Anti-life style disease agent

Abstract

The purpose of the present invention is to provide an anti-lifestyle disease agent which is safer and has an anti-obesity activity, an activity of improving insulin resistance, an activity of lowering blood sugar level, an activity of lowering blood lipid level, and the like. The anti-lifestyle disease agent is characterized by containing a compound represented by Formula (I) or a salt thereof as an active ingredient.　R1O2C-CH2-CO2R2 ... (I) (In the formula, R1 and R2 independently represent H or a C1-6 alkyl group.)

Description

Anti-lifestyle disease agents

[0001] The present invention relates to an agent for preventing lifestyle-related diseases which exhibits anti-obesity effects, insulin resistance improving effects, blood glucose lowering effects, blood lipid lowering effects, and the like.

[0002] Lifestyle-related diseases are generally defined as a group of diseases whose onset and progression are related to lifestyle habits such as dietary habits, exercise habits, rest, smoking, and drinking, and examples include non-insulin-dependent diabetes mellitus, obesity, non-familial dyslipidemia, hyperuricemia, non-congenital cardiovascular disease, non-familial cancer, hypertension, dyslipidemia, etc. In particular, in recent years, obesity has become a problem in Japan due to factors such as the Westernization of dietary habits and lack of exercise, and obese people are approximately two to three times more likely to suffer from hypertension than people of normal weight.Furthermore, obese people are said to be more likely to suffer from hypo-HDL cholesterolemia, which is a condition in which HDL cholesterol, a good cholesterol that prevents arteriosclerosis, decreases, and hypertriglyceridemia.

[0003] Various dietary restriction therapies have been proposed for weight loss. However, unless accompanied by medical supervision, dietary restriction therapies have the potential to lead to physical and mental disorders due to nutritional imbalances. Furthermore, while so-called diet drugs such as lipase inhibitors have been approved in Japan, synthetic pharmaceuticals always come with the problem of side effects. For example, the lipase inhibitor orlistat can cause diarrhea as well as serious side effects such as liver damage, kidney damage, and cholelithiasis. Therefore, safer anti-lifestyle disease drugs are needed.

[0004] For example, Patent Document 1 discloses a composition having antioxidant properties, which is obtained from the residual liquid from the distillation of barley shochu, a by-product in the production of shochu made from barley, and which contains organic acids such as malic acid.

[0005] Biguanide hypoglycemic agents are known as compounds that exhibit hypoglycemic activity, and organic acids such as malonic acid are sometimes exemplified as counter anions of biguanide compounds (see, for example, Patent Document 2).

[0006] JP 2004-238453 A JP 2021-169522 A

[0007] As mentioned above, Patent Document 1 discloses a composition containing an organic acid and having antioxidant properties. However, the invention described in Patent Document 1 aims to prevent lifestyle-related diseases by scavenging hydroxyl radicals. It has been shown that hydroxyl radicals damage DNA and cause arteriosclerosis and cancer. However, because hydroxyl radicals are highly reactive and have a short lifespan, it is unclear whether ingesting antioxidants that scavenge hydroxyl radicals can actually prevent arteriosclerosis and other conditions by scavenging hydroxyl radicals before they cause cell damage. Furthermore, Patent Document 2 and other documents cite organic acids as examples of anions that form salts, but few drugs actually contain malonic acid as a counter anion. The present invention aims to provide an anti-lifestyle-related disease agent that is safer and exhibits anti-obesity, insulin resistance-improving, hypoglycemic, and blood lipid-lowering effects.

[0008] The present inventors have conducted extensive research to solve the above problems. As a result, they have discovered that malonic acid or its ester, which is also found in sugar beets and fruits, can actually inhibit the differentiation of preadipocytes into adipocytes and the accumulation of lipid droplets in adipocytes, lower blood glucose levels in insulin-resistant individuals, and reduce blood triglyceride levels, thereby completing the present invention. The present invention is described below.

[0009] [1] An anti-lifestyle disease agent characterized by containing a compound represented by the following formula (I) as an active ingredient: 1 O2C-CH2-CO2R 2 ... (I) [wherein, R 1 and R 2 are independently H or C 1-6represents an alkyl group.] [2] An anti-obesity agent comprising the compound represented by the above formula (I) as an active ingredient. [3] An anti-diabetic agent comprising the compound represented by the above formula (I) as an active ingredient. [4] An insulin resistance improving agent comprising the compound represented by the above formula (I) as an active ingredient. [5] A blood sugar lowering agent comprising the compound represented by the above formula (I) as an active ingredient. [6] A therapeutic agent for dyslipidemia comprising the compound represented by the following formula (I) or a salt thereof as an active ingredient. R 1 O2C-CH2-CO2R 2 ... (I) [wherein, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.] [7] The anti-lifestyle disease agent, anti-obesity agent, anti-diabetic agent, insulin resistance improving agent, hypoglycemic agent or therapeutic agent for dyslipidemia according to any one of the above [1] to [5], wherein the compound represented by formula (I) is administered to a human in an amount of 1 mg / kg body weight or more and 20 mg / kg body weight or less per day.

[0010] [8] Use of a composition containing the compound represented by formula (I) or a salt thereof as an active ingredient for treating a lifestyle-related disease. [9] The use according to [8], wherein the lifestyle-related disease is obesity.

[10] The use according to [8], wherein the lifestyle-related disease is diabetes.

[11] The use according to [8], wherein the lifestyle-related disease is insulin resistance.

[12] The use according to [8], wherein the lifestyle-related disease is hyperglycemia.

[13] The use according to [8], wherein the lifestyle-related disease is dyslipidemia.

[14] The use according to any of [8] to

[13] , wherein the compound represented by formula (I) or a salt thereof is administered to a human at a dose of 1 mg / kg body weight or more and 20 mg / kg body weight or less per day.

[0011]

[15] A method for treating a lifestyle-related disease, comprising a step of administering the compound represented by formula (I) or a salt thereof as an active ingredient to a patient suffering from the lifestyle-related disease.

[16] The method according to

[15] , wherein the lifestyle-related disease is obesity.

[17] The method according to

[15] , wherein the lifestyle-related disease is diabetes.

[18] The method according to

[15] , wherein the lifestyle-related disease is insulin resistance.

[19] The method according to

[15] , wherein the lifestyle-related disease is hyperglycemia.

[20] The method according to

[15] , wherein the lifestyle-related disease is dyslipidemia.

[21] The method according to any one of

[15] to

[20] , wherein the compound represented by formula (I) or a salt thereof is administered to a human in an amount of 1 mg / kg body weight or more and 20 mg / kg body weight or less per day.

[0012] The anti-lifestyle-related disease agent of the present invention contains malonic acid or its ester as an active ingredient. Malonic acid or its ester is a component found in fruits and is therefore considered safer than synthetic drugs. Furthermore, the inventors have experimentally demonstrated that malonic acid or its ester actually inhibits the differentiation of preadipocytes into adipocytes, suppresses obesity due to fat accumulation in mice fed a high-nutrition diet, improves insulin resistance in mice fed a high-nutrition diet, lowers blood glucose levels, and reduces blood triglyceride concentrations. Therefore, the present invention is industrially highly advantageous as a drug capable of preventing or ameliorating lifestyle-related diseases, which have become increasingly problematic in recent years.

[0013] Figure 1 (1-1) and Figure 1 (1-2) are photomicrographs of adipose precursor cells (fibroblasts) cultured in a differentiation-inducing medium containing malonic acid or a differentiation-inducing medium containing malonic acid and stained with oil red. Figure 1 (2-1) and Figure 1 (2-2) are photomicrographs of adipose precursor cells (fibroblasts) cultured in a differentiation-inducing medium containing dimethylmalonic acid or a differentiation-inducing medium containing dimethylmalonic acid and stained with oil red. Figure 2 (1) is a graph showing the relative quantitative value of oil red when adipose precursor cells (fibroblasts) are cultured in a differentiation-inducing medium containing malonic acid or a differentiation-inducing medium containing malonic acid and stained with oil red. Figure 2 (2) is a graph showing the relative quantitative value of oil red when adipose precursor cells (fibroblasts) are cultured in a differentiation-inducing medium containing no malonic acid or a differentiation-inducing medium containing dimethylmalonic acid and stained with oil red. Figure 3 (1) is a graph showing the food intake of each group of control mice, malonic acid-administered mice, and dimethylmalonic acid-administered mice, and Figure 3 (2) is a graph showing the change in body weight over time in each group. Figure 4 is a graph showing the change in blood glucose levels over time in control mice, malonic acid-administered mice, and dimethylmalonic acid-administered mice after high glucose loading. Figure 5 is a photograph of three representative examples of epididymal fat in control mice, malonic acid-administered mice, and dimethylmalonic acid-administered mice after glucose loading. Figure 6 is a graph showing the weights of epididymal fat (1) and subcutaneous fat (2) in control mice, malonic acid-administered mice, and dimethylmalonic acid-administered mice after glucose loading. Figure 7 is a micrograph of HE-stained epididymal adipose tissue in control mice (1), malonic acid-administered mice (2), and dimethylmalonic acid-administered mice (3) after glucose loading. Figure 8 is a graph showing the time course of blood glucose levels in control mice given a high-fat diet ad libitum and administered insulin, malonic acid-administered mice given malonic acid in addition to insulin, and dimethylmalonic acid-administered mice given dimethylmalonic acid in addition to insulin. Figure 9 is a HE-stained micrograph of subcutaneous adipose tissue from a control mouse given a high-fat diet ad libitum and administered insulin (1), and a malonic acid-administered mouse given malonic acid in addition to insulin (2).Figure 10 is a graph showing the ratio of beige adipocytes to the total number of cells in thin frozen sections of subcutaneous adipose tissue from control mice given a high-fat diet ad libitum and insulin, and from malonic acid-treated mice given malonic acid in addition to insulin. Figure 11 is a graph showing the blood triglyceride levels in control mice given a high-fat diet ad libitum and from malonic acid-treated mice.

[0014] Fat accumulation in adipocytes increases blood lipid levels and also reduces insulin activity, leading to insulin resistance. Furthermore, adipocytes secrete various substances, such as the hypertensive angiotensinogen, which disrupts the function of the autonomic nervous system and hormones, causing excessive blood vessel constriction and excessive salt accumulation in the body, leading to increased blood pressure. In contrast, the present inventors have demonstrated that the anti-lifestyle-related disease agent of the present invention can suppress fat accumulation in adipocytes and adipose tissue expansion caused by a high-glucose diet. Therefore, the anti-lifestyle-related disease agent of the present invention is believed to exhibit not only anti-obesity effects, but also insulin resistance-improving effects, blood glucose-lowering effects, blood lipid-lowering effects, and blood pressure-lowering effects. In fact, the present inventors have demonstrated that the anti-lifestyle-related disease agent of the present invention improves insulin resistance, lowers blood glucose levels, and reduces blood triglyceride concentrations. Therefore, the anti-lifestyle-related disease agent of the present invention can also be used as an anti-obesity agent, anti-diabetic agent, insulin resistance-improving agent, blood glucose-lowering agent, or dyslipidemia treatment agent. Hereinafter, the anti-lifestyle-related disease agent, anti-obesity agent, anti-diabetic agent, insulin sensitizer, hypoglycemic agent and dyslipidemia therapeutic agent of the present invention may be collectively referred to as "the anti-lifestyle-related disease agent, etc. of the present invention."

[0015] The anti-lifestyle-related disease agent of the present invention contains, as an active ingredient, a compound represented by formula (I). Hereinafter, the compound represented by formula (I) may be abbreviated as "compound (I)." [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.]

[0016] In formula (I), R 1 and R 2may be different from each other, but are preferably the same as each other. 1 or R 2 is H, the carboxy group is -CO2 - or may form a salt with a cation. Such salts are preferably pharmaceutically acceptable salts. Examples of cations that form such salts include alkali metal ions such as lithium ion, sodium ion, and potassium ion; Group 2 element ions such as calcium ion and magnesium ion; primary to quaternary ammonium ions; and pyridinium ion. 1 and R 2 is C 1-6 When the group is an alkyl group, the fat solubility of compound (I) increases, improving its absorbability in the body, and after absorption, it may be hydrolyzed by esterase to form malonic acid, thereby exerting its effects.

[0017] "C 1-6 The term "alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, and n-hexyl. Preferably, C 1-4 alkyl group, more preferably C 1-2 It is preferably an alkyl group, and even more preferably methyl.

[0018] In compound (I), R 1 =R 2 The compound where R = H is malonic acid, which is a known compound that is also commercially available. 1 and R 2 At least one of them is C 1-6 Those skilled in the art can synthesize compounds that are alkyl groups by esterification of malonic acid with the corresponding alcohol compound.

[0019] The dosage form of the anti-lifestyle-related disease agent of the present invention is not particularly limited, and may be, for example, oral preparations such as tablets, capsules, liquids, granules, powders, and syrups; inhalants such as aerosols; injections; and suppositories. Oral preparations such as oral preparations are preferred. The anti-lifestyle-related disease agent of the present invention may contain various additives depending on the dosage form. For example, bases, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, humectants, stabilizers, preservatives, solvents, solubilizers, suspending agents, surfactants, antioxidants, adjuvants, buffers, pH adjusters, sweeteners, and flavorings may be added. The amounts of these additives may be appropriately determined as needed, as long as they do not interfere with the effects of the present invention. Furthermore, other medicinal ingredients may also be added.

[0020] The anti-lifestyle-related disease agents of the present invention exhibit excellent anti-obesity effects, insulin resistance-improving effects, blood glucose-lowering effects, blood lipid-lowering effects, etc. On the other hand, because the active ingredients are components also contained in vegetables and fruits, it is considered that the safety is relatively high and that constant use may be possible. Therefore, for example, it may be possible to take the agent multiple times a day for the remission of lifestyle-related diseases such as suppressing obesity, and it may also be possible to take the agent constantly for the purpose of preventing lifestyle-related diseases, etc.

[0021] The method for treating lifestyle-related diseases according to the present invention includes administering the compound represented by formula (I) or a salt thereof as an active ingredient to a patient suffering from lifestyle-related diseases. The amount of the anti-lifestyle-related disease agent of the present invention should be adjusted appropriately depending on the patient's condition, age, sex, etc., and is not particularly limited. For example, the dosage of the anti-lifestyle-related disease agent of the present invention may be adjusted appropriately within a range in which the above-mentioned action effect is observed. For example, the agent may be administered once or more and five or less times per day so that the daily dose of compound (I) or a salt thereof per kg of body weight for humans is approximately 1 mg or more and 20 mg or less. Note that the patient is not limited to those who exhibit symptoms or characteristics of lifestyle-related diseases, etc., but also includes those who do not exhibit symptoms or characteristics of lifestyle-related diseases, etc., but who need to be prevented from developing lifestyle-related diseases, etc. Furthermore, the patient may include not only humans but also non-human animals such as pets.

[0022] The anti-lifestyle-related disease agent etc. of the present invention can be applied to the tolerance of lifestyle-related diseases, such as suppressing obesity, improving insulin resistance, and lowering blood glucose levels and blood lipids. Furthermore, since the anti-lifestyle-related disease agent etc. of the present invention is considered to be relatively safe, in addition to the above-mentioned purposes, it can also be used constantly and continuously as a drug for the prevention of obesity, hyperglycemia, dyslipidemia etc., or as a health food or health drink having a preventive effect on obesity, hyperglycemia, dyslipidemia etc.

[0023] This application claims the benefit of priority based on Japanese Patent Application No. 2022-63060, filed on April 5, 2022. The entire contents of the specification of Japanese Patent Application No. 2022-63060, filed on April 5, 2022, are incorporated herein by reference.

[0024] The present invention will be explained in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is of course possible to carry out the invention by making appropriate modifications within the scope of the above and below-described aims, and all such modifications are included in the technical scope of the present invention.

[0025] Example 1 (1) Induction of Adipocyte Differentiation Mouse fibroblast 3T3-L1 cells were plated on a 24-well plate at 5.0 × 10 cells per well. 4 0.5 mL of cell dispersion was added to the 24-well plate and incubated overnight at 37°C. The following day, cells were confirmed to have grown to confluence. Separately, a differentiation medium containing 1 μM dexamethasone, 100 μM isobutylmethylxanthine (IBMX), and 1 μg / mL insulin was prepared. Malonic acid was added at 0 mM, 1 mM, 5 mM, or 10 mM, and dimethylmalonic acid (DMM) was added at 0 mM, 1 mM, 5 mM, or 10 mM. Dimethylmalonic acid was dissolved in dimethyl sulfoxide before addition, but the dimethyl sulfoxide concentration in the medium was adjusted to 5% or less. 0.5 mL of the differentiation medium was added per well to the 24-well plate and cultured at 37°C. On the fifth day after the addition of the differentiation medium, mouse fibroblast 3T3-L1 cells were placed in three wells of a 24-well plate at 5.0 × 10 cells per well as a blank for absorbance measurement.4 0.5 mL of cell dispersion was added.

[0026] (2) Oil Red Staining On the sixth day after the addition of differentiation medium, adipocytes were stained with Oil Red staining. Specifically, Oil Red O (30 mg) was dissolved in 2-propanol (10 mL) to prepare an Oil Red O stock solution. The resulting stock solution was mixed with distilled water in a 3:2 ratio and filtered through Whatman filter paper to prepare an Oil Red O staining solution. On the sixth day after the addition of differentiation medium, the medium was removed from the 24-well plate, the cells were rinsed with PBS, and then 250 μL of 4% paraformaldehyde (PFA) solution was added per well and fixed by incubation for 30 minutes. The 4% PFA solution was removed, and the cells were washed three times with distilled water. Next, 300 μL of Oil Red O staining solution was added per well, and the cells were gently shaken on a shaker and incubated at room temperature for 20 minutes. The staining solution was removed, and the cells were washed with distilled water. 60% 2-propanol (1 mL) was added, mixed, and immediately discarded. Then, PBS (1 mL) was added, mixed, and discarded. PBS (1 mL) was then added and observed under a microscope. Micrographs of the control (0 mM malonic acid and dimethylmalonic acid) and the medium containing 5 mM malonic acid or dimethylmalonic acid are shown in Figure 1. The PBS was removed from each well, and 2-propanol (300 μL) was added and mixed. The resulting mixture (150 μL) was added to a 96-well microplate, and the absorbance at 492 nm was measured to quantify Oil Red O. The relative absorbance values ​​relative to the control (100%) are shown in Figure 2. The results for malonic acid are shown in Figure 2(1), and the results for dimethylmalonic acid are shown in Figure 2(2). In Figure 2, "*" indicates a significant difference at p<0.05 in the Tukey test. As shown in Figures 1 and 2, it was demonstrated that malonic acid and malonic acid esters significantly inhibit the differentiation of adipose precursor cells (fibroblasts) into adipocytes, and may be able to suppress obesity.

[0027] Example 2: Animal Experiment Twelve 5-week-old male C57BL / 6J (Japan SLC) mice were randomly divided into a control group, a malonic acid (Mal)-treated group, and a dimethylmalonic acid (DMM)-treated group (four mice per group). 100 mg of malonic acid or 200 mg of dimethylmalonic acid per kg of mouse body weight was dissolved in 10 μL of 10% DMSO / PBS per g of mouse body weight, and the resulting solution was intraperitoneally administered once daily for 35 days. During this time, each mouse was provided with a high-fat diet ("High Fat Diet 32 ​​(HFD32)" manufactured by CLEA Japan) and water ad libitum. Body weight and food intake were also measured daily. On day 36 after an 18-hour fast, 1.5 g / kg of glucose was administered intraperitoneally in 10 μL of PBS per gram of body weight. Blood glucose levels were measured at 0, 15, 30, 60, and 120 minutes after administration. Each mouse was then euthanized by CO2 inhalation, and the left and right epididymal fat, subcutaneous fat, anterior subcutaneous fat, and interscapular brown fat were collected. The weights of the epididymal and subcutaneous fat were measured and fixed in 4% paraformaldehyde (PFA). Thin frozen sections were prepared from the fixed epididymal fat, stained with hematoxylin and eosin, and examined microscopically. The food intake of each group is shown in Figure 3 (1), the body weight in Figure 3 (2), the time course of blood glucose concentration after glucose loading is shown in Figure 4, photographs of three representative examples of epididymal fat in each group are shown in Figure 5, the weights of epididymal fat and subcutaneous fat in each group are shown in Figure 6, and micrographs of HE-stained epididymal adipose tissue are shown in Figure 7. In Figures 3, 4, and 6, "*" indicates a significant difference from the control in Tukey's test at p<0.05, and "**" indicates a significant difference from the control in Tukey's test at p<0.01.

[0028] As shown in Figure 3, no substantial difference in food intake was observed between the groups. However, administration of dimethylmalonic acid tended to result in a decrease in body weight compared to the control group, and administration of malonic acid significantly reduced body weight. Furthermore, as shown in Figure 4, in the control group, high glucose loading increased blood glucose levels. In contrast, administration of dimethylmalonic acid resulted in significantly lower blood glucose levels immediately after high glucose loading compared to the control group. Furthermore, administration of malonic acid resulted in significantly lower blood glucose levels 60 and 120 minutes after high glucose loading compared to the control group. Therefore, administration of dimethylmalonic acid appears to have the effect of suppressing the normal increase in blood glucose levels due to ingestion of a high-fat diet, and administration of malonic acid appears to have the effect of improving the loss of blood glucose regulation function and insulin resistance due to ingestion of a high-fat diet.

[0029] As shown in Figures 5 and 6, the amount of epididymal fat and the amount of subcutaneous fat were significantly lower in the rats administered malonic acid or dimethylmalonic acid compared to the control group. Furthermore, as shown in Figure 7, the control group showed enlarged adipocytes, likely due to lipid droplets, whereas the rats administered malonic acid or dimethylmalonic acid clearly inhibited such enlargement. These experimental results demonstrate that malonic acid and dimethylmalonic acid can significantly inhibit fat accumulation in adipocytes, despite the intake of a high-fat diet.

[0030] Example 3: Animal Experiment (1) Measurement of Blood Glucose Concentration Thirteen 5-week-old C57BL / 6J (Japan SLC) male mice were randomly divided into a control group (5 mice), a malonic acid (Mal)-administered group (4 mice), and a dimethylmalonic acid (DMM)-administered group (4 mice). 100 mg of malonic acid or 200 mg of dimethylmalonic acid per kg of mouse body weight was dissolved in 10 μL of 10% DMSO / PBS per g of mouse body weight, and the resulting solution was intraperitoneally administered once daily for 35 days. During this time, each mouse was given a high-fat diet ("High Fat Diet 32 ​​(HFD32)" manufactured by CLEA Japan) and water ad libitum. On the 36th day from the start of the experiment, after a 5-hour fast, 0.5 g / kg of insulin ("Humulin") was administered. (R) ® (Eli Lilly Japan) was dissolved in 10 μL of PBS per gram of body weight and administered intraperitoneally, and blood glucose levels were measured 0, 15, 30, 60, and 120 minutes later. The results are shown in Figure 8. In Figure 8, "*" indicates a significant difference from the control at p<0.05 in the Tukey test, and "**" indicates a significant difference from the control at p<0.01 in the Tukey test. As shown in Figure 8, in the control group, despite insulin administration, blood glucose levels remained high, likely due to insulin resistance caused by the high-fat diet. In contrast, administration of dimethylmalonic acid tended to result in lower blood glucose levels, while administration of malonic acid significantly reduced blood glucose levels. These results demonstrate that malonic acid and its esters can improve insulin resistance and reduce blood glucose levels.

[0031] (2) Observation of Subcutaneous Adipose Tissue Next, each mouse was euthanized by CO2 inhalation, and the subcutaneous adipose tissue was collected and fixed in 4% paraformaldehyde (PFA) solution. Thin frozen sections were prepared from the fixed subcutaneous adipose tissue, stained with hematoxylin and eosin, and observed under a microscope. Figure 9(1) shows a HE-stained micrograph of the subcutaneous adipose tissue of a control mouse, and Figure 9(2) shows a HE-stained micrograph of the subcutaneous adipose tissue of a malonic acid-treated mouse. As shown in Figure 9(1), subcutaneous adipose tissue is generally composed of white adipocytes. White adipocytes contain a single lipid droplet within the cell. In contrast, as shown in Figure 9(2), beige adipocytes containing multiple lipid droplets within the cell were observed in the subcutaneous adipose tissue of malonic acid-treated mice. Furthermore, the number of cells in the thin frozen sections of subcutaneous adipose tissue of control mice and malonic acid-treated mice was counted, and the proportion of beige adipocytes was calculated. The results are shown in Figure 10.

[0032] The results shown in Figures 9 and 10 suggest that the improvement in insulin resistance and reduction in blood glucose levels following administration of malonic acid and its esters is due to an increase in the proportion of beige cells in adipose tissue. Adipose tissue generally consists of white adipocytes, which absorb excess carbohydrates and lipids as triglycerides and store them as energy. However, when excessive carbohydrate and lipid intake leads to the enlargement and increase in number of white adipocytes, harmful factors such as angiotensin II, TNF-α, MCP-1, and PAI-1 are released from white adipocytes, causing so-called lifestyle-related diseases. Angiotensin II is involved in high blood pressure, TNF-α causes immune system inflammation and insulin resistance, MCP-1 is involved in the development and worsening of arteriosclerosis, and PAI-1 is involved in the formation of blood clots. Meanwhile, brown adipocytes have the ability to break down and burn fat. Beige fat cells have properties similar to brown fat cells, and while brown fat cells are found only in limited locations such as the neck, armpits, and around the heart and kidneys, beige fat cells are induced in subcutaneous adipose tissue by long-term cold stimulation and generate heat. Specifically, it has been revealed that malonic acid and malonic acid esters according to the present invention promote the induction of beige fat cells in adipose tissue, suppress the production of harmful factors by white adipose cells through fat decomposition, thereby suppressing the production of harmful factors of lifestyle-related diseases derived from adipose tissue, improving insulin resistance and reducing blood glucose levels, thereby contributing to the improvement of lifestyle-related diseases.

[0033] Example 4: Measurement of Blood Triglyceride Concentration Seven 5-week-old male C57BL / 6J (Japan SLC) mice were randomly divided into a control group (4 mice) and a malonic acid (Mal)-treated group (3 mice). 100 mg of malonic acid per kg of mouse body weight was dissolved in 10 μL of 10% DMSO / PBS per g of mouse body weight. The resulting solution was intraperitoneally administered to the malonic acid-treated group once daily for 35 days. During this time, each mouse was provided with a high-fat diet ("High Fat Diet 32 ​​(HFD32)" manufactured by CLEA Japan) and water ad libitum. On day 36 after the start of the experiment, blood triglyceride concentrations were measured after a 5-hour fast. The results are shown in Figure 11. In Figure 11, "*" indicates a significant difference from the control in the Tukey test (p<0.05). As shown in Figure 11, when malonic acid was administered, the blood triglyceride concentration was significantly reduced compared to the control group. These results demonstrate that malonic acid can reduce the increase in blood neutral fat concentration caused by a high-fat diet.

Claims

1. 1. An anti-lifestyle-related disease agent comprising a compound represented by the following formula (I) or a salt thereof as an active ingredient: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

2. An anti-obesity agent comprising a compound represented by the following formula (I) or a salt thereof as an active ingredient: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

3. 1. An antidiabetic agent comprising a compound represented by the following formula (I) or a salt thereof as an active ingredient: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

4. An insulin resistance improving agent comprising, as an active ingredient, a compound represented by the following formula (I) or a salt thereof: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

5. A hypoglycemic agent comprising, as an active ingredient, a compound represented by the following formula (I) or a salt thereof: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

6. A therapeutic agent for dyslipidemia, comprising a compound represented by the following formula (I) or a salt thereof as an active ingredient: R 1 O 2 C-CH 2 -CO 2 R 2 ・・・ (I) [In the formula, R 1 and R 2 are independently H or C 1-6 represents an alkyl group.

7. The anti-lifestyle-related disease agent, anti-obesity agent, anti-diabetic agent, insulin resistance improving agent, hypoglycemic agent or therapeutic agent for dyslipidemia according to any one of claims 1 to 6, wherein the compound represented by formula (I) or a salt thereof is administered to a human in an amount of 1 mg / kg body weight or more and 20 mg / kg body weight or less per day.