHrP. This fraction was lyophilized to give 12 g of PTHrP (Example Product 4). When this PTHrP was analyzed by HPLC, the purity was 90% or more. The PTHrP thus obtained can be used as it is as the obesity suppressant of the present invention.

<Test Example 1>
The effects of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP on the activation of brown adipocytes were investigated.
HB2 cells, which are brown adipose progenitor cells, were seeded in a 12-well plate and cultured in DMEM (high glucose) containing 10% FBS. Two days after reaching confluence, succinic acid of Example 1 was dissolved in 10% FBS-containing DMEM (high glucose) containing 20 nM insulin, centrifuged, and then filter sterilized (final concentration: 500 ng). / Ml), or the one in which the gluconic acid of Example 2 was dissolved and centrifuged and then filter sterilized (final concentration: 4000 ng / ml), or the 2-keto-D-gluconic acid of Example 3 was dissolved and centrifuged. After that, filter sterilized (final concentration: 40 ng / ml), PTHrP of Example 4 was dissolved and centrifuged, and then filter sterilized (final concentration: 1000 ng / ml), and succinic acid of Example 1 was dissolved. A mixture of a filter sterilized product (final concentration: 250 ng / ml) and a filter sterilized product (final concentration: 2000 ng / ml) after centrifuging and centrifuging the gluconic acid of Example 2 was carried out. The succinic acid of Example 1 was dissolved and centrifuged and then filter sterilized (final concentration: 250 ng / ml) and the 2-keto-D-gluconic acid of Example 3 was dissolved and centrifuged and then filter sterilized. (Final concentration: 20 ng / ml) mixed, succinic acid of Example 1 dissolved and centrifuged, and then filter sterilized (final concentration: 250 ng / ml) and PTHrP of Example 4 dissolved and centrifuged. A mixture of separated and sterilized by filter (final concentration: 500 ng / ml), a mixture of succinic acid of Example 1 dissolved and centrifuged, and sterilized by filter (final concentration: 150 ng / ml) and Example 2 The gluconic acid of Example 3 was dissolved and centrifuged and then filter sterilized (final concentration: 1600 ng / ml), and the 2-keto-D-gluconic acid of Example 3 was dissolved and centrifuged and then filter sterilized (final concentration). Concentration: 16 ng / ml) mixed, succinic acid (manufactured by Wako Pure Chemical Industries, Ltd.) dissolved and centrifuged, and then filter sterilized (final concentration: 500 ng / ml), gluconic acid (Wako Pure Chemical Industries, Ltd.) (Manufactured by Sigma) was dissolved and centrifuged and then filter sterilized (final concentration: 4000 ng / ml), 2-keto-D-gluconic acid (manufactured by Sigma Aldrich) was dissolved and centrifuged, and then filter sterilized. (Final concentration: 40 ng / ml) and PTHrP (manufactured by Sigma Aldrich) were dissolved and centrifuged, and then filter sterilized (final concentration: 1000 ng / ml). The control was a medium containing only DMEM (high glucose) containing 20 nM insulin and containing 10% FBS. After culturing each for 8 days, the medium was replaced with a medium supplemented with 10 μM isoproterenol (Iso), and the cells were further cultured for 4 hours. Then, all RNA was extracted from the cultured cells using Sepazol RNA 1 SuperG reagent (manufactured by Nacalai Tesque). For the reverse transcription reaction, RiverTra Ace qPCR RT Master Mix (manufactured by Toyobo Co., Ltd.) was used. Using the obtained cDNA, real-time PCR was performed with THUNDERBIRD qPCR Mix (manufactured by Toyobo Co., Ltd.) to quantify the expression level of the UCP1 gene. The expression level of the 36B4 gene is used as an internal standard for evaluating the gene expression level. For the analysis, the primers of SEQ ID NOs: 1 and 2 in UCP1 are used, and the primers of SEQ ID NOs: 3 and 4 in the sequence listing are used in 36B4. Primer was used. As a result, as shown in Table 2, the succinic acid of Example product 1, the gluconic acid of Example product 2, the 2-keto-D-gluconic acid of Example product 3, and the PTHrP of Example product 4 were brown fat cells. The expression of the UCP1 gene in was significantly increased. Also, when succinic acid and gluconic acid, succinic acid and 2-keto-D-gluconic acid, succinic acid and PTHrP, succinic acid and gluconic acid and 2-keto-D-gluconic acid are added, succinic acid and gluconic acid are also added. , 2-keto-D-ketogluconic acid, and PTHrP were added alone, and the expression level of the UCP1 gene in brown fat cells was increased. Furthermore, experimental reagents such as succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP were also found to significantly increase the expression of the UCP1 gene in brown adipose cells. Therefore, it was found that succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP of the present invention activate brown adipocytes and can be used as an obesity suppressant.

<Test Example 2>
The effects of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP on the differentiation of 3T3-L1 cells, which are white preadipocytes, into brown adipocytes were investigated.
3T3-L1 cells were seeded in 12-well plates and cultured in DMEM (high glucose) containing 10% FBS. Two days after reaching confluence, 10% containing 10 μg / ml, 0.5 mM, 0.25 μM, and 50 nM of insulin, IBMX, DEX, and triiodothyronine (T3) for differentiation into brown adipocytes, respectively. The cells were replaced with FBS-containing DMEM (high glucose) and cultured for 2 days. Next, insulin, IBMX, T3, and rosiglitazone were exchanged for 10% FBS-containing DMEM (high glucose) containing 10 μg / ml, 0.5 mM, 50 nM, and 1 μM, respectively, and cultured for another 6 days. Further, from the start of induction of differentiation into brown fat cells, succinic acid of Example 1 was dissolved in the above medium, centrifuged, and then filtered and sterilized (final concentration: 500 ng / ml), or gluconic acid of Example 2. Was dissolved and centrifuged and then filter sterilized (final concentration: 4000 ng / ml), and 2-keto-D-gluconic acid of Example 3 was dissolved and centrifuged and then filter sterilized (final concentration: 40 ng). / Ml), PTHrP of Example 4 was dissolved, centrifuged, filtered sterilized (final concentration: 1000 ng / ml), and cultured for 8 days (no control was added), and then cultured. The medium was replaced with a medium in which 10 μM Iso was added, and the cells were further cultured for 4 hours. Then, all RNA was extracted by the same method as in Test Example 1 and the expression level of the UCP1 gene was quantified by real-time PCR. As a result, as shown in Table 3, when succinic acid of Example product 1, gluconic acid of Example product 2, 2-keto-D-ketogluconic acid of Example product 3 and PTHrP of Example product 4 were added. , The expression level of the UCP1 gene was significantly increased. Therefore, it was found that the succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP of the present invention promote the differentiation of white adipose progenitor cells into brown adipocytes and can be used as an obesity suppressant.

<Test Example 3>
Using a co-culture system of adipocytes and macrophages cells, which is a cell experiment that mimics the inflammatory state in adipose tissue, through suppression of inflammation in adipose tissue of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP. HB2 cells, which are brown adipocytes whose activation effect of brown adipose tissue was examined, were seeded on a 12-well plate and cultured in DMEM (high glucose) containing 10% FBS. Two days after reaching confluent, the cells were replaced with DMEM (high glucose) containing 20 nM insulin containing 10% FBS and cultured for 7 days in order to differentiate into brown fat cells. Then, Raw264.7 cells, which are mouse macrophage-like cell lines, were added to the wells in which HB2 cells were cultured so as to have 1 × 10 ^ 5 cells / well, and the cells were cultured for 24 hours. At that time, the succinic acid of Example 1 was dissolved and centrifuged and then filter sterilized (final concentration: 500 ng / ml), or the gluconic acid of Example 2 was dissolved and centrifuged and then filter sterilized. (Final concentration: 4000 ng / ml), 2-keto-D-gluconic acid of Example 3 was dissolved, centrifuged, and then filter sterilized (final concentration: 40 ng / ml), PTHrP of Example 4 was dissolved. After centrifugation and sterilization by filter (final concentration: 1000 ng / ml), each was added. The control was a medium containing only DMEM (high glucose) containing 20 nM insulin and containing 10% FBS. After culturing, all RNA was extracted by the same method as in Test Example 1 and the expression levels of the TNFα gene and the UCP1 gene were quantified by real-time PCR. The primers of SEQ ID NOs: 5 and 6 in the Sequence Listing were used for the analysis of the gene expression level of TNFα.
As a result, as shown in Table 5, when succinic acid of Example product 1, gluconic acid of Example product 2, 2-keto-D-ketogluconic acid of Example product 3 and PTHrP of Example product 4 were added. , The expression level of the TNFα gene was significantly decreased, and the expression level of the UCP1 gene was significantly increased. Therefore, it was found that succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP activate brown adipose tissue through suppression of inflammation in adipose tissue and can be used as an obesity suppressant.

<Test Example 4>
Using mice, the obesity-suppressing effect of activation of brown adipocytes of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP was investigated.
After acclimatizing 4-week-old male C57BL6 / JJcl mice for 1 week, 10 mice each were administered with 10 mg and 100 mg of succinic acid per 1 kg of mouse body weight so that there was no difference in average body weight. A group in which 80 mg and 800 mg of gluconic acid were administered per 1 kg of mouse body weight, a group in which 0.8 mg and 8 mg of 2-keto-D-gluconic acid in Example 3 were administered per 1 kg of mouse body weight, and a group in which PTHrP of Example 4 was administered per 1 kg of mouse body weight. The subjects were divided into 20 mg and 200 mg dose groups, and were orally administered once daily with a sonde. In addition, a group (control) in which only water, which is a solvent, was administered was provided, and the effects on the suppression of weight gain and the activation of brown adipocytes were compared and verified. All mice were allowed to freely ingest a high-fat diet (manufactured by Japan Claire Co., Ltd.) for 4 weeks. At the end of the test, after fasting for 5 hours, peritesticular fat and brown adipose tissue were removed, and peritesticular fat was weighed. The brown adipose tissue was washed with physiological saline and then disrupted using a polytron homogenizer, and the expression level of the UCP1 gene was quantified by real-time PCR in the same manner as in Test Example 1.
The results are shown in Tables 6 and 7. As shown in Table 6, 10 mg and 100 mg of succinic acid, 80 mg and 800 mg of gluconic acid, 0.8 mg and 8 mg of 2-keto-D-gluconic acid, and 20 mg and 200 mg of PTHrP were ingested per 1 kg of mouse body weight, respectively. In the group, the body weight and the weight of peri-anticipatory fat were significantly reduced compared to the control that did not take any of them, and the effect was 100 mg of succinic acid and 800 mg of gluconic acid per 1 kg of mouse body weight. It was remarkable when 8 mg of 2-keto-D-gluconic acid and 200 mg of PTHrP were ingested. In addition, as shown in Table 7, per 1 kg of mouse body weight, 10 mg and 100 mg of succinic acid, 80 mg and 800 mg of gluconic acid, 0.8 mg and 8 mg of 2-keto-D-gluconic acid, and 20 mg and 200 mg of PTHrP were ingested, respectively. In the group, the expression level of the UCP1 gene in brown adipose tissue was significantly increased as compared with the control.
Therefore, succinic acid of Example product 1, gluconic acid of Example product 2, 2-keto-D-ketogluconic acid of Example product 3, and PTHrP of Example product 4 are produced by activating brown adipocytes. It was found to suppress excess fat accumulation and obesity. The effects are as follows: succinic acid 10 mg or more, gluconic acid 80 mg or more, 2-keto-D-gluconic acid 0.8 mg or more, PTHrP 20 mg or more, preferably 100 mg or more succinic acid per 1 kg of mouse body weight. , 800 mg or more of gluconic acid, 8 mg or more of 2-keto-D-gluconic acid, and 200 mg or more of PTHrP were found to be observed.

<Test Example 5>
Using mice, the obesity-suppressing effect of brown adipose tissue activation through inflammation suppression in adipose tissue of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP was investigated.
After acclimatizing 4-week-old male C57BL6 / JJcl mice for 1 week, 10 mice each so that there is no difference in average body weight, a group in which 100 mg of succinic acid of Example 1 is administered per 1 kg of mouse body weight, gluconic acid of Example 2 Is divided into a group in which 800 mg / kg of mouse body weight is administered, a group in which 2-keto-D-gluconic acid of Example 3 is administered in an amount of 8 mg / kg of mouse body weight, and a group in which PTHrP of Example 4 is administered in an amount of 200 mg / kg of mouse body weight. It was orally administered once daily with a sonde. In addition, a group (control) in which only water, which is a solvent, was administered was provided, and the effects on the suppression of weight gain and the activation of brown adipocytes were compared and verified. All mice were allowed to freely ingest a high-fat diet (manufactured by Japan Claire Co., Ltd.) for 16 weeks. At the end of the test, after fasting for 5 hours, peritesticular fat and brown adipose tissue were removed, and peritesticular fat was weighed. The brown adipose tissue was washed with physiological saline and then disrupted using a polytron homogenizer, and the expression levels of the TNFα gene and the UCP1 gene were quantified by real-time PCR in the same manner as in Test Example 3.
The results are shown in Tables 8 and 9. As shown in Table 8, 100 mg of succinic acid, 800 mg of gluconic acid, 8 mg of 2-keto-D-gluconic acid, and 200 mg of PTHrP were ingested per 1 kg of mouse body weight. Weight and parathyroid fat weight were significantly reduced compared to no control. In addition, as shown in Table 9, in the group ingesting 100 mg of succinic acid, 800 mg of gluconic acid, 8 mg of 2-keto-D-gluconic acid, and 200 mg of PTHrP per 1 kg of body weight, compared with the control, The expression level of the TNFα gene in brown adipose tissue decreased, and the expression level of the UCP1 gene increased significantly.
Therefore, succinic acid of Example product 1, gluconic acid of Example product 2, 2-keto-D-ketogluconic acid of Example product 3, and PTHrP of Example product 4 should suppress inflammation in brown adipose tissue. It was found that it activates brown fat cells and suppresses excessive fat accumulation and obesity. In addition, it was clarified that the effect is observed when succinic acid is 100 mg or more, gluconic acid is 800 mg or more, 2-keto-D-gluconic acid is 8 mg or more, and PTHrP is 200 mg or more per 1 kg of mouse body weight. rice field.

(Preparation of capsules for obesity suppression)
The raw materials were mixed according to the formulations shown in Table 10, granulated by a conventional method, and filled into capsules to produce the capsule for obesity suppression of the present invention.

(Preparation of tablets for obesity control)
After mixing the raw materials with the formulations shown in Table 11, they were molded into 1 g by a conventional method and tableted to produce the obesity-suppressing tablet of the present invention.

(Preparation of liquid nutritional composition for obesity control)
Dissolve 200 g of gluconic acid (manufactured by Wako Pure Chemical Industries, Ltd.) in 4800 g of deionized water, heat to 40 ° C., and then use a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kagaku Kogyo Co., Ltd.) at 6,000 rpm for 10 minutes. The mixture was stirred and mixed to obtain a 200 g / 5 kg gluconic acid solution. In 5.0 kg of this gluconic acid solution, 5.0 kg of casein, 5.0 kg of soy protein, 1.0 kg of fish oil, 3.0 kg of perilla oil, 17.0 kg of dextrin, 6.0 kg of mineral mixture, 1.95 kg of vitamin mixture, emulsifier 2 Mix 0.0 kg, stabilizer 4.0 kg, and fragrance 0.05 kg, fill a 200 ml retort pouch, and use a retort sterilizer (Type 1 pressure vessel, TYPE: RCS-4CRTGN, manufactured by Nisaka Seisakusho) at 121 ° C. The mixture was sterilized for 20 minutes to produce 50 kg of the liquid nutritional composition for suppressing obesity of the present invention. In addition, 800 mg of gluconic acid was contained in 200 g of the liquid nutritional composition for obesity control of the present invention.

(Preparation of beverages for obesity control)
After dissolving 1 g of succinic acid of Example product 1 in 699 g of deionized water, heating to 40 ° C., and then using an ultra disperser (ULTRA-TURRAX T-25; manufactured by IKA Japan) at 9,500 rpm for 20 minutes. Stirred and mixed. After adding 100 g of maltitol, 2 g of acidulant, 20 g of reduced starch syrup, 2 g of flavor and 176 g of deionized water, the beverage is filled in a 100 ml glass bottle, sterilized at 95 ° C. for 15 seconds, and then sealed. A book (containing 100 ml) was prepared. In addition, 100 g of the obesity-suppressing beverage of the present invention contained 100 mg of succinic acid.

(Preparation of feed for obesity control for dogs)
1.6 g of 2-keto-D-gluconic acid of Example 3 is dissolved in 3,998.4 g of deionized water, heated to 40 ° C., and then TK homomixer (MARK II 160 type; manufactured by Tokushu Kika Kogyo Co., Ltd.). A 1.6 g / 4 kg gluconic acid solution was obtained by stirring and mixing at 3,600 rpm for 20 minutes. In 2 kg of this gluconic acid solution, 1 kg of soybean meal, 1 kg of defatted milk powder, 0.4 kg of soybean oil, 0.2 kg of corn oil, 2.3 kg of palm oil, 1 kg of corn starch, 0.9 kg of wheat flour, 0.2 kg of bran, and a vitamin mixture 0. 5 kg, 0.3 kg of cellulose and 0.2 kg of a mineral mixture were blended and sterilized by heating at 120 ° C. for 4 minutes to produce 10 kg of the feed for suppressing obesity of the present invention. The obesity-suppressing feed of the present invention contained 8 mg of 2-keto-D-gluconic acid.

(Preparation of milk powder for obesity control)
100 g of succinic acid of Example 1, 9.2 kg of skim milk powder, and 90 kg of deionized water are mixed, heated to 40 ° C., and then used with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.) at 10 at 6,000 rpm. Stir and mix for minutes. This solution was spray-dried to produce 10 kg of milk powder for obesity control of the present invention. In addition, 100 mg of succinic acid was contained in 10 g of the obesity-suppressing milk powder of the present invention.

(Preparation of milk drink for obesity control)
40 g of gluconic acid and 9.96 kg of milk of Example 2 were mixed, heated to 40 ° C., and then stirred and mixed at 6,000 rpm for 10 minutes with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.). After heat sterilization at 130 ° C. for 2 seconds, the mixture was cooled to 10 ° C. or lower to produce 10 kg of the milk beverage for obesity control of the present invention. In addition, 800 mg of gluconic acid was contained in 200 g of the milk beverage for obesity control of the present invention.

(Preparation of fermented milk for obesity control)
5 g of succinic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 1700 g of skim milk powder, 300 g of glucose, and 7695 g of deionized water were mixed and sterilized by heating by holding at 95 ° C. for 2 hours. This was cooled to 37 ° C., 300 g of a lactic acid bacterium starter (Lb. Casei) was inoculated, stirred and mixed, and then fermented to pH 4.0 in an incubator maintained at 37 ° C. After reaching pH 4.0, the mixture was cooled to 10 ° C. or lower to produce 10 kg of fermented milk for obesity control of the present invention. In addition, 200 g of fermented milk for obesity control of the present invention contained 100 mg of succinic acid.

(Preparation of lactic acid bacteria beverage for obesity control)
1700 g of skim milk powder, 300 g of glucose, and 7700 g of deionized water were mixed and sterilized by heating by holding at 95 ° C. for 2 hours. This was cooled to 37 ° C., 300 g of a lactic acid bacterium starter (Lb. Casei) was inoculated, stirred and mixed, and then fermented to pH 4.0 in an incubator maintained at 37 ° C. After reaching pH 4.0, the mixture was cooled to 10 ° C. or lower with stirring to obtain a fermentation base. Further, 50 g of gluconic acid, 1800 g of white sugar, 20 g of acidulant, 10 g of flavor and 8120 g of deionized water of Example 2 were mixed and sterilized at 90 ° C. for 10 minutes and then cooled to 10 ° C. or lower to obtain a sugar solution. 2000 g of the above-mentioned fermentation base and 8000 g of sugar solution were mixed, the tissue was smoothed with a homogenizer, dispensed into 50 paper containers containing 200 ml, and sealed with an aluminum lid to produce 10 kg of the lactic acid bacteria beverage for obesity control of the present invention. .. In addition, 800 mg of gluconic acid was contained in 200 ml of the lactic acid bacteria beverage for obesity suppression of the present invention.

(Preparation of soft drinks for obesity control)
2-keto-D-gluconic acid (manufactured by Sigma-Aldrich) 200 mg, 50% lactic acid 0.75 kg, erythritol 5.7 kg, fragrance 1 kg, deionized water 42.55 kg are mixed, heated to 40 ° C, and then TK homomixer (TK homomixer (manufactured by Sigma-Aldrich). The mixture was stirred and mixed at 6,000 rpm for 10 minutes at TK ROBO MICS (manufactured by Tokushu Kika Kogyo Co., Ltd.). This solution was sterilized at 90 ° C. for 10 minutes and then cooled to 10 ° C. or lower to produce 50 kg of the soft drink for obesity control of the present invention. In addition, 200 ml of the soft drink for obesity control of the present invention contained 8 mg of 2-keto-D-gluconic acid.

(Preparation of cheese for obesity control)
9 kg of Gouda cheese, 9 kg of cheddar cheese, 1 kg of stripped clams, 100 g of succinic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 200 g of sodium citrate, and 700 g of deionized water were mixed and emulsified at 85 ° C. After emulsification, the carton was filled with cheese and cooled at 5 ° C. for 2 days and nights to produce 20 kg of the obesity-suppressing cheese of the present invention. In addition, 100 g of the obesity-suppressing cheese of the present invention contained 100 mg of succinic acid.

(Preparation of margarine for obesity control)
An oil layer was prepared by mixing 2 kg of hydrogenated soybean oil, 4 kg of soybean white squeezed oil, 2.5 kg of palm oil, and 50 g of glycerin fatty acid ester. Next, 8 g of 2-keto-D-gluconic acid, 10 g of lactic acid, and 1432 g of deionized water of Example 3 were mixed and added to an oil layer to obtain a water-in-oil emulsion. This emulsion was used as a margarine maker. 10 kg of margarine for suppressing obesity of the present invention was produced by cooling, solidifying and kneading with. In addition, 10 g of the obesity-suppressing margarine of the present invention contained 8 mg of 2-keto-D-gluconic acid.

(Preparation of cream for obesity control)
An oil phase was prepared by mixing 4.5 kg of rapeseed hardening oil, 40 g of lecithin, 10 g of monoglycerin fatty acid ester, and 10 g of sorbitan fatty acid ester. Next, 8 g of 2-keto-D-gluconic acid of Example 3, 400 g of skim milk powder, 10 g of casein sodium, 20 g of sugar ester, 10 g of phosphate, 5 g of xanthan gum, and 4.987 kg of deionized water were mixed to form an aqueous phase. Was prepared. The aqueous phase is heated to 65 ° C., the oil phase heated to 70 ° C. is added little by little with stirring, and the TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.) is used at 6,000 rpm for 10 minutes. Stirred and mixed. This was homogenized with a homogenizing machine to produce 10 kg of the obesity-suppressing cream of the present invention. In addition, 10 g of the obesity-suppressing cream of the present invention contained 8 mg of 2-keto-D-gluconic acid.

(Preparation of obesity-suppressing pudding)
Honey 2000g, gluconic acid (manufactured by Wako Pure Chemical Industries, Ltd.) 70gg, skim milk powder 800g, mascarpone 300g, liquid water candy 700g, granulated sugar 500g, fresh cream 250g, butter 200g, sweetened egg yolk 400g, gelatin 40g, agar 15g, locust bean gum 120 g and 4605 g of deionized water were mixed to prepare a pudding mix. This pudding mix is stirred and mixed at 6,000 rpm for 10 minutes with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kagaku Kogyo Co., Ltd.), heated to 60 ° C. to dissolve, and then filled in a container in 100 g portions and cooled. As a result, 100 obesity-suppressing purines of the present invention were produced. In addition, 800 mg of gluconic acid was contained in 100 g of the obesity-suppressing purine of the present invention.

(Preparation of jelly for obesity control)
PTHrP (manufactured by Sigma Aldrich) 20 g, fructose 2000 g, granulated sugar 1500 g, starch syrup 500 g, agar 100 g, flavor 10 g, deionized water 5870 g are mixed and TK homomixer (TK ROBO MICS; manufactured by Tokushu Kagaku Kogyo Co., Ltd.). The jelly for suppressing obesity of the present invention was produced by stirring and mixing at 6,000 rpm for 10 minutes, heating to 50 ° C. to dissolve the jelly, and then filling the container with 100 g each and cooling the mixture. In addition, 200 mg of PTHrP was contained in 100 g of the obesity-suppressing jelly of the present invention.

(Preparation of wafers for obesity control)
After mixing 0.02 kg of PTHrP of Example 4, 8.5 kg of wheat flour, 1.21 kg of cornstarch, 0.22 kg of palm oil, and 0.05 kg of leavening agent, an appropriate amount of deionized water was added to prepare a batter, and then a wafer baking machine was used. To produce 10 kg of the wafer for suppressing obesity of the present invention. The obesity-suppressing wafer of the present invention contained 100 mg of PTHrP.

Claims (11)

An obesity suppressant containing succinic acid as an active ingredient and promoting the differentiation of white adipose progenitor cells into brown adipocytes. The obesity suppressant according to claim 1, wherein the succinic acid is derived from milk. The obesity-suppressing agent according to claim 1 or 2, wherein the obesity-suppressing effect enhances energy metabolism. The obesity-suppressing agent according to any one of claims 1 to 3, wherein the obesity-suppressing effect activates brown adipose tissue. The obesity-suppressing agent according to any one of claims 1 to 4, wherein the obesity-suppressing effect suppresses inflammation in adipose tissue. An obesity-suppressing food or drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug, which comprises the obesity-suppressing agent according to any one of claims 1 to 5. The food or drink for suppressing obesity according to claim 6, wherein the food or drink is any of milk powder, milk drink, lactic acid bacteria drink, fermented milk, soft drink, cheese, margarine, cream, pudding, jelly, and wafer. A method for suppressing obesity by orally ingesting the obesity suppressant according to any one of claims 1 to 5 (excluding administration to humans). An obesity suppressant that activates brown adipose tissue and contains succinic acid as an active ingredient. An obesity suppressant containing succinic acid as an active ingredient and suppressing inflammation in adipose tissue. An agent containing succinic acid as an active ingredient to promote the differentiation of white adipose progenitor cells into brown adipocytes.