JP7263426B2 - obesity inhibitor - Google Patents

Description

The present invention promotes differentiation from white adipose precursor cells to brown adipocytes, activates uncoupling protein 1 (uncoupling protein 1: UCP1) in brown adipocytes, and increases energy consumption in brown adipose tissue. , and / or, through the suppression of inflammation in adipose tissue, by activating brown adipose tissue and increasing energy consumption in brown adipose tissue, suppressing fat accumulation in the body and suppressing obesity The present invention relates to an obesity inhibitor that is excellent, effective for the prevention and treatment of lifestyle-related diseases and metabolic syndrome, and has excellent stability and safety. The present invention also relates to an obesity-suppressing food and drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug containing the obesity-suppressing agent.

With recent changes in eating habits and lifestyle habits, 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 increased medical costs, is as high as 28% for men and 20% for women, posing a serious social problem (Non-Patent Document 1). On the other hand, a state in which lifestyle-related diseases and obesity, particularly visceral fat-type obesity, accumulate in one individual is called metabolic syndrome, and is known to lead to serious diseases such as stroke. In recent years, visceral fat-type obesity has also frequently occurred in mammals other than humans, such as domestic pets, and has become a serious problem from the viewpoint of animal welfare.

Obesity is mainly caused by enlargement of fat cells. In addition, hypertrophied adipocytes secrete inflammatory cytokines such as Tumor Necrosis Factor α (TNFα) and free fatty acids to induce insulin resistance from chronic inflammatory conditions, leading to the development of lifestyle-related diseases including diabetes. It is thought that On the other hand, non-hypertrophied adipocytes are known to secrete anti-inflammatory cytokines such as adiponectin and leptin to enhance insulin sensitivity. Therefore, preventing fat cell hypertrophy and suppressing inflammation is very important in preventing obesity, lifestyle-related diseases associated with obesity, and various diseases such as metabolic syndrome (Patent Document 1. , 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 accumulate fat in the form of triglycerides within the cell and store energy. On the other hand, brown adipocytes, like white adipocytes, accumulate fat in the cells, but due to the action of UCP1 present on the mitochondrial membrane, the proton gradient generated by the electron transport system is converted into ATP. Convert to heat energy. In other words, in vivo, the balance of whole-body energy and body fat is adjusted by energy storage by white adipocytes and energy consumption by heat production by brown adipocytes. In recent research, brown adipocytes are classified into two types: the “existing type”, in which the cell fate is already determined at the early stage of embryogenesis, and the “induced type”, in which the differentiation is induced from white adipocytes by various environmental factors in adults. It is known that there are two types (Non-Patent Document 2). In humans, existing brown adipocytes exist in small amounts in limited areas such as around the shoulder blades, the back of the neck, and armpits, and decrease with age. On the other hand, it has been reported that long-term cold stimulation and administration of PPARγ agonists activate existing brown adipose tissue in adults, and white adipose precursor cells present in white adipose tissue differentiate into brown adipocytes. . Therefore, by promoting the differentiation of white adipose precursor cells into brown adipocytes and by activating brown adipocytes, energy metabolism is enhanced to suppress excess fat accumulation and obesity in the body, and metabolic syndrome, etc. can be prevented or ameliorated.

Furthermore, recently, when a diet with a high fat content is ingested, the function of UCP1 in brown adipocytes is reduced, resulting in obesity. It has been reported that obesity does not occur Therefore, pharmaceuticals and foods that are expected to enhance the function of UCP1 and suppress obesity are being actively searched for. In addition, since inflammatory conditions cause dysfunction of UCP1 present in brown adipocytes, drugs and foods that are expected to have an anti-obesity suppressing effect by enhancing the function of UCP1 through anti-inflammatory effects are also being explored. . However, in this case, it is important to review lifestyle habits, especially dietary habits, in order to prevent excessive accumulation of fat in the body and obesity. It is important that there are no safety problems even if taken for a long period of time.

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

Japanese Patent Application Laid-Open No. 2006-28049 JP 2011-153093 A Japanese Patent Application Laid-Open No. 2009-190980 WO2003/057245

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

The present invention promotes differentiation from white adipose precursor cells to brown adipocytes, activates UCP1 in brown adipocytes, 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, preventing lifestyle-related diseases and metabolic syndrome. It relates to an obesity inhibitor that is effective for the treatment of obesity and has excellent stability and safety. Another object of the present invention is to provide an obesity-suppressing food and drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug containing the obesity-suppressing agent.

The present inventors have made intensive studies to solve the above problems, and found that succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP promote differentiation from white adipose precursor cells to brown adipocytes. or by activating UCP1 in brown adipose tissue to increase energy expenditure in brown adipose tissue and/or through suppression of inflammation in adipose tissue to activate brown adipose tissue and increase energy in brown adipose tissue We have found that increasing consumption has a significant anti-obesity effect.
That is, the present invention includes the following aspects.
(1) An anti-obesity agent containing succinic acid, gluconic acid, 2-keto-D-gluconic acid and/or PTHrP as an active ingredient.
(2) The anti-obesity agent according to (1) above, wherein the succinic acid, gluconic acid, 2-keto-D-gluconic acid and/or PTHrP are derived from milk.
(3) The anti-obesity agent according to (1) or (2) above, wherein the anti-obesity effect promotes energy metabolism.
(4) The obesity inhibitor according to (1) to (3) above, wherein the obesity inhibitory effect promotes the differentiation of white adipose precursor cells into brown adipocytes.
(5) The anti-obesity agent according to (1) to (3) above, wherein the anti-obesity effect activates brown adipose tissue.
(6) The anti-obesity agent according to (1) to (3) or (5) above, wherein the anti-obesity effect is to suppress 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, comprising the obesity-suppressing agent according to any one of (1) to (6) above.
(8) The obesity-suppressing food and drink according to (7), wherein the food and drink is any one of powdered milk, milk drinks, lactic acid bacteria drinks, fermented milk, soft drinks, cheese, margarine, cream, pudding, jelly, and wafers ( 9) A method for suppressing obesity by orally ingesting the obesity suppressing agent according to any one of (1) to (8).

The obesity suppressing agent of the present invention promotes differentiation from white adipose precursor cells to brown adipocytes, activates UCP1 in brown adipocytes, increases energy consumption in brown adipose tissue, and / or fat Through suppressing inflammation in tissues, it activates brown adipose tissue and has a remarkable effect of increasing energy consumption in brown adipose tissue. It is effective for the prevention and treatment of lifestyle-related diseases such as arteriosclerosis, arteriosclerosis, and such lifestyle-related diseases and obesity, especially metabolic syndrome in which visceral fat-type obesity accumulates in one individual. In addition, since the obesity inhibitor of the present invention contains substances contained in mammalian milk as active ingredients, it can be safely ingested on a daily basis for a long period of time.

Succinic acid, gluconic acid, 2-keto-D-gluconic acid and PTHrP, which are active ingredients of the obesity inhibitor of the present invention, can be prepared by known methods. For example, those prepared from the milk of mammals such as humans, cows, buffaloes, goats, sheep, camels, horses, llamas, and yaks; It is possible to use those produced by the method, those chemically synthesized, those produced by genetic engineering techniques, those purified from blood or organs, and the like. It is also possible to use purified and commercially available reagents.

Succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, which are active ingredients of the obesity inhibitor of the present invention, may be used as they are as obesity inhibitors, but if necessary, they may be powdered according to conventional methods. , granules, tablets, capsules, drinks and the like. In addition, as it is or after formulation, nutritional supplements, milk powder, milk drinks, lactic acid bacteria drinks, fermented milk, soft drinks, cheese, margarine, cream, pudding, jelly, wafers and other foods and drinks, nutritional compositions, feeds and pharmaceuticals 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 contain succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, either alone or optionally. It can contain raw materials such as stabilizers, sugars, lipids, flavors, vitamins, minerals, flavonoids, polyphenols, etc. that are usually contained in other foods and drinks, feeds and medicines. In addition, the obesity-suppressing food and drink, the obesity-suppressing nutritional composition, the obesity-suppressing feed, and the obesity-suppressing drug of the present invention contain active ingredients such as succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP. In addition to this, it is also possible to use other ingredients having an anti-obesity action, such as κ-casein and lactoferrin. Furthermore, such obesity-suppressing foods and drinks, obesity-suppressing nutritional compositions, obesity-suppressing feeds, and obesity-suppressing pharmaceuticals can be used as raw materials, and raw materials normally contained in other food and beverages can be blended to prepare them. It is possible.

The amount of succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP in the obesity inhibitor, obesity-suppressing food and drink, obesity-suppressing nutritional composition, obesity-suppressing feed, and obesity-suppressing drug of the present invention Is not particularly limited, but in order to promote differentiation from white adipose precursor cells to brown adipocytes or to activate brown adipocytes, 10 to 100 mg of succinic acid per day for adults, Preferably 100 mg or more, 80 to 800 mg, preferably 800 mg or more for gluconic acid, 0.8 to 8 mg, preferably 8 mg or more for 2-keto-D-gluconic acid, 20 to 200 mg, preferably for PTHrP is preferably 200 mg or more, and the amount to be added to foods and drinks, nutritional compositions, feeds, medicines, etc. is adjusted so that it can be orally ingested.

The powdered milk, which is the obesity-suppressing food and drink of the present invention, refers to raw milk, cow's milk, special cow's milk, or powdered powder obtained by spray-drying or freeze-drying these raw materials. Powders, whole milk powders, whey powders, milk mineral concentrates, dried cheese powders, WPIs, WPCs, infant formula or specialty milk powders, and the like. As auxiliary raw materials, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juices, scallops, grains, sugars, spices, flavors, nutritional substances, and other auxiliary raw materials generally used in the production of powdered milk are used. It is possible. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The milk beverage, which is the obesity-suppressing food and drink of the present invention, refers to raw milk, cow's milk, special milk, or a beverage produced using these raw materials, and has a milk solids content of 3.0% or more. Vegetable juice, fruit juice, stabilizer, emulsifier, starch, processed starch, vegetable fat, shellfish juice, scallop, grains, sugars, spices, fragrances, nutritional substances, etc., as auxiliary materials, generally used in the production of milk beverages. Any of the auxiliary materials used can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The lactic acid bacterium beverage, which is an obesity-suppressing food and drink of the present invention, refers to a beverage processed or made mainly from raw milk, milk, special milk, or raw milk fermented with lactic acid bacteria or yeast, and lactic acid bacteria. The number or yeast count is 10,000,000/ml or more. Vegetable juice, fruit juice, stabilizer, emulsifier, starch, modified starch, vegetable fat, shellfish juice, scallop, grains, sugars, spices, flavorings, nutritional substances, etc., as auxiliary materials for the production of lactic acid beverages. Any of the auxiliary materials used can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The fermented milk, which is the obesity-suppressing food and drink of the present invention, may be raw milk, cow's milk or special milk, or those obtained by fermenting these raw materials with lactic acid bacteria or yeast. is 10 million cells/ml or more, hard type that has a pudding-like structure that is fermented in a retail container, soft type that crushes the fermented curd and fills the container, and curd It includes liquid fermented milk that is homogenized after crushing and liquefied. Vegetable juice, fruit juice, stabilizer, emulsifier, starch, processed starch, vegetable fat, shellfish juice, scallop, grains, sugars, spices, flavorings, nutritional substances, etc., as auxiliary materials, generally used in the production of fermented milk. Any of the auxiliary materials used can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

Soft drinks, which are foods and drinks for obesity control of the present invention, refer to beverages containing less than 1% by volume of alcoholic beverages excluding lactic acid beverages, milk and dairy products, carbonated beverages, fruit beverages, coffee beverages, tea-based beverages, Sports drinks, dairy drinks, functional drinks, nutritional drinks, soy milk drinks, etc. are included. As auxiliary raw materials, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juices, scallops, grains, sugars, spices, flavors, nutritional substances, etc., which are generally used in the production of soft drinks are all used. It is possible. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The cheese, which is the obesity-suppressing food and drink of the present invention, may be natural cheese or processed cheese. White mold cheese, blue mold cheese such as Gorgonzola, Stilton and Roquefort, washed cheese such as Livalo, semi-hard cheese such as Provolone and Gouda, natural cheese such as grana, emmental and cheddar hard cheese, processed cheese, cheese food and milk, etc. Including all cheeses, etc., such as foods that use The raw cheese for processed cheeses is not particularly limited as long as it is used in the production of normal processed cheeses, for example, either hard or semi-hard natural cheese, or a combination of such cheeses Anything can be used. Processed cheeses can also be used as part of the ingredients. The molten salt and emulsifier for processed cheeses are not particularly limited as long as they are used in the production of normal processed cheeses, for example, citrate, phosphate, sucrose fatty acid ester, etc., or A combination of such a molten salt and an emulsifier can also be used. Dairy products such as skimmed milk powder, milk ingredients, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juices, scallops, grains, sugars, spices, flavorings, etc., are generally used in the production of processed cheese. Any of the auxiliary materials used can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but may not be used unless particularly necessary.

Margarines, which are foods and drinks for obesity control of the present invention, refer to water-in-oil emulsion compositions such as margarine and fat spread, and are prepared using one or more of fats, milk components, emulsifiers, etc. as main raw materials. be. The oil and fat raw material is not particularly limited as long as it is used in the production of water-in-oil emulsion compositions such as ordinary margarines and spreads. Examples include rapeseed oil, soybean oil, palm oil, corn oil, and safflower oil. , vegetable oils such as coconut oil or olive oil, or animal oils such as milk fat, fish oil, beef tallow, pork fat, hydrogenated oils, transesterified oils, fractionated oils, etc., or combinations of such oils can be used even if there is Dairy products such as skimmed milk powder, milk ingredients, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juices, scallops, grains, sugars, spices, flavors, etc., which are generally used in the manufacture of margarines as auxiliary raw materials. Any of the available auxiliary materials can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The cream, which is the obesity-suppressing food and drink of the present invention, refers to an oil-in-water emulsified composition such as whipped cream and coffee cream, and is prepared using one or more of oils and fats, milk components, emulsifiers, etc. as main raw materials. . The oil and fat raw material is not particularly limited as long as it is used in the production of ordinary oil-in-water emulsion compositions such as whipped cream and coffee cream. Examples include rapeseed oil, soybean oil, palm oil, corn oil, and safflower. Oil, vegetable oils and fats such as coconut oil and olive oil, or animal oils and fats such as milk fat, fish oil, beef tallow and lard, or their hydrogenated oils, interesterified oils, fractionated oils, etc., or combinations of such oils and fats can even be used. Dairy products such as skimmed milk powder, milk ingredients, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juice, scallops, grains, sugars, spices, flavors, etc. are generally used in the production of creams as auxiliary materials. Any of the available auxiliary materials can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The pudding, which is the obesity-suppressing food and drink of the present invention, refers to pudding using heat coagulation of egg protein or pudding using 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 examples include agar, gelatin, locust bean gum, xanthan gum, gellan gum, carrageenan, sodium alginate, starch, guar gum, tamarind seed gum, and karaya gum. , pectin, carboxymethylcellulose, psyllium seed gum, pullulan or curdlan, or a combination of such gelling agents.
As auxiliary raw materials, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juices, scallops, grains, sugars, spices, flavors, and the like, which are generally used in the production of puddings, can be used. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The jelly, which is the obesity-suppressing food and drink of the present invention, refers to a jelly solidified using a gelling agent, and is prepared using one or more of fruit juice, vegetable juice, and saccharides as main raw materials. One or two or more of instant coffee, fruit juice, pulp, flavoring agent, coloring agent, and the like can be added to the jelly. Also, jelly that has been whipped or has air bubbles retained therein can be used. The gelling agent is not particularly limited as long as it is used in ordinary jelly production, and examples include agar, gelatin, locust bean gum, xanthan gum, gellan gum, carrageenan, sodium alginate, starch, guar gum, tamarind seed gum, and karaya gum. , pectin, carboxymethylcellulose, psyllium seed gum, pullulan, curdlan, etc., or a combination of such gelling agents.

The wafer, which is the obesity-suppressing food and drink of the present invention, is prepared by mixing one or more raw materials such as wheat flour, milk powder, egg yolk, expanding agent, salt, flavoring, oil and fat, and adding water to adjust the concentration of the dough. Then, one or more of cream, chocolate, caramel, jelly, etc. Dairy products such as skimmed milk powder, milk ingredients, stabilizers, emulsifiers, starches, modified starches, vegetable fats, shellfish juice, scallops, grains, sugars, spices, spices, etc., which are generally used in the manufacture of wafers. Any auxiliary material can be used. For the purpose of nutritional enhancement, vitamins, minerals, vegetable powder, wheat germ, oligosaccharides, etc. can be added. These auxiliary materials are used for the purpose of adjusting physical properties and flavor, but they may not be used unless particularly necessary.

The anti-obesity agent of the present invention can be administered orally by adding a suitable adjuvant to succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP, which are the active ingredients described above, and formulating it into an arbitrary form. It can be a composition for suppressing obesity. For formulation, commonly used diluents or excipients such as fillers, extenders, binders, disintegrants, surfactants and lubricants can be used. Examples of excipients include sucrose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium aluminate, synthetic aluminum silicate, magnesium aluminometasilicate, calcium carbonate, sodium hydrogencarbonate, and calcium hydrogenphosphate. , carboxymethyl cellulose calcium, etc., or a combination of two or more thereof.

EXAMPLES The present invention will be described in detail below with reference to Examples and Test Examples, but these are merely examples and the present invention is not limited to them.

(Method for preparing succinic acid)
Using a cream separator, skimmed milk was obtained from 200 kg of raw milk. This skim milk was subjected to a UF membrane (HFK131 (manufactured by KOCH Membrane System)) having a molecular weight cutoff of 10 kDa to remove proteins. This protein-removed solution is passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)) to convert the organic acid into a free form, and then the eluate is subjected to a strongly basic anion exchange resin. (IR400 (manufactured by Organo)) was passed through a column to adsorb the organic acid to the resin. After washing 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 again passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)). After removing ammonia, the mixture was concentrated under reduced pressure. After this concentrated solution was passed through a column packed with Diaion HP20SS (Mitsubishi Chemical Co., Ltd.) to adsorb the organic acid on the resin, methanol with a concentration of 0-100% was passed stepwise, Fractions containing succinic acid were collected. This fraction was vacuum dried to obtain 100 g of succinic acid (Example product 1). Analysis of this succinic acid by HPLC revealed a purity of 90% or more. The succinic acid thus obtained can be used directly as the anti-obesity agent of the present invention.

(Method for preparing gluconic acid)
Using a cream separator, skimmed milk was obtained from 400 kg of raw milk. This skim milk was subjected to a UF membrane (HFK131 (manufactured by KOCH Membrane System)) having a molecular weight cutoff of 10 kDa to remove proteins. This protein-removed solution is passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)) to convert the organic acid into a free form, and then the eluate is subjected to a strongly basic anion exchange resin. (IR400 (manufactured by Organo)) was passed through a column to adsorb the organic acid to the resin. After washing 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 again passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)). After removing ammonia, the mixture was concentrated under reduced pressure. After this concentrated solution was passed through a column packed with Diaion HP20SS (Mitsubishi Chemical Co., Ltd.) to adsorb the organic acid on the resin, methanol with a concentration of 0-100% was passed stepwise, Fractions containing gluconic acid were collected. This fraction was vacuum dried to obtain 100 g of gluconic acid (Example product 2). This gluconic acid was analyzed by HPLC and found to be 90% or more pure. The gluconic acid thus obtained can be used as it is as the anti-obesity agent of the present invention.

(Method for preparing 2-keto-D-gluconic acid)
Using a cream separator, skimmed milk was obtained from 200 kg of raw milk. This skim milk was subjected to a UF membrane (HFK131 (manufactured by KOCH Membrane System)) having a molecular weight cutoff of 10 kDa to remove proteins. This protein-removed solution is passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)) to convert the organic acid into a free form, and then the eluate is subjected to a strongly basic anion exchange resin. (IR400 (manufactured by Organo)) was passed through a column to adsorb the organic acid to the resin. After washing 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 again passed through a column packed with a strongly acidic cation exchange resin (IR120B (manufactured by Organo)). After removing ammonia, the mixture was concentrated under reduced pressure. This concentrated solution was applied to μBondpak C18 column (manufactured by Waters) and passed through 20% acetonitrile/3 mM phosphate buffer to collect fractions containing 2-keto-D-gluconic acid. This fraction was lyophilized to give 80 g of 2-keto-D-gluconic acid (Example product 3). Analysis of this 2-keto-D-gluconic acid by HPLC revealed a purity of 90% or higher. The 2-keto-D-gluconic acid thus obtained can be used as it is as the anti-obesity agent of the present invention.

(Method for preparing PTHrP)
Skimmed milk was obtained from 80,000 kg of raw milk using a cream separator. This skim milk was passed through a UF membrane with a cutoff molecular weight of 10 kDa to remove proteins, concentrated under reduced pressure, and 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 with a concentration of 0 to 1 M was passed stepwise through the column to collect 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 of cyanogen bromide and allowed to stand overnight. 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 collect a fraction containing PTHrP. This fraction was lyophilized to give 12 g of PTHrP (Example Product 4). Analysis of this PTHrP by HPLC revealed a purity of 90% or higher. PTHrP thus obtained can be used as an anti-obesity agent of the present invention.

<Test Example 1>
The effects of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP on activation of brown adipocytes were examined.
HB2 cells, which are brown adipose precursor cells, were seeded in a 12-well plate and cultured in 10% FBS-containing DMEM (high glucose). Two days after reaching confluence, the succinic acid of Example 1 was dissolved in DMEM containing 10% FBS containing 20 nM insulin (high glucose), centrifuged, and then filter-sterilized (final concentration: 500 ng). /ml), or gluconic acid in Example 2 was dissolved and centrifuged and then filter sterilized (final concentration: 4000 ng/ml), 2-keto-D-gluconic acid in Example 3 was dissolved and centrifuged. (final concentration: 40 ng/ml), PTHrP of Example 4 was dissolved, centrifuged and then filter sterilized (final concentration: 1000 ng/ml), and succinic acid of Example 1 was dissolved. (final concentration: 250 ng/ml) and filter sterilized after centrifugation (final concentration: 2000 ng/ml). Dissolve succinic acid in Example 1, centrifuge, and then filter sterilize (final concentration: 250 ng/ml) and Dissolve 2-keto-D-gluconic acid in Example 3, centrifuge, and then filter sterilize (final concentration: 20 ng/ml), the succinic acid of Example 1 was dissolved, centrifuged and then filter-sterilized (final concentration: 250 ng/ml), and the PTHrP of Example 4 was dissolved and centrifuged. A mixture of separated and then filter-sterilized (final concentration: 500 ng/ml), a mixture of Example 2, which was obtained by dissolving succinic acid in Example 1, centrifuging, and then filter-sterilizing (final concentration: 150 ng/ml) gluconic acid was dissolved and centrifuged and then filter sterilized (final concentration: 1600 ng/ml) and 2-keto-D-gluconic acid in Example 3 was dissolved and centrifuged and then filter sterilized (final concentration: 16 ng / ml), succinic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved, centrifuged and then filter sterilized (final concentration: 500 ng / ml), gluconic acid (Wako Pure Chemical Industries, Ltd. (manufactured by Sigma-Aldrich)) 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), PTHrP (manufactured by Sigma-Aldrich) was dissolved, centrifuged, and then filter-sterilized (final concentration: 1000 ng/ml), and replaced with the added medium. The control was a medium containing only 10% FBS-containing DMEM (high glucose) containing 20 nM insulin. After each was cultured for 8 days, the medium was replaced with the above medium supplemented with 10 μM isoproterenol (Iso), and cultured for an additional 4 hours. Thereafter, all RNA was extracted from the cultured cells using Sepasol RNA 1 SuperG reagent (manufactured by Nacalai Tesque). For the reverse transcription reaction, ReverTra 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. As an internal standard for evaluating the gene expression level, the expression level of the 36B4 gene was used. of primers were used. As a result, as shown in Table 2, succinic acid of Example product 1, gluconic acid of Example product 2, 2-keto-D-gluconic acid of Example product 3, and PTHrP of Example product 4 were found in brown adipocytes. significantly increased the expression of the UCP1 gene in 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 were added, succinic acid and gluconic acid , 2-keto-D-ketogluconic acid, and PTHrP alone increased the expression level of the UCP1 gene in brown adipocytes. Furthermore, it was found that the experimental reagents succinic acid, gluconic acid, 2-keto-D-gluconic acid, and PTHrP also significantly increased the expression of the UCP1 gene in brown adipocytes. 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 anti-obesity agents.

<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 examined.
3T3-L1 cells were seeded in 12-well plates and cultured in DMEM (high glucose) containing 10% FBS. Two days after reaching confluence, insulin, IBMX, DEX, and triiodothyronine (T3) were added at 10 µg/ml, 0.5 mM, 0.25 µM, and 50 nM, respectively, in order to differentiate into brown adipocytes. The cells were replaced with FBS-containing DMEM (high glucose) and cultured for 2 days. Next, insulin, IBMX, T3, and rosiglitazone were replaced with 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 adipocytes, the succinic acid of Example 1 was dissolved in the medium, centrifuged, and then filter-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), 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, and then filter-sterilized (final concentration: 1000 ng/ml). The above medium was replaced with a medium supplemented with 10 μM Iso, and the cells were further cultured for 4 hours. Thereafter, all RNA was extracted in the same manner 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 succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP of the present invention promote differentiation from white adipose precursor cells to brown adipocytes and can be used as obesity inhibitors.

<Test Example 3>
Using a co-culture system of adipocytes and macrophage cells, which is a cell experiment that mimics the inflammatory state in adipose tissue, we investigated the inhibition of inflammation in adipose tissue by succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP. HB2 cells, which are brown adipose precursor cells, were seeded in a 12-well plate and cultured in 10% FBS-containing DMEM (high glucose). Two days after reaching confluence, the cells were changed to DMEM containing 10% FBS containing 20 nM insulin (high glucose) and cultured for 7 days in order to differentiate into brown adipocytes. Thereafter, Raw264.7 cells, a mouse macrophage-like cell line, were added to the wells in which HB2 cells were being cultured so as to give 1×10̂5 cells/well, and cultured for 24 hours. At that time, the succinic acid in Example 1 was dissolved, centrifuged, and then filter-sterilized (final concentration: 500 ng/ml), or the gluconic acid in Example 2 was dissolved, 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), and PTHrP of Example 4 was dissolved. After centrifugation with a filter sterilization (final concentration: 1000 ng/ml), each was added. As a control, a medium containing 10% FBS-containing DMEM (high glucose) containing 20 nM insulin was used. After culturing, all RNA was extracted in the same manner as in Test Example 1, and the expression levels of TNFα gene and UCP1 gene were quantified by real-time PCR. For the analysis of the gene expression level of TNFα, the primers of SEQ ID NOs:5 and 6 were used.
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 anti-obesity agents.

<Test Example 4>
Using mice, succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP were examined for their obesity-suppressing effects by activating brown adipocytes.
After acclimating 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 in Example 1 so that there was no difference in average body weight. Groups in which 80 mg and 800 mg of gluconic acid were administered per kg of mouse body weight, groups in which 0.8 mg and 8 mg of 2-keto-D-gluconic acid in Example 3 were administered per kg of mouse body weight, and groups in which PTHrP in Example 4 was administered per kg of mouse body weight. They were divided into groups of 20 mg and 200 mg and orally administered with a probe once a day. In addition, a group (control) to which only water as a solvent was administered was provided, and the effects on suppression of weight gain and activation of brown adipocytes were compared and verified. All mice were fed a high-fat diet (manufactured by CLEA Japan, Inc.) ad libitum for 4 weeks. At the end of the test, the mice were fasted for 5 hours, then the peri-epiticular fat and brown adipose tissue were removed, and the weight of the peri-epiticular fat was measured. After washing the brown adipose tissue with physiological saline, it was crushed 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 kg of mouse body weight, respectively. In the group, the body weight and the weight of the epididymal fat were significantly reduced compared to the control that did not take any of them, and the effect was that 100 mg of succinic acid, 800 mg of gluconic acid, It was remarkable when 8 mg of 2-keto-D-gluconic acid and 200 mg of PTHrP were taken. In addition, as shown in Table 7, 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 subjected to the treatment, the expression level of the UCP1 gene in brown adipose tissue was significantly increased compared to 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 activate brown adipocytes, It was found to suppress the accumulation of excess fat and obesity. In addition, the effect is 10 mg or more of succinic acid, 80 mg or more of gluconic acid, 0.8 mg or more of 2-keto-D-gluconic acid, 20 mg or more of PTHrP, preferably 100 mg or more of 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.

<Test Example 5>
Using mice, the obesity-suppressing effects of succinic acid, gluconic acid, 2-keto-D-ketogluconic acid, and PTHrP by activation of brown adipose tissue through suppression of inflammation in adipose tissue were investigated.
After acclimating 4-week-old male C57BL6/JJcl mice for 1 week, 10 mice were administered with succinic acid of Example 1 at 100 mg per 1 kg of mouse body weight, and gluconic acid of Example 2 was administered to each 10 mice so that there was no difference in average body weight. A group administered 800 mg per 1 kg mouse body weight, a group administered 8 mg per 1 kg mouse body weight of 2-keto-D-gluconic acid in Example 3, and a group administered 200 mg per 1 kg mouse body weight of PTHrP in Example 4. It was orally administered with a probe once a day. In addition, a group (control) to which only water as a solvent was administered was provided, and the effects on suppression of weight gain and activation of brown adipocytes were compared and verified. All mice were fed a high-fat diet (manufactured by CLEA Japan, Inc.) ad libitum for 16 weeks. At the end of the test, the mice were fasted for 5 hours, then the peri-epiticular fat and brown adipose tissue were removed, and the weight of the peri-epiticular fat was measured. After washing the brown adipose tissue with physiological saline, it was crushed 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, the groups 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 mouse body weight did not ingest any of them. Body weight and peri-epididymal fat weight were significantly reduced compared to controls without the treatment. In addition, as shown in Table 9, in the group ingested 100 mg of succinic acid, 800 mg of gluconic acid, 8 mg of 2-keto-D-gluconic acid, and 200 mg of PTHrP per kg of body weight, compared with the control, The expression level of TNFα gene in brown adipose tissue was decreased, and the expression level of UCP1 gene was significantly increased.
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 suppress inflammation in brown adipose tissue. By activating brown adipocytes, it was found that excess fat accumulation and obesity were suppressed. In addition, it was revealed that the effect was observed when 100 mg or more of succinic acid, 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 ingested per 1 kg of mouse body weight. rice field.

(Preparation of Capsules for Controlling Obesity)
After mixing raw materials according to the formulation shown in Table 10, the mixture was granulated by a conventional method and filled into capsules to produce the obesity-suppressing capsules of the present invention.

(Preparation of tablets for obesity control)
After mixing the raw materials according to the formulation shown in Table 11, the mixture was molded into 1 g and tableted by a conventional method to produce an anti-obesity tablet of the present invention.

(Preparation of Liquid Nutrient Composition for Controlling Obesity)
200 g of gluconic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 4800 g of deionized water, heated to 40° C., and then mixed with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.) at 6,000 rpm for 10 minutes. A 200 g/5 kg gluconic acid solution was obtained by stirring and mixing. To 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 0 kg of stabilizer, 4.0 kg of stabilizer, and 0.05 kg of fragrance are mixed, filled in a 200 ml retort pouch, and sterilized at 121 ° C with a retort sterilizer (first class pressure vessel, TYPE: RCS-4CRTGN, manufactured by Hisaka Seisakusho). After sterilization for 20 minutes, 50 kg of the obesity-suppressing liquid nutritional composition of the present invention was prepared. 800 mg of gluconic acid was contained in 200 g of the obesity-suppressing liquid nutritional composition of the present invention.

(Preparation of anti-obesity drink)
After dissolving 1 g of succinic acid of Example product 1 in 699 g of deionized water, heating to 40° C., using an ultra disperser (ULTRA-TURRAX T-25; manufactured by IKA Japan) at 9,500 rpm for 20 minutes. Stir 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 bottle is filled into a 100 ml glass bottle, sterilized at 95° C. for 15 seconds, and sealed. A book (100 ml) was prepared. 100 mg of succinic acid was contained in 100 g of the obesity-suppressing beverage of the present invention.

(Preparation of obesity-suppressing feed for dogs)
1.6 g of 2-keto-D-gluconic acid of Example 3 was dissolved in 3,998.4 g of deionized water, heated to 40° C., and then mixed with a TK homomixer (MARK II 160 type; manufactured by Tokushu Kika Kogyo Co., Ltd.). was stirred and mixed at 3,600 rpm for 20 minutes to obtain a 1.6 g/4 kg gluconic acid solution. To 2 kg of this gluconic acid solution, 1 kg of soybean meal, 1 kg of skim 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, 0.2 kg of vitamin mixture. 5 kg of cellulose, 0.3 kg of cellulose, and 0.2 kg of a mineral mixture were blended and heat-sterilized at 120° C. for 4 minutes to produce 10 kg of the obesity-suppressing feed of the present invention. 8 mg of 2-keto-D-gluconic acid was contained in 100 g of the obesity-suppressing feed of the present invention.

(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 were mixed, heated to 40° C., and then mixed with a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.) at 6,000 rpm for 10 minutes. Stir mixed for 1 minute. This solution was spray-dried to produce 10 kg of the obesity-suppressing powdered milk of the present invention. 100 mg of succinic acid was contained in 10 g of the obesity-suppressing powdered milk of the present invention.

(Preparation of obesity-suppressing milk drink)
40 g of gluconic acid of Example 2 and 9.96 kg of milk were mixed, heated to 40° C., and 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 obesity-suppressing milk beverage of the present invention. 800 mg of gluconic acid was contained in 200 g of the obesity-suppressing milk drink of the present invention.

(Preparation of fermented milk for suppressing obesity)
5 g of succinic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 1700 g of skimmed milk powder, 300 g of glucose and 7695 g of deionized water were mixed and heat sterilized by holding at 95° C. for 2 hours. This was cooled to 37°C, inoculated with 300 g of lactic acid bacteria starter (Lb. casei), 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 the fermented milk for preventing obesity of the present invention. 200 g of the obesity-suppressing fermented milk of the present invention contained 100 mg of succinic acid.

(Preparation of lactic acid bacteria drink for obesity control)
1,700 g of skim milk powder, 300 g of glucose, and 7,700 g of deionized water were mixed and heat sterilized by holding at 95° C. for 2 hours. This was cooled to 37°C, inoculated with 300 g of lactic acid bacteria starter (Lb. casei), 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 while stirring to obtain a fermentation base. Further, 50 g of gluconic acid, 1800 g of white sugar, 20 g of acidulant, 10 g of flavoring agent, and 8120 g of deionized water were mixed, sterilized at 90° C. for 10 minutes, and cooled to 10° C. or lower to obtain a sugar solution. 2000 g of the fermented base and 8000 g of the sugar solution were mixed, smoothed with a homogenizer, dispensed into 50 paper containers containing 200 ml each, and then sealed with aluminum lids to produce 10 kg of the lactic acid bacteria drink for controlling obesity of the present invention. . 800 mg of gluconic acid was contained in 200 ml of the obesity-suppressing lactic acid bacteria drink of the present invention.

(Preparation of soft drink 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 TK homomixer ( The mixture was stirred and mixed at 6,000 rpm for 10 minutes using 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 obesity-suppressing soft drink of the present invention. 200 ml of the obesity-suppressing soft drink of the present invention contained 8 mg of 2-keto-D-gluconic acid.

(Preparation of obesity-suppressing cheese)
9 kg of gouda cheese, 9 kg of cheddar cheese, 1 kg of shelled 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 cheese was filled into carton and cooled at 5° C. for 2 days and nights to produce 20 kg of the cheese for preventing obesity of the present invention. 100 mg of succinic acid was contained in 100 g of the obesity-suppressing cheese of the present invention.

(Preparation of Margarine for Controlling Obesity)
An oil layer was prepared by mixing 2 kg of hydrogenated soybean oil, 4 kg of refined soybean oil, 2.5 kg of palm oil, and 50 g of glycerin fatty acid ester. Next, 8 g of 2-keto-D-gluconic acid of Example 3, 10 g of lactic acid, and 1432 g of deionized water were mixed and added to the oil layer to obtain a water-in-oil emulsion. was cooled, solidified and kneaded to produce 10 kg of margarine for preventing obesity of the present invention. 8 mg of 2-keto-D-gluconic acid was contained in 10 g of the obesity-suppressing margarine of the present invention.

(Preparation of anti-obesity cream)
4.5 kg of hydrogenated rapeseed oil, 40 g of lecithin, 10 g of monoglycerin fatty acid ester, and 10 g of sorbitan fatty acid ester were mixed to prepare an oil phase. Next, 8 g of 2-keto-D-gluconic acid of Example 3, 400 g of skimmed milk powder, 10 g of sodium caseinate, 20 g of sugar ester, 10 g of phosphate, 5 g of xanthan gum, and 4.987 kg of deionized water are mixed to form an aqueous phase. was prepared. The water phase was heated to 65° C., and the oil phase heated to 70° C. was added little by little while stirring. Stir mixed. This was homogenized in a homogenizer to prepare 10 kg of the anti-obesity cream of the present invention. 8 mg of 2-keto-D-gluconic acid was contained in 10 g of the anti-obesity cream of the present invention.

(Preparation of obesity-suppressing purine)
2000 g honey, 70 g gluconic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 800 g skimmed milk powder, 300 g mascarpone, 700 g liquid starch syrup, 500 g granulated sugar, 250 g fresh cream, 200 g butter, 400 g sweetened egg yolk, 40 g gelatin, 15 g agar, locust bean gum 120 g and 4605 g of deionized water were mixed to form a pudding mix. This pudding mix is stirred and mixed at 6,000 rpm for 10 minutes in a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.), heated to 60 ° C. to dissolve, and then filled into containers in 100 g increments and cooled. Thus, 100 obesity-suppressing puddings of the present invention were produced. 800 mg of gluconic acid was contained in 100 g of the obesity-suppressing purine of the present invention.

(Preparation of obesity-suppressing jelly)
20 g of PTHrP (manufactured by Sigma-Aldrich), 2000 g of fructose, 1500 g of granulated sugar, 500 g of starch syrup, 100 g of agar, 10 g of flavor, and 5870 g of deionized water were mixed, After stirring and mixing at 6,000 rpm for 10 minutes and heating to 50° C. to dissolve, 100 g of the obesity-suppressing jelly of the present invention was produced by filling each container with 100 g and cooling. 100 g of the obesity-suppressing jelly of the present invention contained 200 mg of PTHrP.

(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 a swelling agent, an appropriate amount of deionized water was added to prepare a batter, and then a wafer baking machine to produce 10 kg of the obesity-suppressing wafers of the present invention. 50 g of the obesity control wafer of the present invention contained 100 mg of PTHrP.

Claims (7)

An oral anti-obesity agent containing succinic acid as an active ingredient and promoting differentiation from white adipose precursor cells to brown adipocytes,
The oral anti-obesity agent, wherein the anti-obesity effect is to activate brown adipose tissue. An oral anti-obesity agent containing succinic acid as an active ingredient and promoting differentiation from white adipose precursor cells to brown adipocytes,
The oral anti-obesity agent, wherein the anti-obesity effect is to suppress inflammation in adipose tissue. 3. The oral anti-obesity agent according to claim 1, wherein said succinic acid is derived from milk. An obesity-suppressing food or drink, an obesity-suppressing nutritional composition, an obesity-suppressing feed, or an obesity-suppressing drug comprising the oral obesity-suppressing agent according to any one of claims 1 to 3, wherein The obesity-suppressing food or drink, the obesity-suppressing nutritional composition, the obesity-suppressing feed, or the obesity-suppressing effect, wherein the suppressive effect is to activate brown adipose tissue or suppress inflammation in adipose tissue. Suppressive drug . 5. The food and drink for obesity control according to claim 4, wherein the food and drink is any one of powdered milk, milk drink, lactic acid bacteria drink, fermented milk, soft drink, cheese, margarine, cream, pudding, jelly, and wafer. A method of suppressing obesity by orally ingesting the oral anti-obesity agent according to any one of claims 1 to 3 (excluding administration to humans) , wherein the anti-obesity effect activates brown adipose tissue. or suppressing inflammation in adipose tissue . An oral anti-obesity agent containing succinic acid as an active ingredient and suppressing inflammation in adipose tissue.