KR102239074B1 - Composition for Preventing or Treating Obesity Comprising IF1 - Google Patents

Abstract

The present invention relates to a composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1), and more particularly, to a pharmaceutical composition and food for preventing or treating obesity containing IF1 having an appetite suppressing effect as an active ingredient. About. IF1 (ATPase inhibitory factor 1) according to the present invention exhibits the effect of suppressing weight gain and lowering dietary intake without side effects in a mouse model in which obesity is induced, so it is very useful as a prevention, improvement or treatment of metabolic diseases such as obesity and as an appetite suppressant. Do.

Description

Pharmaceutical composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient {Composition for Preventing or Treating Obesity Comprising IF1}

The present invention relates to a composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1), and more particularly, to a pharmaceutical composition and food for preventing or treating obesity containing IF1 having an appetite suppressing effect as an active ingredient. About.

Obesity is caused by the accumulation of excessive energy due to an imbalance in the regulation of the accumulation and release of energy, and the fact that obesity can lead to serious diseases such as cardiovascular diseases such as hyperlipidemia, diabetes, arteriosclerosis, and high blood pressure. In light of the light, obesity is considered as a disease beyond simple metabolic disorders or risk factors for disease (Mantzoros et al, J Clin Endocrinol Metab , 85:4000-2, 2000).

Efforts to treat obesity have been continuing, and in addition to exercise therapy and diet, obesity medications and surgical therapies such as liposuction have emerged. Currently, there are two main types of obesity treatment drugs: one is a drug that inhibits the absorption of fat or increases energy consumption from the food that has already been eaten, and the other is an'appetite suppressant' that acts on the central nervous system to suppress appetite. In the former case, even if the digestion of ingested food is inhibited or the generated fat is decomposed, if energy is continuously supplied to the body through continuous food intake, there is inevitably a limit to the treatment of obesity. The representative appetite suppressants include furing and fentisine, which are composed of'pentimetrazine', but the advantage is that the appetite suppressing effect is fast and strong, and the drug is cheap, but it is classified as a drug, so it is prohibited to take it continuously for one month or more. It cannot be prescribed mixed with the formulation. In addition, because of the high risk of cardiovascular diseases such as reductil, linovan, and slimmer, which are components of'sibutramine', voluntary recall recommendations were issued in 2010 in Korea following the US and Europe.

Recently, due to the rapid drug development research on obesity, appetite suppressants acting on the central nervous system are being developed as new drugs for treating obesity (DJ Heal et al., International Journal of Obesity 37:107-117, 2013; DJ Heal et al. al., Neuropharmacology 63:132-146, 2012). For example, in 2012, the US FDA approved two new appetite suppressants: Belviq (locarserin) and Qsymia (Pentermine + Toiramide). In addition, GLP-1 (Glucagon-Like peptide) peptides Exernatide (Byetta) and Liraglutide (Victoza) are currently licensed and marketed as type 2 diabetes treatments, and have the effect of suppressing appetite by increasing satiety. According to the evaluation of domestic medical staff, Belvik's overall evaluation is a drug that can be used comfortably without side effects, but has the disadvantage of not being able to expect a remarkable weight loss effect, and that the drug is expensive. Qsymia has superior weight loss effect compared to Belvik, but it is not recommended for patients with cardiovascular disease because it has not been approved for use in Europe due to cardiovascular and brain disease.

Accordingly, there is an urgent need for new obesity treatments and appetite suppressants for obesity treatment, and the demand for them is constantly increasing.

On the other hand, energy generation in cells constituting the human body is one of the most essential elements for survival, and mitochondria present in cells are important organs involved in metabolism through such energy generation and regulation. Mitochondria induce oxidative phosphorylation by forming an electron transport system in the inner mitochondrial membrane (IMM) of the double cell membrane composed of the outer membrane and the inner membrane. ATPase, the fifth of the five structures that make up the electron transport system, contributes to the synthesis of ATP, and ATP is the most effective in energy transfer and substance activation, and the importance of ATPase because about 40 kg per day is a substance used in the human body of adults. (Yoshida et al., Nat Rev Mol Cell Biol . 2(9):669-77, 2001).

ATPase inhibitory factor 1 (hereinafter referred to as IF1) is a major protein that interferes with the function of ATPase and is naturally produced in the human body and has been studied as a target that regulates ATP production and degradation by mitochondria (Campanella et al., Cell Metab). , 8:13-25, 2008). However, all existing studies related to IF1 only evaluate the function of endogenous IF1, and the efficacy and mechanism of exogenous IF1 for obesity are not known at all.

Accordingly, as a result of the present inventors making diligent efforts to develop a treatment for obesity with no side effects and excellent effect, it was confirmed that the weight gain of obese mice was suppressed and the dietary intake decreased by the administration of the IF1 recombinant protein, and the present invention was completed. .

It is an object of the present invention to provide a pharmaceutical composition and food for the prevention or treatment of obesity containing IF1 (ATPase inhibitory factor 1), which exhibits weight loss and appetite suppressing effects, as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

The present invention also provides a food for preventing or improving obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

The present invention also provides a pharmaceutical composition for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

The present invention also provides a functional food for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

IF1 (ATPase inhibitory factor 1) according to the present invention exhibits the effect of suppressing weight gain and lowering dietary intake without side effects in a mouse model in which obesity is induced, so it is very useful as a prevention, improvement or treatment of metabolic diseases such as obesity and as an appetite suppressant. Do.

1 shows the overall experimental schedule for obesity induction and IF1 administration in mice.
Figure 2 shows the effect of reducing the weight of the mouse by IF1 treatment, (A) is the weight change over time, (B) shows the final body weight after 4 weeks of IF1 administration. * P <0.05 compared with HF-GST group
Figure 3 shows the change in dietary intake in mice by IF1 treatment, (A) shows the value obtained by dividing the total dietary intake (g) by the day of the experiment, and (B) is FER (Food efficiency ratio) ). FER is calculated as weight gain (g/day) / dietary intake (g/day). * P <0.05 compared with HF-GST group
Figure 4 shows the reduction in fat weight and liver weight in mouse tissues by IF1 treatment, (A) epididymal fat, (B) perirenal fat, (C) mesenteric fat, (D) Retroperitoneal fat, (E) sum of total visceral fat, and (F) liver weight. * P <0.05 compared with HF-GST group
Figure 5 shows the change of components in the mouse adipose tissue by IF1 treatment, showing the tissue immunostaining of epididymal fat, and the average area of adipocytes. * P <0.05, ** P <0.01 compared with ND group
Figure 6 shows the changes in mouse blood hormone concentration and energy metabolism regulation index by IF1 treatment, (A) blood concentration of Norepinephrine, (B) mRNA expression of UCP-1 in subcutaneous and tissue immunostaining It shows the results. * P <0.05, ** P <0.01, *** P <0.001 compared with ND group

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by an expert skilled in the art to which the present invention belongs. In general, the nomenclature used in this specification is well known and commonly used in the art.

ATPase inhibitory factor 1 (IF1) is a 9.6-kDa basic protein consisting of 84 amino acids and is encoded by the ATP5IF1 gene. ATPase consists of F0 and F1 domains, central and pheripheral stalk, and is subdivided into several subunits. The inhibition of IF1 is initiated by interfering with the rotational motion by binding to the α and β subunits of ATPase. IF1 binds to F1Fo ATP synthase (multi-subunit, membrane-bound assembly), which is involved in the synthesis and degradation of ATP synthesis in mitochondria, and IF1 binds to F1Fo ATP synthase and inhibits ATP degradation during hypoxia such as cardiac ischemia. It is known to prevent ATP depletion and thus inhibit apoptosis.

However, the mechanism for obesity of IF1 is not known at all.

Accordingly, in the present invention, a recombinant protein (SEQ ID NO: 1) is produced through cloning of IF1 DNA data including GST-tag, and IF1 is administered to an obesity-inducing mouse model to inhibit weight gain by IF1, reduce dietary intake, and total Effects such as reduction of visceral fat mass and reduction of liver weight were confirmed. That is, the anti-obesity effect of ATPase inhibitory factor 1 (IF1) was demonstrated.

Therefore, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

In the present invention, the obesity may be characterized in that it includes complications due to obesity.

Complications due to obesity include visceral fat syndrome, metabolic abnormality syndrome, hypertriglyceridemia, hypoHDLemia, angina pectoris, myocardial infarction, osteoarthritis, weight gain-related cancer, orthostatic hypotension, pulmonary hypertension, diabetes, hypertension, impaired glucose tolerance. , Coronary artery thrombosis, atherosclerosis, gallbladder diseases such as cholelithiasis, insulin resistance, chronic arterial obstruction, thromboembolism, heart disease, lipid syndrome, and hyperglycemia.It may be one or more selected from the group consisting of, but is not limited thereto.

The term "obesity" of the present invention means a condition or disease with excess body fat due to energy imbalance. By administering the pharmaceutical composition according to the present invention to an individual, weight loss can prevent or treat obesity.

The term "prevention" of the present invention means any action that suppresses or delays the onset of obesity by administration of the pharmaceutical composition according to the present invention.

The term "treatment" of the present invention refers to any action in which the symptoms of obesity are improved or beneficially changed by administering the pharmaceutical composition of the present invention.

The obesity treatment can be applied to any mammal where obesity may occur, and examples thereof include, without limitation, livestock such as cattle, pigs, sheep, horses, dogs and cats, as well as humans and primates, but preferably humans Can be

In the present invention, "administration" means introducing a predetermined substance to a patient by any suitable method, and the route of administration of the compositions may be administered through any general route as long as the drug can reach the target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc. may be used, but are not limited thereto.

In addition, in the present invention, it was specifically confirmed through the change of norepinephrine (NE) that IF1 regulates diet and energy metabolism through activation of the nervous system.

Norepinephrine (NE) is a major neurotransmitter in the sympathetic nervous system and is known to suppress appetite through activation of the central nervous system.

IF1 (ATPase inhibitory factor 1) of the present invention increases norepinephrine and increases the expression level of UCP-1 gene that regulates energy metabolism through brown localization of white fat.

Therefore, in another aspect, the present invention relates to a pharmaceutical composition for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

The term "appetite suppression" as used herein refers to any action that suppresses or delays appetite by administering the composition.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, and the term "pharmaceutically effective amount" of the present invention is used to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention. It means a sufficient amount, and the effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the rate of excretion. It can be determined according to the duration of treatment, factors including drugs used in combination or concurrent with the composition of the present invention used, and other factors well known in the medical field.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered single or multiple. Considering all of the above factors, it is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects.

The dosage of the pharmaceutical composition of the present invention can be determined by a person skilled in the art in consideration of the purpose of use, the degree of addiction to the disease, the age, weight, sex, history, or type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention may be administered to mammals including humans at 10 to 100 mg/kg, more preferably 10 to 30 mg/kg for a day, and the frequency of administration of the composition of the present invention is Although not particularly limited thereto, it may be administered once to three times a day or divided into several doses.

The pharmaceutical composition of the present invention may be prepared in the form of a pharmaceutical composition for treating or preventing obesity, which further comprises an appropriate carrier, excipient, or diluent commonly used in the preparation of pharmaceutical compositions, the carrier being an unnatural carrier. (non-naturally occuring carrier) may be included.

Specifically, the pharmaceutical composition is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions according to a conventional method. I can.

In the present invention, the carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, or lactose. It is prepared by mixing (lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid preparations for oral use include water and liquid paraffin, which are simple diluents commonly used for suspensions, liquid solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweetening agents, fragrances, and preservatives. have. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The pharmaceutical composition may be in the form of a sterile injectable preparation as an aqueous or oily suspension for sterile injection. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol). Vehicles and solvents that can be used permissively include mannitol, water, Ringel's solution and isotonic sodium chloride solution. In addition, sterile nonvolatile oils are commonly used as solvents or suspending media. For this purpose, any less irritating nonvolatile oil can be used, including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in injection formulations as are pharmaceutically acceptable natural oils (eg olive oil or castor oil), especially their polyoxyethylated.

The pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

Parenteral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment relates to an easily accessible area or organ by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of the present invention can also be applied topically to the lower intestine by rectal suppositories and as a suitable enema. Topically applied transdermal patches are also included in the present invention.

The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceuticals and are prepared in saline using benzyl alcohol or other suitable preservatives, absorption accelerators to enhance bioavailability, fluorocarbons and/or other solubilizing or dispersing agents known in the art. It can be prepared as a solution.

The content of the agent included in the pharmaceutical composition of the present invention is not particularly limited thereto, but may be included in an amount of 0.0001 to 50% by weight, more preferably 0.01 to 10% by weight, based on the total weight of the final composition.

In another aspect, the present invention relates to a method for preventing or treating obesity, comprising administering to an individual a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

In another aspect, the present invention relates to a use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient for the prevention or treatment of obesity.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing as an active ingredient IF1 (ATPase inhibitory factor 1) for the manufacture of a drug for preventing or treating obesity.

In another aspect, the present invention relates to a method for suppressing appetite comprising administering to an individual a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

In another aspect, the present invention relates to a use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient for appetite suppression.

In another aspect, the present invention relates to the use of a pharmaceutical composition containing as an active ingredient IF1 (ATPase inhibitory factor 1) for the manufacture of an appetite suppressant.

The term "subject" of the present invention means all animals including humans who have already developed or are likely to develop obesity, and by administering the composition of the present invention to an individual, the disease can be effectively prevented and treated.

In another aspect, the present invention relates to a food for preventing or improving obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

In the present invention, the obesity may be characterized in that it includes complications due to obesity.

Complications due to obesity include visceral fat syndrome, metabolic abnormality syndrome, hypertriglyceridemia, hypoHDLemia, angina pectoris, myocardial infarction, osteoarthritis, weight gain-related cancer, orthostatic hypotension, pulmonary hypertension, diabetes, hypertension, impaired glucose tolerance. , Coronary artery thrombosis, atherosclerosis, gallbladder diseases such as cholelithiasis, insulin resistance, chronic arterial obstruction, thromboembolism, heart disease, lipid syndrome, and hyperglycemia.It may be one or more selected from the group consisting of, but is not limited thereto.

The term "improvement" of the present invention means any action that at least reduces the severity of a parameter related to the condition being treated, for example a symptom.

In another aspect, the present invention relates to a functional food for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.

When using the food composition of the present invention as a food additive, the composition may be added as it is or may be used with other foods or food ingredients, and may be appropriately used according to a conventional method. In general, when preparing food or beverage, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or for health control purposes, it may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount greater than the above range.

The food of the present invention can be prepared in all forms such as functional food, nutritional supplement, health food, and food additives. For example, as a health food, the composition of the present invention may be prepared in the form of tea, juice, and drinks to be consumed, or granulated, encapsulated, and powdered to be consumed. In addition, functional foods include beverages (including alcoholic beverages), fruits and processed foods thereof (eg, canned fruit, bottled, jam, marmalade, etc.), fish, meat and processed foods thereof (eg, ham, sausage, corn beef, etc.). , Breads and noodles (e.g. udon, soba, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, syrup, dairy products (e.g. butter, cheese, etc.), edible vegetable oil, margarine, vegetable protein, retort food , Frozen food, various seasonings (eg, miso, soy sauce, sauce, etc.), and the like, can be prepared by adding the composition of the present invention.

The health functional food also includes various forms such as functional foods, nutritional supplements, health foods, and food additives as a food composition, and in various forms according to a conventional method known in the art, for example, of the present invention mentioned above. Various foods such as beverages, fruits and processed foods, fish oil, meat and processed foods, breads, noodles, seasonings, etc. by preparing the composition in the form of tea, juice, drink, granulating, encapsulating, powdering, or using such compounds or extracts It can be provided by adding to it and preparing it.

The health beverage composition of the present invention may contain various flavoring agents or natural carbohydrates as an additional component, like a conventional beverage. As the natural carbohydrates described above, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame may be used. . The proportion of the natural carbohydrate can be appropriately determined by the choice of a person skilled in the art.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, Carbonating agents used in carbonated beverages and the like may be contained. In addition, the composition of the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination. The proportion of these additives can also be appropriately selected by a person skilled in the art.

[Example]

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples.

Example 1: Obesity induction animal model production

A C57BL/6J male was used as an animal model, and a 5-week-old mouse was distributed from JOONGAH BIO, and a regular diet was provided for 1 week, and an adaptation period was performed. As for the breeding environment, the humidity of 18~24℃ and 50~60% was always maintained, and free feeding was implemented in both the adaptation period and the experiment period.

After the 1-week adaptation period was over, they were divided into 3 groups and reared for 6 weeks under the following conditions, respectively.

Group 1: Normal diet (ND) control (n=10)

Group 2: high fat diet (HFD) control group (n=15)

Group 3: High fat diet (HFD) experimental group (n=15)

A normal diet and a high fat diet were prepared and provided as shown in Table 1 below.

Composition Table of Normal (ND) and High Fat Diet (HFD; 40% High Fat Diet) Ingredients ND (g) HFD (g) corn starch 15 15 Casein 20 20 Sucrose 50 34 corn oil 5 3 Mineral mix 3.5 3.5 Vitamin mix One One Cellulose 5 5 DL-methionine 0.3 0.3 choline bitartrate 0.2 0.2 Lard 17 Cholesterol One BHT 0.001 0.001 Total 100 (g) 100 (g)

Mice at the end of the 1-week adaptation period induce obesity for 6 weeks on a high fat diet, and then receive IF1. The entire experimental schedule for induction of obesity and administration of IF1 in mice is shown in FIG. 1.

Example 2: Effect of IF1 administration on weight gain inhibition

IF1 (5mg/kg BW) was intraperitoneally injected 4 times a week for 4 weeks after the adaptation period 1 week to mice that induce persistent obesity for 6 weeks (FIG. 1). For IF1, DNA data of IF1 including GST-tag was isolated and purified through cloning to produce a recombinant protein.

Conditions for administering IF1 to three groups of mice of Example 1 are as follows.

Group 1: Normal diet (ND) control + GST intraperitoneal injection (n=10)

Group 2: high fat diet (HFD) control + GST intraperitoneal injection (n=15)

Group 3: High fat diet (HFD) experimental group + IF1 intraperitoneal injection (n=15) (5mg/kg BW)

For 4 weeks of IF1 administration to obese-induced mice, body weight was measured immediately before administration of IF1 on the day of intraperitoneal injection.

As a result, weight gain was significantly suppressed in the IF1 administration group compared to the high fat diet control group from 7 weeks after IF1 administration (FIG. 2A). In other words, the body weight increased sharply until the 7th week when obesity was induced by the high fat diet, but the weight gain was suppressed for 4 weeks after the 7th week of IF1 administration. In Figure 2B, the weight of the final mice at the end of the 11th week was compared between groups and shown.

Example 3: Reduction of dietary intake following IF1 administration

Feed intake was measured daily for 4 weeks of IF1 administration to 3 groups of mice.

In FIG. 3A, the total dietary intake (g) is divided by the experimental elapsed day (day), and the difference in dietary intake between the three groups is shown. As a result, compared to the high-fat diet group, the IF1 administered group showed a statistically significant decrease in dietary intake.

Then, as a result of calculating FER (Food efficiency ratio) by dividing the mouse's weight gain (g/day) by the dietary intake (g/day) (FER = weight gain/dietary intake), IF1 was administered compared to the high fat diet group. The FER decreased in the group (Fig. 3B). That is, it was found that the weight gain suppression effect of obese mice was due to the decrease in dietary intake due to appetite suppression.

Example 4: according to IF1 administration Within the organization Reduces fat accumulation and reduces liver weight

Mice were dissected and tissue was obtained after 11 weeks after the completion of all experiments until 4 weeks of IF1 administration. For dissection, they were fasted for 16 hours, and the next day, 1.5 g/ml of urethane was injected intraperitoneally to completely anesthetize. The anesthesia was verified through the reflex action of the leg, and when anesthesia was performed, blood was collected through an insulin syringe. The blood obtained by blood collection was immediately centrifuged at 2500 rpm for 30 minutes at 4° C. to separate the serum, and the mouse after blood collection was dissected to separate muscle, adipose tissue, and bone tissue, and then quickly immersed in PBS to remove foreign substances on the surface. After measuring the mass and length of each tissue, it was fixed in 10% formaldehyde solution and stored at -80°C for subsequent analysis.

Epididymal fat (Fig. 4A), perirenal fat (Fig. 4B), mesenteric fat (Fig. 4C), retroperitoneal fat (Fig. 4D), total viscera isolated from dissected mice (visceral) The weight of the sum of fat (FIG. 4E) was compared in three groups of mice, and liver weight (FIG. 4F) was also compared.

As a result, compared to the high-fat diet group, the sum of the masses of fat and total visceral fat in each tissue of the IF1 group was significantly decreased, and the weight of the liver was also decreased.

Example 5: Changes in adipose tissue-forming cells following IF1

The change in the morphology of the epididymal fat constituent cells isolated from the mouse of Example 4 was observed.

As a result, in the case of adipose tissue, the size of the adipocytes of the high fat diet control group increased significantly, whereas the IF1 administration experimental group did not show a significant difference compared to the normal diet control group (FIG. 5).

Example 6: Activation of the nervous system according to IF1 administration and regulation of diet and energy metabolism through it

In order to specifically confirm that the administration of IF1 can improve obesity diseases through diet control by appetite suppression, enzyme-linked immunosorbent test for related hormones (ELISA, Enzyme- linked immunosorbent assay) was performed. Changes in blood concentrations of norepinephrine (NE), which are known to suppress appetite through activation of the central nervous system, as a major neurotransmitter of the sympathetic nervous system were confirmed.

As a result, the concentration of norepinephrine (NE) in the high fat diet control group was significantly decreased, while the IF1 administration experimental group showed a tendency to increase compared to the normal diet control group (FIG. 6A).

Next, since stimulation of norepinephrine to the sympathetic nerve is associated with energy metabolism regulation, the expression level of UCP-1 (uncoupling protein 1), which regulates energy metabolism through brown localization of white fat, was examined.

As a result, the increase in the expression level of UCP-1 in subcutaneous fat tissues by the administration of IF1 was confirmed by PCR and tissue immunostaining (FIG. 6B).

As described above, specific parts of the present invention have been described in detail, and it will be apparent to those of ordinary skill in the art that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

<110> Korea University Research and Business Foundation <120> Composition for Preventing or Treating Obesity Comprising IF1 <130> P19-B179 <150> KR 10-2018-0110413 <151> 2018-09-14 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 81 <212> PRT <213> Artificial Sequence <220> <223> Recombinant IF1 <400> 1 Val Ser Asp Ser Ser Asp Ser Met Asp Thr Gly Ala Gly Ser Ile Arg 1 5 10 15 Glu Ala Gly Gly Ala Phe Gly Lys Arg Glu Lys Ala Glu Glu Asp Arg 20 25 30 Tyr Phe Arg Glu Lys Thr Lys Glu Gln Leu Ala Ala Leu Arg Lys His 35 40 45 His Glu Asp Glu Ile Asp His His Ser Lys Glu Ile Glu Arg Leu Gln 50 55 60 Lys Gln Ile Glu Arg His Lys Lys Lys Ile Gln Gln Leu Lys Asn Asn 65 70 75 80 His

Claims (10)

A pharmaceutical composition for preventing or treating obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
The pharmaceutical composition according to claim 1, wherein the obesity includes complications due to obesity.
The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient, or diluent.
Food for preventing or improving obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
The food according to claim 4, wherein the obesity includes complications due to obesity.
The food according to claim 4, further comprising a food supplementary additive acceptable for food.
A pharmaceutical composition for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
The pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable carrier, excipient, or diluent.
Functional food for appetite suppression containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
[10] The functional food according to claim 9, further comprising a food supplementary additive that is acceptable for food.

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