KR20200031998A - Composition for Preventing or Treating Obesity Comprising IF1 - Google Patents
Composition for Preventing or Treating Obesity Comprising IF1 Download PDFInfo
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- KR20200031998A KR20200031998A KR1020190110741A KR20190110741A KR20200031998A KR 20200031998 A KR20200031998 A KR 20200031998A KR 1020190110741 A KR1020190110741 A KR 1020190110741A KR 20190110741 A KR20190110741 A KR 20190110741A KR 20200031998 A KR20200031998 A KR 20200031998A
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Classifications
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- A61K38/1761—Apoptosis related proteins, e.g. Apoptotic protease-activating factor-1 (APAF-1), Bax, Bax-inhibitory protein(s)(BI; bax-I), Myeloid cell leukemia associated protein (MCL-1), Inhibitor of apoptosis [IAP] or Bcl-2
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/332—Promoters of weight control and weight loss
Abstract
Description
본 발명은 IF1 (ATPase inhibitory factor 1)을 함유하는 비만의 예방 또는 치료용 조성물에 관한 것으로, 더욱 자세하게는 식욕억제 효과를 가지는 IF1을 유효성분으로 함유하는 비만의 예방 또는 치료용 약학 조성물 및 식품에 관한 것이다.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 as an active ingredient having an appetite suppressing effect. It is about.
비만은 에너지의 축적과 방출에 대한 조절의 불균형으로 인하여 과도한 에너지가 축적되어 발생하는 것으로, 비만으로 인해 고지혈증, 당뇨, 동맥경화, 고혈압 등과 같은 심혈관계질환 등의 심각한 질환이 발생될 수 있다는 사실에 비추어 비만은 단순한 대사 장애나 질병의 위험 인자를 넘어 하나의 질환으로 여겨지고 있다 (Mantzoros et al, J Clin Endocrinol Metab, 85:4000-2, 2000).Obesity is caused by excessive energy accumulation due to an imbalance in the regulation of energy accumulation and release, and obesity can cause serious diseases such as cardiovascular diseases such as hyperlipidemia, diabetes, arteriosclerosis, and hypertension. In the light of obesity, obesity is considered to be a disease that goes beyond simple metabolic disorders or disease risk factors (Mantzoros et al, J Clin) Endocrinol Metab , 85: 4000-2, 2000).
비만을 치료하기 위한 노력이 그간 계속되어 운동요법, 식이요법 외에 비만치료제, 지방흡입술과 같은 수술요법까지 등장하게 되었다. 현재 비만치료제는 크게 두 가지 종류로, 하나는 이미 섭취된 음식에 대하여 지방의 흡수를 억제하거나 에너지 소모를 증가시키는 약물이고 다른 하나는 중추신경에 작용해 식욕을 억제하는 `식욕억제제`이다. 전자의 경우 섭취하는 식품의 소화를 저해하거나 생성된 지방을 분해한다고 하더라도 지속적인 음식섭취에 의하여 에너지가 지속적으로 체내에 공급된다면 소화저해나 지방분해는 비만 치료에 있어 한계가 있을 수 밖에 없다. 식욕억제제의 대표적인 것으로는 `펜티메트라진` 성분의 푸링과 펜티신이 있는데 식욕억제 효과가 빠르고 강하게 나타나며 약값이 싸다는 것이 장점이나, 마약으로 분류되어 있어 한 달 이상 연속 복용하는 것이 금지되어 있으며, 다른 제제와 섞어 처방하지 못한다. 또한, `시부트라민` 성분의 리덕틸, 리노반, 슬리머 등은 심혈관계 질환의 위험이 크다는 이유로, 미국, 유럽에 이어 국내에서도 2010년 자발적 회수권고조치가 내려졌다.Efforts to treat obesity have been continued, and in addition to exercise therapy and diet therapy, obesity treatments and surgical treatments such as liposuction have emerged. Currently, there are two types of anti-obesity drugs, one that suppresses the absorption of fat or increases energy consumption for already consumed food, and the other is 'an appetite suppressant' that suppresses appetite by acting on the central nervous system. In the former case, even if it inhibits digestion of food ingested or decomposes the produced fat, digestion impairment or fat decomposition must be limited in treating obesity if energy is continuously supplied to the body through continuous food intake. Typical examples of appetite suppressants include furin and pentisin of the 'pentimethazine' component, which have the effect of suppressing the appetite quickly and strongly and having low drug prices, but because they are classified as drugs, it is prohibited to take them continuously for more than a month. It cannot be prescribed by mixing with the preparation. In addition, due to the high risk of cardiovascular diseases such as reductyl, linoban, and slimmer of the 'sibutramine' component, voluntary withdrawal recommendations were issued in 2010 following the United States and Europe.
최근 비만에 관한 비약적인 약물개발연구로 인하여 중추신경에 작용하는 식욕억제제들이 새로운 비만치료 약물 제제들로 개발되고 있다 (D J Heal et al., International Journal of Obesity 37:107-117, 2013; D J Heal et al., Neuropharmacology 63:132-146, 2012). 대표적인 예로 미국 FDA는 2012년 벨빅 (Belviq; locarserin)과 큐시미아 (Qsymia; Phentermine + Toiramide) 라는 2개의 새로운 식욕 억제제를 허가하였다. 또한 GLP-1(Glucagon-Like peptide) 펩타이드인 Exernatide (Byetta) 와 Liraglutide (Victoza)는 현재 제2형 당뇨병 치료제로 허가, 판매되고 있으며 포만감을 증가시켜 식욕을 억제하는 효능이 있다. 국내 의료진의 평가에 따르면 벨빅의 전반적인 평가는 부작용 없이 편안하게 쓸 수 있는 약물이지만 현저한 체중감량 효과를 기대할 수 없고, 약값이 비싸다는 단점이 있다. 큐시미아는 벨빅에 비하여 체중감량 효과는 뛰어나지만, 유럽에서는 심혈관뇌질환을 이유로 사용허가가 나지 않아 심혈관 질환이 있는 환자에게는 권고되지 않고 있다.Due to recent rapid drug development studies on obesity, appetite suppressants that act on the central nervous system are being developed as new anti-obesity drugs (DJ Heal et al., International Journal of Obesity 37: 107-117, 2013; DJ Heal et al., Neuropharmacology 63: 132-146, 2012). For example, the U.S. FDA approved two new appetite suppressants in 2012: Belvik (lolvserin) and Qsymia (Phentermine + Toiramide). In addition, GLP-1 (Glucagon-Like peptide) peptides Exernatide (Byetta) and Liraglutide (Victoza) are currently licensed and marketed as treatments for type 2 diabetes and have the effect of suppressing appetite by increasing satiety. According to the evaluation of the domestic medical staff, the overall evaluation of Belvic is a drug that can be used comfortably without side effects, but there is a disadvantage in that a remarkable weight loss effect cannot be expected and the drug price is expensive. Kushimia is superior in weight loss to Belvic, but in Europe it is not recommended for patients with cardiovascular disease because it is not licensed for cardiovascular disease.
따라서, 부작용이 적고 효과가 확실한 새로운 비만 치료제 및 비만 치료를 위한 식욕억제제가 절실히 요구되고 있으며, 이에 대한 수요가 지속적으로 증가하고 있는 상황이다. Therefore, there is an urgent need for a new anti-obesity drug with less side effects and certain effects, and an appetite suppressant for the treatment of obesity, and the demand for this is constantly increasing.
한편, 인체를 구성하는 세포에 있어서 에너지 생성은 생존을 위한 가장 필수적인 요소 중 하나이며, 세포 내에 존재하는 미토콘드리아는 이러한 에너지 생성 및 조절을 통해 물질대사에 관여하는 중요한 기관이다. 미토콘드리아는 외막, 내막으로 구성되는 이중세포막 중 내막 (inner mitochondrial membrane, IMM)에 전자전달계를 구성함으로서 산화적 인산화 (oxidative phosphorylation)를 야기한다. 전자전달계를 구성하는 다섯 가지 구조체중 다섯번째 구조체인 ATPase는 ATP합성에 기여하는데, ATP는 에너지 전달 및 물질 활성화에 있어 가장 효과적이며, 하루에 약 40kg이 성인의 인체에서 사용되는 물질이기에 ATPase의 중요성이 강조되고 있다 (Yoshida et al., Nat Rev Mol Cell Biol. 2(9):669-77, 2001). 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 energy generation and regulation. Mitochondria form an electron transport system in an inner mitochondrial membrane (IMM) of a double cell membrane composed of an outer membrane and an inner membrane, thereby causing oxidative phosphorylation. ATPase, the fifth of the five structures that make up the electron transport system, contributes to the synthesis of ATP. ATP is the most effective in energy transfer and material activation, and the importance of ATPase because about 40 kg per day is used in the adult human body. Is emphasized (Yoshida et al., Nat Rev Mol Cell Biol . 2 (9): 669-77, 2001).
ATPase inhibitory factor 1 (이하 IF1)은 ATPase의 기능을 방해하는 주요한 단백질로서 인체 내에서 자연적으로 생성되어 미토콘드리아에 의한 ATP 생성 및 분해를 조절하는 타겟으로서 많은 연구가 이루어져 있다 (Campanella et al., Cell Metab , 8:13-25, 2008). 하지만, 기존의 IF1 관련한 연구들은 모두 내재적 (endogenous) IF1의 기능을 평가하는데 그치고 있을 뿐, 외인성 (exogenous) IF1의 비만에 대한 효능 및 기작은 전혀 알려진 바가 없다.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 for controlling ATP production and degradation by mitochondria (Campanella et al., Cell Metab) , 8: 13-25, 2008). However, all existing studies related to IF1 are only evaluating the function of endogenous IF1, and the efficacy and mechanisms of exogenous IF1 against obesity are not known at all.
이에, 본 발명자들은 부작용이 없고 효과가 우수한 비만 치료제를 개발하고자 예의 노력한 결과, IF1 재조합 단백질 투여에 의해 비만 마우스의 체중 증가가 억제되고, 식이 섭취량이 감소하는 것을 확인하고, 본 발명을 완성하게 되었다.Thus, the present inventors confirmed that as a result of earnest efforts to develop an anti-obesity treatment with no side effects and excellent effects, the weight gain of obese mice was suppressed by the administration of IF1 recombinant protein, and the dietary intake was reduced, and the present invention was completed. .
본 발명의 목적은 체중 감소 및 식욕 억제 효과를 나타내는 IF1 (ATPase inhibitory factor 1)를 유효성분으로 함유하는 비만의 예방 또는 치료용 약학 조성물 및 식품을 제공하는데 있다.An object of the present invention is to provide a pharmaceutical composition and food for the prevention or treatment of obesity containing as an active ingredient IF1 (ATPase inhibitory factor 1) showing weight loss and appetite suppression effect.
상기 목적을 달성하기 위하여, 본 발명은 IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 비만의 예방 또는 치료용 약학 조성물을 제공한다.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.
본 발명은 또한, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 비만의 예방 또는 개선용 식품을 제공한다.The present invention also provides a food for preventing or improving obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명은 또한, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 식욕억제용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for suppressing appetite, which contains IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명은 또한, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 식욕억제용 기능성 식품을 제공한다.The present invention also provides a functional food for suppressing appetite containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명에 따른 IF1 (ATPase inhibitory factor 1)은 비만이 유발된 마우스 모델에서 부작용 없이 체중 증가 억제 및 식이 섭취량 저하의 효과를 나타내므로, 비만 등 대사성 질환의 예방, 개선 또는 치료제 및 식욕억제제로 매우 유용하다.IF1 (ATPase inhibitory factor 1) according to the present invention exhibits an effect of suppressing weight gain and reducing dietary intake without side effects in a mouse model in which obesity is induced, and thus is very useful as a preventive, ameliorating or therapeutic agent for appetite suppression and metabolic diseases such as obesity Do.
도 1은 마우스에서 비만 유도 및 IF1 투여에 대한 전체 실험 스케줄을 보여주는 것이다.
도 2는 IF1 처리에 의한 마우스의 체중 감소 효과를 보여주는 것으로, (A)는 시간에 따른 체중변화이며, (B)는 IF1 투여 4주 후 최종 체중을 나타낸 것이다. * P < 0.05 compared with HF-GST group
도 3은 IF1 처리에 의한 마우스에서의 식이섭취량 변화를 보여주는 것으로, (A)는 전체 식이섭취량(g)을 실험경과일(day)로 나눈 값을 나타낸 것이며, (B)는 FER (Food efficiency ratio)를 나타낸 것이다. FER은 체중 증가량(g/day) / 식이섭취량(g/day)으로 산출함. * P < 0.05 compared with HF-GST group
도 4는 IF1 처리에 의한 마우스 조직에서의 지방 무게 감소 및 간 무게 감소를 보여주는 것으로, (A) 부고환 (epididymal) 지방, (B) 신장 주위 (perirenal) 지방, (C) 장간막 (mesenteric) 지방, (D) 후복막 (retroperitoneal) 지방, (E) 총 내장 (visceral) 지방의 합, (F) 간의 무게를 나타낸 것이다. * P < 0.05 compared with HF-GST group
도 5는 IF1 처리에 의한 마우스 지방조직에서 구성요소의 변화를 보여주는 것으로, 부고환 (epididymal) 지방의 조직면역염색, 지방세포의 평균면적을 나타낸 것이다. * P < 0.05, ** P < 0.01 compared with ND group
도 6은 IF1 처리에 의한 마우스 혈중 호르몬 농도와 에너지대사 조절 지표의 변화를 보여주는 것으로, (A) Norepinephrine의 혈중 농도, (B) 피하지방 (subcutaneous)에서 UCP-1의 mRNA 발현도 및 조직면역염색 결과를 나타낸 것이다. * P < 0.05, ** P < 0.01, *** P < 0.001 compared with ND group1 shows the overall experimental schedule for induction of obesity and administration of IF1 in mice.
Figure 2 shows the weight loss effect of mice by IF1 treatment, (A) is a change in body weight over time, (B) shows the
Figure 3 shows the change in dietary intake in mice by IF1 treatment, (A) shows the total dietary intake (g) divided by the experimental date (day), (B) 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 a reduction in fat weight and liver weight in mouse tissues by IF1 treatment, (A) epididymal fat, (B) perirenal fat, (C) mesenteric fat, It shows the weight of (D) the amount of liver between the peritoneal (retroperitoneal) fat, (E) total visceral fat, and (F). * P <0.05 compared with HF-GST group
Figure 5 shows the change in the components in mouse adipose tissue by IF1 treatment, showing the tissue immunostaining of epididymal fat, the average area of adipocytes. * P <0.05, ** P <0.01 compared with ND group
FIG. 6 shows changes in mouse blood hormone concentration and energy metabolism control index by IF1 treatment, (A) blood concentration of Norepinephrine, (B) mRNA expression level and tissue immunostaining of UCP-1 in subcutaneous The results are shown. * P <0.05, ** P <0.01, *** P <0.001 compared with ND group
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로 본 명세서에서 사용된 명명법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein is well known in the art and commonly used.
ATPase inhibitory factor 1 (IF1)은 84개 아미노산으로 이루어진 9.6-kDa basic 단백질이고, ATP5IF1 유전자에 의해 암호화된다. ATPase는 F0, F1 domain과 central, pheripheral stalk로 구성되며 여러 subunit으로 세분화된다. IF1의 inhibition 작용은 ATPase의 α subunit, β subunit 부위에 결합함으로서 회전운동을 방해하여 시작된다. IF1은 미토콘드리아내에서 ATP synthesis 합성 및 분해에 관여하는 F1Fo ATP synthase (multi-subunit, membrane-bound assembly) 에 결합하며, IF1은 심허혈 등과 같은 hypoxia 시에 F1Fo ATP synthase에 결합 및 ATP 분해를 저해함으로써 ATP depletion을 막게 되고, 따라서 세포사멸을 억제하는 것으로 알려져 있다.ATPase inhibitory factor 1 (IF1) is a 9.6-kDa basic protein composed of 84 amino acids and is encoded by the ATP5IF1 gene. ATPase is composed of F0, F1 domain and central, pheripheral stalk, and is subdivided into several subunits. The inhibition of IF1 begins by interfering with the rotational motion of ATPase by binding to the α subunit and β subunit. 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 in hypoxia such as cardiac ischemia It is known to block ATP depletion and thus inhibit apoptosis.
하지만, IF1의 비만에 대한 메커니즘은 전혀 알려져 있지 않다.However, no mechanism for obesity in IF1 is known.
이에, 본 발명에서는 GST-tag를 포함한 IF1의 DNA data를 클로닝을 통하여 재조합 단백질 (서열번호 1)을 생산하고, IF1을 비만 유도 마우스 모델에 투여하여 IF1에 의한 체중 증가 억제, 식이 섭취량 감소, 총 내장 지방량 감소 및 간 무게 감소 등의 효과를 확인하였다. 즉, ATPase inhibitory factor 1 (IF1) 의 항비만 효과를 입증하였다.Thus, in the present invention, recombinant protein (SEQ ID NO: 1) is produced by cloning DNA data of IF1 including GST-tag, and IF1 is administered to a model of obesity-inducing mouse to suppress weight gain by IF1, reduce dietary intake, and total Effects such as reduction in visceral fat and reduction in liver weight were confirmed. That is, the anti-obesity effect of ATPase inhibitory factor 1 (IF1) was demonstrated.
따라서, 본 발명은 일 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 비만의 예방 또는 치료용 약학 조성물에 관한 것이다.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.
본 발명에 있어서, 상기 비만은 비만으로 인한 합병증을 포함하는 것을 특징으로 할 수 있다.In the present invention, the obesity may be characterized as including complications due to obesity.
상기 비만으로 인한 합병증은 내장 지방 증후군, 대사이상 증후군, 고트리글리세라이드 혈증, 저HDL 혈증, 협심증, 심근경색, 골관절염, 체중증가와 관련된 암, 기립성 저혈압, 폐고혈압, 당뇨병, 고혈압, 손상된 내당력, 관상동맥혈전증, 아테롬성동맥경화증, 담석증과 같은 담낭 질병, 인슐린 저항성, 만성 동맥폐색증, 혈전색전증, 심장질환, 지질증후군 및 과혈당증으로 구성된 군에서 선택되는 하나 이상일 수 있으나, 이에 한정되는 것은 아니다.Complications due to obesity include visceral fat syndrome, metabolic syndrome, hypertriglyceridemia, hypoHDLemia, angina, myocardial infarction, osteoarthritis, cancer associated with weight gain, orthostatic hypotension, pulmonary hypertension, diabetes, hypertension, impaired history , May be one or more selected from the group consisting of coronary artery thrombosis, atherosclerosis, gallbladder disease such as cholelithiasis, insulin resistance, chronic arterial occlusion, thromboembolism, heart disease, lipid syndrome and hyperglycemia, but is not limited thereto.
본 발명의 용어 "비만"이란, 에너지 불균형에 의하여 과다한 체지방을 가진 상태(condition) 또는 질환(disease)을 의미한다. 본 발명에 따른 약학 조성물을 개체에 투여함으로써 체중을 감량하여 비만을 예방 또는 치료할 수 있다.The term "obesity" of the present invention means a condition or disease with excessive body fat due to energy imbalance. By administering the pharmaceutical composition according to the present invention to an individual, weight loss can be prevented or treated.
본 발명의 용어 "예방"이란, 본 발명에 따른 약학적 조성물의 투여로 비만의 발병을 억제 또는 지연시키는 모든 행위를 의미한다.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.
본 발명의 용어 "치료"란, 본 발명의 약학 조성물을 투여함으로써, 비만의 증세가 호전되거나 이롭게 변경시키는 모든 행위를 의미한다.The term "treatment" of the present invention means any act of improving or beneficially altering the symptoms of obesity by administering the pharmaceutical composition of the present invention.
상기 비만 치료는 비만이 발생할 수 있는 임의의 포유 동물에 적용이 가능하며, 그 예로 인간 및 영장류뿐만 아니라, 소, 돼지, 양, 말, 개 및 고양이 등 가축을 제한없이 포함하나, 바람직하게는 인간일 수 있다.The treatment of obesity is applicable to any mammal that may develop obesity, and includes, for example, humans and primates as well as cattle, pigs, sheep, horses, dogs, cats, and other domestic animals, but is preferably human. Can be
본 발명에서 "투여"는 어떠한 적절한 방법으로 환자에게 소정의 물질을 도입하는 것을 의미하며, 상기 조성물들의 투여 경로는 약물이 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비강내 투여, 폐내 투여, 직장 내 투여 등이 될 수 있으나, 이에 제한되지는 않는다. In the present invention, "administration" means introducing a predetermined substance to a patient in any suitable way, and the route of administration of the compositions can 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, and the like, but are not limited thereto.
또한, 본 발명에서는 IF1은 신경계 활성화를 통해 식이 및 에너지대사를 조절함을 노르에피네프린 (norepinephrine, NE) 변화를 통해 구체적으로 확인하였다. In addition, in the present invention, IF1 regulates diet and energy metabolism through activation of the nervous system, and was specifically confirmed through norepinephrine (NE) changes.
노르에피네프린 (norepinephrine, NE)은 교감신경계의 주요한 신경전달물질로서 중추신경계의 활성화를 통한 식욕억제를 나타내는 것으로 알려져 있다. Norepinephrine (NE) is a major neurotransmitter of the sympathetic nervous system and is known to exhibit appetite suppression through activation of the central nervous system.
본 발명의 IF1 (ATPase inhibitory factor 1)은 노르에피네프린을 증가시키고, 백색지방의 갈색지방화를 통해 에너지 대사를 조절하는 UCP-1 유전자 발현도를 증가시켰다.IF1 (ATPase inhibitory factor 1) of the present invention increases norepinephrine and increases UCP-1 gene expression that regulates energy metabolism through brown fat localization of white fat.
따라서, 본 발명은 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 식욕억제용 약학 조성물에 관한 것이다.Accordingly, the present invention, in another aspect, relates to a pharmaceutical composition for suppressing appetite, which contains IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명의 용어, “식욕억제”란 조성물의 투여로 식욕을 억제 또는 지연시키는 모든 행위를 의미한다.The term "an appetite suppression" of the present invention means any act of suppressing or delaying appetite by administration of the composition.
상기 본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명의 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, the term "pharmaceutically effective amount" of the present invention to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention By sufficient amount, the effective dose level refers to the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, patient's sensitivity to the drug, the time of administration, route of administration and rate of excretion of the composition of the invention used. The duration of treatment, factors including drugs used in combination or coincidental with the composition of the present invention used, and other factors well known in the medical field.
본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects.
본 발명의 약학조성물의 투여량은 사용목적, 질환의 중독도, 환자의 연령, 체중, 성별, 기왕력, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 당업자가 결정할 수 있다. 예를 들어, 본 발명의 약학 조성물을 사람을 포함하는 포유동물에 하루 동안 10 내지 100 ㎎/㎏, 보다 바람직하게는 10 내지 30 ㎎/㎏으로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 내지 3회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다.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 poisoning of the disease, the age, weight, sex, history of the patient, or the type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention may be administered to mammals including humans for 10 to 100 mg / kg, more preferably 10 to 30 mg / kg for one day, and the frequency of administration of the composition of the present invention is It is not particularly limited, but may be administered once to three times a day or divided into doses and administered several times.
본 발명의 약학적 조성물은, 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함하는 비만 치료 또는 예방용 약학 조성물의 형태로 제조될 수 있는데, 상기 담체는 비자연적 담체 (non-naturally occuring carrier)를 포함할 수 있다. The pharmaceutical composition of the present invention may be prepared in the form of a pharmaceutical composition for the treatment or prevention of obesity, further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition, the carrier being a non-natural carrier (non-naturally occuring carrier).
구체적으로, 상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. Specifically, the pharmaceutical composition is formulated in the form of an oral dosage form such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, external preparation, suppository, and sterile injection solution, respectively, according to a conventional method. You can.
본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. In the present invention, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, 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, disintegrating agents and surfactants.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. 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, lubricants such as magnesium stearate and talc are used in addition to simple excipients.
경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. Liquid preparations for oral use may include various excipients, such as wetting agents, humectants, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are simple diluents commonly used for suspending agents, liquid solutions, emulsions, syrups, etc. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
의약 조성물은 멸균 주사용 수성 또는 유성 현탁액으로서 멸균 주사용 제제의 형태일 수 있다. 이 현탁액은 적합한 분산제 또는 습윤제(예, 트윈 80) 및 현탁화제를 사용하여 본 분야에 공지된 기술에 따라 제형될 수 있다. 멸균 주사용 제제는 또한 무독성의 비경구적으로 허용되는 희석제 또는 용매중의 멸균 주사용액 또는 현탁액(예, 1,3-부탄디올중의 용액)일 수 있다. 허용적으로 사용될 수 있는 비히클 및 용매로는 만니톨, 물, 링겔 용액 및 등장성 염화나트륨 용액이 있다. 또한, 멸균 불휘발성 오일이 통상적으로 용매 또는 현탁화 매질로서 사용된다. 이러한 목적을 위해, 합성 모노 또는 디글리세라이드를 포함하여 자극성이 적은 어떠한 불휘발성 오일도 사용할 수 있다. 올레산 및 이의 글리세라이드 유도체와 같은 지방산이 약제학적으로 허용되는 천연오일(예, 올리브유 또는 피마자유), 특히 이들의 폴리옥시에틸화된 것과 마찬가지로 주사 제제에 유용하다.The pharmaceutical composition may be in the form of a sterile injectable preparation as an aqueous or oily suspension for sterile injectable use. This suspension can be formulated according to techniques known in the art using suitable dispersants or wetting agents (eg Tween 80) and suspending agents. Sterile injectable preparations may also be non-toxic parenterally acceptable diluents or sterile injectable solutions or suspensions in solvents (eg solutions in 1,3-butanediol). Vehicles and solvents that may be acceptable are mannitol, water, Ringel's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspending media. For this purpose, any non-volatile oil with less irritation can be used, including synthetic mono or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof are useful in injection formulations, such as pharmaceutically acceptable natural oils (eg olive oil or castor oil), especially their polyoxyethylated.
본 발명의 의약 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다. 이들 조성물은 본 발명의 화합물을 실온에서 고형이지만 직장 온도에서는 액상인 적합한 비자극성 부형제와 혼합하여 제조할 수 있다. 이러한 물질로는 이들로 한정되는 것은 아니지만 코코아 버터, 밀랍 및 폴리에틸렌 글리콜이 포함된다.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 the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperatures. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
본 발명에 따른 의약 조성물의 비경구 투여는 목적하는 치료가 국소 적용으로 접근이 용이한 부위 또는 기관과 관련이 있을 때 특히 유용하다. 피부에 국소적으로 적용하는 경우, 의약 조성물은 담체에 현탁 또는 용해된 활성성분을 함유한 적합한 연고로 제형되어야 한다. 본 발명의 화합물을 국소 투여하기 위한 담체로는 이들로 한정되는 것은 아니지만 광유, 유동 파라핀, 백색 와셀린, 프로필렌 글리콜, 폴리옥시에틸렌, 폴리옥시프로필렌 화합물, 유화 왁스 및 물이 포함된다. 다른 방도로서, 의약 조성물은 담체에 현탁 또는 용해된 활성 화합물을 함유한 적합한 로션 또는 크림으로 제형될 수 있다. 적합한 담체로는 이들로 한정되는 것은 아니지만 광유, 솔비탄 모노스테아레이트, 폴리솔베이트 60, 세틸 에스테르 왁스, 세테아릴 알코올, 2-옥틸도데카놀, 벤질 알코올 및 물이 포함된다. 본 발명의 의약 조성물은 또한 직장 좌제에 의해 또한 적합한 관장제로 하부 장관으로 국소 적용할 수 있다. 국소 적용된 경피 패치가 또한 본 발명에 포함된다.Parenteral administration of a pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves a site or organ that is accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated with 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 topically applied to the lower intestinal tract by rectal suppositories and also with suitable enema. Topical applied transdermal patches are also included in the present invention.
본 발명의 의약 조성물은 비내 에어로졸 또는 흡입에 의해 투여할 수 있다. 이러한 조성물은 약제의 분야에 잘 알려진 기술에 따라 제조하며 벤질 알코올 또는 다른 적합한 보존제, 생체이용율을 증강시키기 위한 흡수 촉진제, 플루오로카본 및/또는 기타 본 분야에 알려진 가용화제 또는 분산제를 사용하여 염수중의 용액으로서 제조할 수 있다.The pharmaceutical composition of the present invention can be administered by intranasal aerosol or inhalation. Such compositions are prepared in accordance with techniques well known in the art of medicament, and are used in benzyl alcohol or other suitable preservatives, absorption accelerators to enhance bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art in saline. It can be prepared as a solution.
본 발명의 약학 조성물에 포함된 상기 제제의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총중량을 기준으로 0.0001 내지 50 중량%, 보다 바람직하게는 0.01 내지 10 중량%의 함량으로 포함할 수 있다.The content of the formulation contained in the pharmaceutical composition of the present invention is not particularly limited, 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.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물을 개체에 투여하는 단계를 포함하는 비만의 예방 또는 치료 방법에 관한 것이다.In another aspect, the present invention relates to a method for preventing or treating obesity, comprising administering to a subject a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물을 비만의 예방 또는 치료에 사용하는 용도에 관한 것이다.In another aspect, the present invention relates to the use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient in the prevention or treatment of obesity.
본 발명은 또 다른 관점에서, 비만의 예방 또는 치료용 약제의 제조를 위한 IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물의 용도에 관한 것이다.In another aspect, the present invention relates to the use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) for the prevention or treatment of obesity as an active ingredient.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물을 개체에 투여하는 단계를 포함하는 식욕을 억제시키는 방법에 관한 것이다.In another aspect, the present invention relates to a method for suppressing appetite, comprising administering a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient to an individual.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물을 식욕억제에 사용하는 용도에 관한 것이다.In another aspect, the present invention relates to the use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient in appetite suppression.
본 발명은 또 다른 관점에서, 식욕억제제의 제조를 위한 IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 약학 조성물의 용도에 관한 것이다.In another aspect, the present invention relates to the use of a pharmaceutical composition containing IF1 (ATPase inhibitory factor 1) as an active ingredient for the manufacture of an appetite suppressant.
본 발명의 용어 "개체"란 비만이 이미 발병하였거나 발병할 가능성이 있는 인간을 포함한 모든 동물을 의미하고, 본 발명의 조성물을 개체에게 투여함으로써, 상기 질환을 효과적으로 예방 및 치료할 수 있다.The term "individual" 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.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 비만의 예방 또는 개선용 식품에 관한 것이다.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.
본 발명에 있어서, 상기 비만은 비만으로 인한 합병증을 포함하는 것을 특징으로 할 수 있다.In the present invention, the obesity may be characterized as including complications due to obesity.
상기 비만으로 인한 합병증은 내장 지방 증후군, 대사이상 증후군, 고트리글리세라이드 혈증, 저HDL 혈증, 협심증, 심근경색, 골관절염, 체중증가와 관련된 암, 기립성 저혈압, 폐고혈압, 당뇨병, 고혈압, 손상된 내당력, 관상동맥혈전증, 아테롬성동맥경화증, 담석증과 같은 담낭 질병, 인슐린 저항성, 만성 동맥폐색증, 혈전색전증, 심장질환, 지질증후군 및 과혈당증으로 구성된 군에서 선택되는 하나 이상일 수 있으나, 이에 한정되는 것은 아니다.Complications due to obesity include visceral fat syndrome, metabolic syndrome, hypertriglyceridemia, hypoHDLemia, angina, myocardial infarction, osteoarthritis, cancer associated with weight gain, orthostatic hypotension, pulmonary hypertension, diabetes, hypertension, impaired history , May be one or more selected from the group consisting of coronary artery thrombosis, atherosclerosis, gallbladder disease such as cholelithiasis, insulin resistance, chronic arterial occlusion, thromboembolism, heart disease, lipid syndrome and hyperglycemia, but is not limited thereto.
본 발명의 용어 “개선”이란 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention means any action that at least reduces the severity of the parameters associated with the condition being treated, for example symptoms.
본 발명은 또 다른 관점에서, IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 식욕억제용 기능성 식품에 관한 것이다.In another aspect, the present invention relates to a functional food for suppressing appetite, which contains IF1 (ATPase inhibitory factor 1) as an active ingredient.
본 발명의 식품 조성물을 식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 15중량% 이하, 바람직하게는 10중량% 이하의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the food composition of the present invention is used as a food additive, the composition may be added as it is or used with other foods or food ingredients, and may be suitably used according to conventional methods. Generally, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, with respect to the raw materials in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for health control, it may be below the above range, and since there is no problem in terms of safety, the active ingredient may also be used in an amount above the above range.
본 발명의 식품은, 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태로 제조할 수 있다. 예를 들면, 건강식품으로는 본 발명의 조성물을 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지, 콘비프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치츠 등), 식용식물유지, 마가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 조성물을 첨가하여 제조할 수 있다.The food of the present invention can be prepared in any form, 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 drink to be consumed or granulated, encapsulated, and powdered. In addition, functional foods include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruits, canned foods, jams, marmalade, etc.), fish, meat, and processed foods (e.g. ham, sausage, corn beef, etc.) , Breads and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), juice, various drinks, cookies, syrup, dairy products (e.g. butter, cheats, etc.), edible vegetable oils, margarine, vegetable protein, retort foods , Frozen food, various seasonings (eg, miso, soy sauce, sauce, etc.) can be prepared by adding the composition of the present invention.
상기 건강 기능식품 또한, 식품조성물로써 기능성 식품, 영양보조제, 건강식품, 식품 첨가제 등의 다양한 형태를 포함하는 것이며, 당업계에 공지된 통상적인 방법에 따라 다양한 형태, 예컨대, 앞서 언급한 본 발명의 조성물을 차, 쥬스, 드링크의 형태로 제조하거나, 과립화, 캡슐화, 분말화 하거나, 이러한 화합물 또는 추출물을 음료, 과실 및 가공식품, 어유, 육류 및 그 가공식품, 빵류, 면류, 조미료 등 각종 식품에 첨가하여 제조함으로써 제공될 수 있다.The health functional food also includes various forms such as functional foods, nutritional supplements, health foods, and food additives as food compositions, and various forms according to conventional methods known in the art, for example, the present invention mentioned above. Prepare the composition in the form of tea, juice, drink, granulate, encapsulate, powder, or drink these compounds or extracts, fruit and processed foods, fish oil, meat and processed foods thereof, breads, noodles, seasonings, etc. It can be provided by manufacturing in addition to.
본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 당업자의 선택에 의해 적절하게 결정될 수 있다.The health drink composition of the present invention may contain various flavoring agents or natural carbohydrates, etc., as additional components, like a conventional beverage. The natural carbohydrates described above may include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, synthetic sweeteners such as saccharin and aspartame. . The proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율 또한 당업자에 의해 적절히 선택될 수 있다.In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And carbonated agents used in carbonated beverages. In addition, the composition of the present invention may contain flesh for the preparation of natural fruit juice, fruit juice beverages and vegetable beverages. These ingredients can be used independently or in combination. The proportions of these additives can also be appropriately selected by those skilled in the art.
[실시예][Example]
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
실시예Example 1: 비만 유도 동물모델 제작 1: Obesity-induced animal model production
동물모델로는 C57BL/6J 수컷을 사용하였으며, JOONGAH BIO에서 5주령의 마우스를 분양받아 1주간 보통식이를 제공하며 적응기간을 거쳤다. 사육환경으로는 18~24℃, 50~60%의 습도를 항시 유지하였으며, 적응기간 및 실험기간 모두 자유급식을 이행하였다.As the animal model, C57BL / 6J males were used, and 5 weeks old mice were pre-saled from JOONGAH BIO to provide a normal diet for 1 week, and then went through an adaptation period. As a breeding environment, the humidity of 18 ~ 24 ℃ and 50 ~ 60% was maintained at all times, and free feeding was performed in both the adaptation period and the experimental period.
1주일 적응기간이 끝난 후, 3가지 그룹으로 나뉘어 각각 다음 같은 조건으로 6주간 사육하였다. After the one-week adaptation period, they were divided into three groups and reared for 6 weeks under the following conditions.
그룹 1: 정상식이(ND) 대조군 (n=10)Group 1: Normal diet (ND) control (n = 10)
그룹 2: 고지방식이(HFD) 대조군 (n=15)Group 2: High fat diet (HFD) control (n = 15)
그룹 3: 고지방식이(HFD) 실험군 (n=15)Group 3: High Fat Diet (HFD) experimental group (n = 15)
정상식이와 고지방식이는 하기 표 1과 같이 제조하여 제공하였다.The normal diet and the high-fat diet were prepared and provided as in Table 1 below.
1주일 적응기간이 끝난 마우스들은 고지방식이로 6주 동안 비만을 유도한 다음, IF1을 투여하였다. 마우스에서 비만 유도 및 IF1 투여에 대한 전체 실험 스케줄은 도 1에 나타내었다.After the 1 week adaptation period, mice were induced obesity for 6 weeks in a high-fat diet, and then administered with IF1. The overall experimental schedule for obesity induction and IF1 administration in mice is shown in FIG. 1.
실시예Example 2: IF1 투여에 따른 체중 증가 억제 효과 2: Effect of suppressing weight gain with IF1 administration
적응기간 1주 이후 6주 동안 지속적인 비만을 유도한 마우스에 IF1 (5mg/kg BW)을 이후 4주 동안 주당 4회 복강주사 하였다 (도 1). IF1은 GST-tag를 포함한 IF1의 DNA data를 클로닝을 통하여 분리, 정제하여 재조합 단백질을 생산하였다.Mice inducing persistent obesity for 6 weeks after 1 week of adaptation period were intraperitoneally injected 4 times per week for 4 weeks after IF1 (5 mg / kg BW). IF1 produced recombinant protein by separating and purifying DNA data of IF1 including GST-tag through cloning.
실시예 1의 마우스 3가지 그룹에 IF1를 투여하는 조건은 다음과 같다.The conditions for administering IF1 to the three groups of mice in Example 1 are as follows.
그룹 1: 정상식이(ND) 대조군 + GST 복강주사 (n=10)Group 1: Normal diet (ND) control + GST intraperitoneal injection (n = 10)
그룹 2: 고지방식이(HFD) 대조군 + GST 복강주사 (n=15)Group 2: High fat diet (HFD) control group + GST intraperitoneal injection (n = 15)
그룹 3: 고지방식이(HFD) 실험군 + IF1 복강주사 (n=15) (5mg/kg BW)Group 3: High Fat Diet (HFD) experimental group + IF1 intraperitoneal injection (n = 15) (5mg / kg BW)
비만이 유도된 마우스에 IF1을 투여하는 4주 동안, IF1을 복강주사 하는 당일 투여 직전에 체중을 측정하였다.For 4 weeks of administering IF1 to obese-induced mice, body weights were measured immediately prior to the same day of intraperitoneal injection of IF1.
그 결과, IF1이 투여된 7주차 이후부터 고지방식이 대조군 대비 IF1 투여군에서 유의하게 체중증가가 억제되었다 (도 2A). 즉, 고지방식이로 비만이 유도된 7주차까지는 체중이 급격하게 증가하였으나, 7주차 이후 IF1이 투여된 4주 동안은 체중 증가가 억제되었다. 도 2B에는 11주차 마지막 최종 마우스의 체중을 그룹간 비교하여 나타냈다.As a result, the weight gain was significantly suppressed in the IF1 administration group compared to the control group in the high-fat diet from the 7th week after IF1 was administered (FIG. 2A). In other words, the body weight increased rapidly until the 7th week when obesity was induced by the high-fat diet, but the weight gain was suppressed for 4 weeks after IF1 was administered after the 7th week. In FIG. 2B, the weights of the final mice at the end of
실시예Example 3: IF1 투여에 따른 식이 섭취량의 감소 3: Reduction in dietary intake following IF1 administration
마우스 3가지 그룹에 IF1를 투여하는 4주 동안 사료 섭취량을 매일 측정하였다. Feed intake was measured daily for 4 weeks of administration of IF1 to 3 groups of mice.
도 3A에는 전체 식이 섭취량 (g)을 실험 경과일 (day)로 나누어 3개의 그룹간 식이 섭취량의 차이를 나타내었다. 그 결과, 고지방식이군에 비해 IF1이 투여된 군은 식이 섭취량이 통계적으로 유의하게 감소하였다.3A shows the difference in dietary intake between the three groups by dividing the total dietary intake (g) by the day of the experiment. As a result, the dietary intake was significantly decreased in the IF1-administered group compared to the high-fat diet group.
그 다음, 마우스의 체중 증가량 (g/day)을 식이 섭취량 (g/day)로 나누어 FER (Food efficiency ratio)를 산출 (FER = 체중 증가량/식이 섭취량)한 결과, 고지방식이군에 비해 IF1이 투여된 군은 FER이 감소하였다 (도 3B). 즉, 비만 마우스의 체중 증가 억제 효과는 식욕억제에 따른 식이 섭취량 감소에 의한 것임을 알 수 있었다.Then, the weight gain (g / day) of the mouse was divided by the dietary intake (g / day) to calculate the food efficiency ratio (FER) (FER = weight gain / dietary intake), and IF1 was administered compared to the high-fat diet group. FER was reduced in the group (Fig. 3B). That is, it was found that the effect of suppressing weight gain in obese mice was due to a decrease in dietary intake according to appetite suppression.
실시예Example 4: IF1 투여에 따른 4: Following IF1 administration 조직내Within the organization 지방축적 감소 및 간 무게 감소 Reduced fat accumulation and reduced liver weight
IF1 투여 4주까지 모든 실험이 종료된 11주차 이후에 마우스를 해부하여 조직을 얻었다. 해부를 위해 16시간 절식시키고, 다음날 우레탄 (urethane) 1.5g/ml을 복강주사 하여 완전히 마취시켰다. 마취 여부는 다리부분의 반사작용을 통해 검증하였으며, 마취가 이루어지면 인슐린 시린지 (syringe)를 통해 채혈하였다. 채혈로 얻어진 혈액은 즉시 2500rpm으로 30분간 4℃에서 원심분리하여 혈청을 분리하고, 채혈이 완료된 마우스는 해부하여 근육과 지방조직, 골조직을 분리하여 빠르게 PBS에 담가 표면에 묻은 이물질을 제거하였다. 각각의 조직은 질량 및 길이를 측정한 후, 다음 분석을 위해 10% 포름알데하이드 용액에 고정하고 -80℃에 보관하였다.Tissues were obtained by dissecting
해부한 마우스에서 분리한 부고환 (epididymal) 지방 (도 4A), 신장 주위 (perirenal) 지방 (도 4B), 장간막 (mesenteric) 지방 (도 4C), 후복막 (retroperitoneal) 지방 (도 4D), 총 내장 (visceral) 지방의 합 (도 4E)의 무게를 마우스 3가지 그룹에서 비교하였으며, 간 무게 (도 4F)도 비교하였다.Epididymal fat (FIG. 4A), perirenal fat (FIG. 4B), mesenteric fat (FIG. 4C), retroperitoneal fat (FIG. 4D), total visceral isolated from dissected mice The weight of the (visceral) fat sum (FIG. 4E) was compared in three groups of mice, and the liver weight (FIG. 4F) was also compared.
그 결과, 고지방식이군에 비해 IF1이 투여된 군의 각 조직내 지방 및 총 내장 지방의 질량 합이 유의하게 감소하였으며, 간 무게 역시 감소하였다.As a result, compared to the high-fat diet group, the mass sum of fat and total visceral fat in each tissue of the group administered with IF1 was significantly reduced, and liver weight was also decreased.
실시예Example 5: IF1 투여에 따른 지방의 조직 구성세포의 변화 5: Changes in adipose tissue cells following IF1 administration
상기 실시예 4의 마우스에서 분리한 부고환 지방 (epididymal fat) 구성세포의 형태 변화를 관찰하였다.The morphological changes of epididymal fat constituent cells isolated from the mouse of Example 4 were observed.
그 결과, 지방조직의 경우 고지방식이 대조군의 지방세포는 크기가 유의하게 증가하는 것에 반해, IF1 투여 실험군은 정상식이 대조군과 비교하여 큰 차이를 나타내지 않았다 (도 5). As a result, in the case of adipose tissue, the fat cells of the high-fat diet control group significantly increased, while the IF1 administration experimental group did not show a significant difference compared to the normal diet control group (FIG. 5).
실시예 6: IF1 투여에 따른 신경계 활성화 및 이를 통한 식이와 에너지대사 조절 Example 6: Activation of the nervous system according to IF1 administration and regulation of diet and energy metabolism through it
IF1의 투여가 식욕억제에 의한 식이조절을 통하여 비만질환을 개선할 수 있음을 구체적으로 확인하기 위해, 실시예 4에서 분리한 혈청을 이용하여 관련 호르몬에 대한 효소결합면역흡착검사 (ELISA, Enzyme-linked immunosorbent assay)를 시행하였다. 교감신경계의 주요한 신경전달물질로서 중추신경계의 활성화를 통한 식욕억제를 나타내는 것으로 알려져 있는 노르에피네프린 (norepinephrine, NE)의 혈중 농도변화를 확인하였다.To specifically confirm that administration of IF1 can improve obesity disease through dietary control by appetite suppression, enzyme-linked immunosorbent assay for related hormones using serum isolated in Example 4 (ELISA, Enzyme- linked immunosorbent assay). As a major neurotransmitter of the sympathetic nervous system, changes in blood levels of norepinephrine (NE), which is known to indicate appetite suppression through activation of the central nervous system, were confirmed.
그 결과, 고지방식이 대조군의 노르에피네프린 (NE) 농도는 유의하게 감소한 반면, IF1 투여 실험군은 정상식이 대조군 대비 증가하는 경향을 나타냈다 (도 6A). As a result, the norepinephrine (NE) concentration of the high-fat diet control group was significantly decreased, while the experimental group of IF1 administration showed a tendency to increase in the normal diet compared to the control group (FIG. 6A).
그 다음, 노르에피네프린의 교감신경에 대한 자극은 에너지대사 조절과 연관되므로 이를 확인하기 위해, 백색지방의 갈색지방화를 통해 에너지 대사를 조절하는 UCP-1 (uncoupling protein 1)의 발현도를 검사하였다.Next, since the stimulation of norepinephrine on the sympathetic nerve is related to the regulation of energy metabolism, the expression level of UCP-1 (uncoupling protein 1), which regulates energy metabolism through brown localization of white fat, was examined.
그 결과, IF1의 투여에 의한 피하지방 (Subcutaneous fat) 조직에서 UCP-1의 발현도 증가를 PCR 및 조직면역염색으로 확인하였다 (도 6B). As a result, an increase in the expression level of UCP-1 in subcutaneous fat tissue by administration of IF1 was confirmed by PCR and tissue immunostaining (FIG. 6B).
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Since the specific parts of the present invention have been described in detail above, 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, the substantial scope of the present invention will be 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
<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
Claims (10)
A pharmaceutical composition for the prevention or treatment of obesity containing IF1 (ATPase inhibitory factor 1) as an active ingredient.
The pharmaceutical composition of claim 1, wherein the obesity includes complications due to obesity.
The pharmaceutical composition of 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 supplement that is food acceptable.
A pharmaceutical composition for suppressing appetite, which contains IF1 (ATPase inhibitory factor 1) as an active ingredient.
The pharmaceutical composition of 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.
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| JP2003527835A (en) * | 1999-11-10 | 2003-09-24 | マイトコー | Regulatory endogenous inhibitors in ATP synthase |
| US20150065556A1 (en) * | 2013-08-05 | 2015-03-05 | Whitehead Institute For Biomedical Research | Therapeutic targets for mitochondrial disorders |
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| JP2003527835A (en) * | 1999-11-10 | 2003-09-24 | マイトコー | Regulatory endogenous inhibitors in ATP synthase |
| US20150065556A1 (en) * | 2013-08-05 | 2015-03-05 | Whitehead Institute For Biomedical Research | Therapeutic targets for mitochondrial disorders |
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