KR101671675B1 - Composition for inducing beige and brown fat cells and method of inducing the same - Google Patents
Composition for inducing beige and brown fat cells and method of inducing the same Download PDFInfo
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- KR101671675B1 KR101671675B1 KR1020160095361A KR20160095361A KR101671675B1 KR 101671675 B1 KR101671675 B1 KR 101671675B1 KR 1020160095361 A KR1020160095361 A KR 1020160095361A KR 20160095361 A KR20160095361 A KR 20160095361A KR 101671675 B1 KR101671675 B1 KR 101671675B1
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- South Korea
- Prior art keywords
- adipocytes
- butein
- obesity
- beige
- ucp
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Abstract
본 발명은 뷰테인(Butein) 또는 뷰테인 유도체, 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 백색 지방세포로부터 베이지 지방세포로의 분화 유도용 조성물 및 이의 방법에 관한 것이다. 본 발명의 유효성분인 Butein 또는 뷰테인 유도체를 이용하여 UCP-1 및 PRDM4의 발현 증가를 확인하였는바, 비만의 예방 또는 치료에 있어서, 보다 근본적으로 접근하여 타겟치료를 할 수 있을 것으로 기대된다.The present invention relates to a composition for inducing differentiation from white adipocytes into beige adipocytes and a method thereof, comprising a butein or a butene derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The increased expression of UCP-1 and PRDM4 was confirmed by using the active ingredient of the present invention, Butein or a butane derivative, and it is expected that the target treatment can be more fundamentally approached in the prevention or treatment of obesity.
Description
본 발명은 뷰테인(Butein) 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는, 갈색 지방세포 유도와 백색 지방세포로부터 베이지 지방세포로의 분화 유도용 조성물 및 이의 방법에 관한 것이다.The present invention relates to a composition for inducing brown adipocytes and inducing differentiation from white adipocytes to beige adipocytes, and a method thereof, comprising as an active ingredient a butein or a derivative thereof, or a pharmaceutically acceptable salt thereof. will be.
비만은 내분비적 요인, 유전적 요인, 사회 환경적 요인 등에 의해 대사 과정의 불균형이 발생하는 경우, 체내에 과잉된 에너지가 지방으로 축적됨으로써 야기되는 피하지방 조직의 이상 비대화에 기인한다. 지방조직의 비대화는 지방세포의 크기가 커지거나(지방세포 비대화) 그 수가 증가하는(지방세포 과형성) 현상으로, 이는 국소 정맥-림프 체계의 정체에도 영향을 미쳐 진피-피하 조직의 혈관조직 질환도 유발할 수 있다. 따라서, 비만은 그 자체로서 독립된 질병으로 인식되며, 세계보건기구에서는 비만을 세계적인 영양문제로 다루어 건강을 해치는 단순 위험인자가 아닌 치료해야 할 질병으로 인식하고 있다.Obesity is caused by abnormal hypertrophy of the subcutaneous fat tissue caused by the accumulation of excess energy in the body when an imbalance in metabolic processes occurs due to endocrine factors, genetic factors, social and environmental factors, etc. Adipose tissue hypertrophy is a phenomenon in which the size of adipocytes increases (adipocyte hypertrophy) or the number of adipocytes increases (adipocyte hyperplasia), which also affects the stagnation of the local venous-lymphatic system, leading to vascular tissue disease in the dermis-subcutaneous tissue. It can be triggered. Therefore, obesity is itself recognized as an independent disease, and the World Health Organization treats obesity as a global nutritional problem and recognizes it as a disease to be treated, not a simple risk factor to harm health.
비만환자에게 과도하게 축적된 중성지방은 지방조직뿐 아니라, 간이나 근육에 저장되어 인슐린 저항성을 유도한다. 따라서, 과도하게 저장된 중성지방의 소모가 근본적인 비만과 이에 따른 대사질환의 예방 및 치료가 될 수 있다. 지방세포는 크게 백색지방, 갈색 지방세포 및 베이지 지방세포로 분류된다. 백색지방세포는 중성지방의 큰 지방구에 저장되어 주로 복부에서 많이 발견되며, 건강에 부정적인 역할을 하는 것으로 알려져 있다. 갈색지방은 백색 지방세포에 비해 많은 미토콘드리아와 작은 크기의 지방구를 함유하고 있으며 열 발생을 통한 체온 유지와 적절한 운동에 의해 유도 될 수 있다고 보고되고 있다. 갈색 지방세포가 많이 함유되도록 유도한 쥐는 고지방식이에 의한 비만에 대해 상대적으로 몸무게 감소와 열량 소모의 증가를 유도하여 비만과 대사질환에 효과적이었다. 또한, 갈색지방에서는 UCP-1(uncoupling protein-1) 단백질이 많이 발현되며, 이는 지방세포에서 열량의 저장이 아닌 열량 소모로 열 발생에 결정적인 역할을 하는 것으로 알려져 있다. 갈색 지방과 더불어 베이지 지방세포 또한 중요한 지방세포로 인식되고 있다. 베이지 지방세포는 건강에 유해한 백색지방세포에서 운동이나 추위 등의 자극에 의해 유도되며 백색지방세포의 형질은 감소되나 갈색지방세포의 특징을 갖게 되어 UCP-1의 발현을 증가를 나타나게 된다. 이들의 베이지 지방세포 또한 쥐에게서 발견되는 갈색 지방세포와 유사하게 비만 및 대사 질환에 유익한 것으로 알려져 있다. 게다가, 인간에게서 발견되는 유익한 갈색지방세포는 대부분 베이지지방세포로 알려짐에 따라 건강에 해로운 백색 지방세포를 건강에 상대적으로 유익한 베이지 지방세포로의 전환 또는 분화 유도에 대한 관심이 높아지고 있는 실정이다.In obese patients, excessively accumulated triglycerides are stored not only in adipose tissue, but also in the liver and muscles to induce insulin resistance. Therefore, the consumption of excessively stored triglycerides can be the prevention and treatment of obesity and metabolic diseases resulting therefrom. Adipocytes are largely classified into white fat, brown fat cells, and beige fat cells. White adipose cells are stored in large fat cells of triglycerides and are mainly found in the abdomen, and are known to play a negative role in health. Brown fat contains more mitochondria and small-sized fat cells than white fat cells, and it has been reported that it can be induced by maintaining body temperature through heat generation and proper exercise. Mice induced to contain a large amount of brown fat cells were effective against obesity and metabolic diseases by inducing weight loss and increased caloric consumption relative to obesity caused by a high fat diet. In addition, a large amount of UCP-1 (uncoupling protein-1) protein is expressed in brown fat, which is known to play a decisive role in the generation of heat by consuming calories rather than storing calories in adipocytes. In addition to brown fat, beige fat cells are also recognized as important fat cells. Beige adipocytes are induced by stimuli such as exercise or cold in white adipocytes, which are harmful to health, and the traits of white adipocytes decrease, but have the characteristic of brown adipocytes, resulting in increased expression of UCP-1. Their beige adipocytes are also known to be beneficial for obesity and metabolic diseases similar to the brown adipocytes found in mice. In addition, as most beneficial brown adipocytes found in humans are known as beige adipocytes, there is a growing interest in inducing the conversion or differentiation of unhealthy white adipocytes into healthy beige adipocytes.
따라서, UCP-1 단백질 활성 조절과 베이지 (혹은 갈색) 지방세포의 생성이 주요한 과제의 대상이 되고 있고, 이에 대한 연구가 이루어지고 있으나(한국 특허공개번호 10-2012-0049214), 아직 미비한 실정이다.Therefore, the regulation of UCP-1 protein activity and the generation of beige (or brown) adipocytes are the subject of major tasks, and research on this is being done (Korean Patent Publication No. 10-2012-0049214), but it is still insufficient. .
본 발명은 상기와 같은 문제점을 해결하기 위해서 안출된 것으로서, 뷰테인(Butein) 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는, 갈색지방세포 유도와 백색 지방세포로부터 베이지 지방세포로의 분화 유도용 조성물을 제공하는 것을 목적으로 한다.The present invention was conceived to solve the above problems, including butein (Butein) or a derivative thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, induction of brown adipocytes and beige from white adipocytes. An object of the present invention is to provide a composition for inducing differentiation into adipocytes.
또한, 본 발명은 뷰테인 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 백색 지방세포에 처리하는 단계를 포함하는, 백색 지방세포로부터 베이지 지방세포로의 분화 유도방법을 제공하는 것을 다른 목적으로 한다.In addition, the present invention is to provide a method for inducing differentiation from white adipocytes into beige adipocytes, comprising the step of treating white adipocytes with butane or a derivative thereof, or a pharmaceutically acceptable salt thereof. do.
또한, 본 발명은 a) in vitro 상에서 지방세포에 비만 치료 후보 물질을 처리하는 단계; b) 상기 지방 세포의 PRDM4의 유전자의 발현을 측정하는 단계; 및 c) 비처리군에 비해 PRDM4의 유전자의 발현을 증진시키는 물질을 비만 치료물질로 선정하는 단계를 포함하는 비만 치료물질 스크리닝 방법을 제공하는 것을 다른 목적으로 한다. In addition, the present invention comprises the steps of: a) treating adipocytes with a candidate substance for treatment of obesity in vitro; b) measuring the expression of the PRDM4 gene in the adipocytes; It is another object of the present invention to provide a method for screening a substance for treating obesity comprising the step of selecting a substance for enhancing the expression of the PRDM4 gene as a substance for treating obesity compared to the untreated group.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명은 뷰테인(Butein) 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는, 백색 지방세포로부터 베이지 지방세포로의 분화 유도용 조성물을 제공한다. The present invention provides a composition for inducing differentiation from white adipocytes to beige adipocytes, including butein or a butein derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일구현 예로서, 상기 뷰테인 유도체는 하기 화학식 1로 표시되는 화합물로서, As an embodiment of the present invention, the butane derivative is a compound represented by the following formula (1),
[화학식 1][Formula 1]
상기 화학식 1에서, R1은 OH, 또는 C1-C6 알킬이고, R2는 OH, 할로젠, 또는 C1-C6 알콕시이고, R3는 OH, 또는 C1-C6 알콕시이고, R4는 수소 또는 C1-C6 알킬일 수 있다. In Formula 1, R 1 is OH, or C 1 -C 6 alkyl, R 2 is OH, halogen, or C 1 -C 6 alkoxy, R 3 is OH, or C 1 -C 6 Alkoxy, and R 4 may be hydrogen or C 1 -C 6 alkyl.
본 발명의 다른 구현예로서, 상기 뷰테인 유도체는 하기 화학식 2로 표시되는 화합물로서, In another embodiment of the present invention, the butane derivative is a compound represented by the following formula (2),
[화학식 2][Formula 2]
상기 화학식 2에서, Ra, Rb, 및 Rc는 각각 동일하거나 다를 수 있으며, 수소 또는 OH이고, Rd는 OH 또는 C1-C6 알콕시이고, Re는 수소, 할로젠, 또는 C1-C6 알콕시일 수 있다. In
본 발명의 또 다른 구현예로서, 상기 뷰테인 유도체는 2-(3,4-다이하이드록시페닐)-7-하이드로록시크로멘-4-온; (E)-1-(2,4-다이하이드록시페닐)-3-(4-하이드록시-3-메톡시페닐)프로프-2-엔-1-온; 7-하이드록시-2-(4-하이드록시-3-메톡시페닐)크로멘-4-온; (E)-1-(2,4-다이하이드록시페닐)-3-(3-하이드록시-4-메톡시페닐)프로프-2-엔-1-온; 7-하이드록시-2-(3-하이드록시-4-메톡시페닐)크로멘-4-온; (E)-1-(2,4-다이하이드록시페닐)-3-(3-플루오로-4-하이드록시페닐)프로프-2-엔-1-온; (E)-1-(2,4-다이하이드록시페닐)-3-(4-하이드록시페닐)프로프-2-엔-1-온; 2-(3,4-다이하이드록시페닐)-7-하이드록시-3-메틸크로멘-4-온; 2-(4-플루오로-3-메톡시페닐)-7-하이드록시크로멘-4-온; (E)-3-(3,4-다이하이드록시페닐)-1-(4-하이드록시페닐)프로프-2-엔-1-온; (E)-1,3-비스(3,4-다이하이드록시페닐)프로프-2-엔-1-온; 및 (E)-1,3-비스(4-하이드록시페닐)프로프-2-엔-1-온일 수 있다. In another embodiment of the present invention, the butane derivative is 2-(3,4-dihydroxyphenyl)-7-hydroxychromen-4-one; (E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one; 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)chromen-4-one; (E)-1-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one; 7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one; (E)-1-(2,4-dihydroxyphenyl)-3-(3-fluoro-4-hydroxyphenyl)prop-2-en-1-one; (E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; 2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methylchromen-4-one; 2-(4-fluoro-3-methoxyphenyl)-7-hydroxychromen-4-one; (E)-3-(3,4-dihydroxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one; (E)-1,3-bis(3,4-dihydroxyphenyl)prop-2-en-1-one; And (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one.
본 발명의 또 다른 구현예로서, 상기 뷰테인 또는 뷰테인 유도체는 갈색 지방세포의 활성을 증가시킬 수 있다. In another embodiment of the present invention, the butane or butane derivative may increase the activity of brown adipocytes.
본 발명의 또 다른 구현예로서, 상기 뷰테인 또는 뷰테인 유도체는 UCP-1(uncoupling protein-1)의 발현을 증가시킬 수 있다.As another embodiment of the present invention, the butane or butane derivative may increase the expression of UCP-1 (uncoupling protein-1).
본 발명의 또 다른 구현 예로서, 상기 뷰테인 또는 뷰테인 유도체는 PRDM4의 유전자의 발현을 증가시킬 수 있다. As another embodiment of the present invention, the butane or butane derivative may increase the expression of the PRDM4 gene.
본 발명은 뷰테인 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 백색 지방세포에 처리하는 단계를 포함하는, 백색 지방세포로부터 베이지 지방세포로의 분화 유도방법을 제공한다.The present invention provides a method for inducing differentiation from white adipocytes to beige adipocytes, comprising the step of treating white adipocytes with butane or a derivative thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 일 구현예로서, 상기 유도 방법은 갈색 지방세포의 활성을 증가시킬 수 있다.As an embodiment of the present invention, the induction method may increase the activity of brown adipocytes.
본 발명은 a) in vitro 상에서 지방세포에 비만 치료 후보 물질을 처리하는 단계; b) 상기 지방 세포의 PRDM4의 유전자의 발현을 측정하는 단계; 및 c) 비처리군에 비해 PRDM4의 유전자의 발현을 증진시키는 물질을 비만 치료물질로 선정하는 단계를 포함하는 비만 치료물질 스크리닝 방법을 제공한다.The present invention comprises the steps of: a) treating adipocytes with a candidate substance for treatment of obesity in vitro; b) measuring the expression of the PRDM4 gene in the adipocytes; And c) selecting a substance that enhances the expression of the PRDM4 gene compared to the untreated group as an obesity treatment substance.
본 발명은 분화 유도용 조성물을 개체에 투여하는 단계를 포함하는 비만의 치료방법을 제공한다.The present invention provides a method for treating obesity comprising administering a composition for inducing differentiation to an individual.
본 발명은 뷰테인 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는 조성물의 비만의 치료용도를 제공한다. The present invention provides a composition comprising butane or a butane derivative, or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of obesity.
본 발명에 따른 조성물은 뷰테인(Butein) 또는 뷰테인 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하고, 본 발명의 유효성분인 뷰테인의 농도가 증가함에 따라 베이지 지방세포의 마커인 UCP-1의 발현 증가를 확인하였는바, 베이지 지방세포로의 분화 유도용 조성물로 사용될 수 있으며, 더 나아가 상기 조성물은 비만 또는 대사 질환의 예방 또는 치료에 유용하게 이용될 수 있을 것으로 기대된다.The composition according to the present invention contains butein or a butein derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and as the concentration of butane, which is an active ingredient of the present invention, increases, a marker of beige adipocytes When it was confirmed that the expression of phosphorus UCP-1 was increased, it can be used as a composition for inducing differentiation into beige adipocytes, and further, the composition is expected to be useful in preventing or treating obesity or metabolic diseases.
도 1은 C3H10T1/2 세포를 지방세포로 유도한 후, Butein을 처리한 경우에서, PPARγ, aP2와 UCP-1의 발현량의 변화를 나타낸 결과이다.
도 2는 T37i 세포를 갈색지방으로 분화시키면서 Butein을 처리한 경우에서, Oil Red O 염색결과 및 real time PCR을 통한 UCP-1, PRDM16, Cidea，PGC-1a 의 mRNA 발현량을 비교한 결과이다.
도 3은 C3H10T1/2 세포를 지방세포로 분화 시킨 후, sulfuretin, fisetin, Butein, resveratrol 또는 genistein을 처리한 경우에서, UCP-1의 발현량을 비교한 결과이다.
도 4는 mouse embryonic fibroblast (MEF)세포에 Butein을 처리한 경우에서, UCP-1의 발현량을 측정한 결과이다.
도 5는 C3H10T1/2 세포에 항비만 효능이 보고된 다양한 항비만 생리활성 물질 및 천연물 유래 단일 물질 등을 24시간 동안 처리한 후의 UCP-1 발현량을 Butein 처리의 경우와 비교한 결과이다.
도 6은 Butein과 PBS를 14일 동안 5mg/kg의 용량으로 마우스의 복강에 주사한 후, 복부지방조직인 epidydymal fat을 분리하여 지방세포 특이적인 PPARγ, aP2, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, Cidea의 발현량을 비교한 결과이다 (Ctrl; PBS를 투여한 그룹 (N=6), Butein; Butein 투여 그룹 (N=6)).
도 7은 Butein과 PBS를 14일 동안 5mg/kg의 용량으로 마우스의 복강에 주사한 후, 피하지방조직인 subcutaneous fat을 분리하여 지방세포 특이적인 PPARγ, aP2, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, Cidea의 발현량을 비교한 결과이다.
도 8은 Butein과 PBS를 14일 동안 5mg/kg의 용량으로 마우스의 복강에 주사한 후, 갈색지방조직인 brown fat을 분리하여 지방세포 특이적인 PPARγ, aP2, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, Cidea의 발현량을 비교한 결과이다 .
도 9는 고지방식이를 투여한 C57BL/6 mice에 Butein을 투여한 실험에서 8주 간의 마우스의 외관상의 변화를 나타낸 사진이다 (ND, normal chow diet를 섭취한 대조군 (N=5), HFD, high fat diet를 섭취한 비만 유도 대조군 그룹 (n= 7); 15, HFD + Butein, high fat diet를 섭취한 그룹에 하루에 15mg/kg 용량으로 복강 주사하여 투여한 그룹 (n= 7)).
도 10은 고지방식이를 투여한 C57BL/6 mice에 Butein을 투여한 실험에서 8주 간의 체중 (body weight) 변화를 나타낸 그래프이다.
도 11은 고지방식이를 투여한 C57BL/6 mice에 Butein을 8주 간 투여한 마우스에서 갈색지방 (BAT, brown Adipose Tissue), 피하지방 (SF, subcutaneous FAT), 복부지방 (AF, abdominal epididymal FAT)의 크기를 비교한 사진이다.
도 12는 고지방식이를 투여하여 비만 유도된 C57BL/6 mice와 Butein을 8주 간 투여한 마우스에서 복부 지방(fat pad)과 간 (liver)의 무게를 비교한 그래프이다.
도 13은 고지방식이를 투여하여 비만 유도된 C57BL/6 mice와 Butein을 8주 간 투여한 마우스에서 복부 지방(AF)과 피하지방 (SF), 갈색지방 (BAT) 조직을 H&E (Hematoxylin and eosin) 염색을 하여 비교한 그림이다.
도 14의 (a)는 고지방식이를 투여하여 비만 유도된 C57BL/6 mice와 Butein을 8주 간 투여한 마우스에서 glucose tolerance test 및 (b) insulin tolerance test의 결과이다.
도 15는 비만 유도된 C57BL/6 mice를 대상으로 Butein을 처리(5, 15mg/kg)한 경우, 피하지방조직인 subcutaneous fat에서 지방세포 특이적인 PPARγ, aP2, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, PGC-1α, CIDEA, COX7a, Dio2의 발현량을 비교한 결과이다( HFD, high fat diet를 섭취한 비만 유도 대조군 그룹 (n= 7); 15, HFD + Butein, high fat diet를 섭취한 그룹에 하루에 5mg/kg 용량으로 복강 주사하여 투여한 그룹 (n= 8). HFD + Butein, high fat diet를 섭취한 그룹에 하루에 15mg/kg 용량으로 복강 주사하여 투여한 그룹 (n= 7)).
도 16은 비만 유도된 C57BL/6 mice를 대상으로 Butein을 처리 (5, 15mg/kg)한 경우, 복부지방조직인 epididymal fat에서 지방세포 특이적인 PPARγ, aP2와 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 PGC-1α, CIDEA, COX7a, Dio2의 발현량을 비교한 결과이다.
도 17은 비만 유도된 C57BL/6 mice를 대상으로 Butein을 처리 (5, 15mg/kg)한 경우, 갈색지방조직인 brown fat에서 지방세포 특이적인 PPARγ, aP2와 베이지 지방세포에서 특이적인 UCP-1, PRDM16, Cox8b, 백색지방세포 특이적인 resistin, Nnmt, 및 베이지 지방세포에서 특이적인 PGC-1α, CIDEA, COX7a, Dio2의 발현량을 비교한 결과이다.
도 18은 비만 유도된 C57BL/6 mice를 대상으로 Butein을 처리(5, 15mg/kg)한 경우, 혈액내 glucose의 변화, 중성지방, 지방산, LDL, cholesterol 등의 변화를 나타낸 결과이다.
도 19는 고지방식이로 비만이 유도된 마우스에 butein 또는 resveratrol을 처리하여, 비만효과를 확인하기 위한 실험의 대략적인 모식도 이다.
도 20은 고지방식이로 비만이 유도된 (a) 20주령 또는 (b) 28주령 마우스에 butein 또는 resveratrol을 처리하여 비만 치료 효과 및 (c) 세 군간 식이량을 비교한 결과이다.
도 21은 고지방식이로 비만이 유도된 마우스에서 Butein 처리에 의한 (a) 항문의 온도 변화, (b) glucose tolerance test, (c) insulin tolerance test 결과를 나타낸 도이다.
도 22는 (a) 3T3-L1세포에서, PRDM4 siRNA (si#1과 si#2) 처리에 의한 지방 축적 정도를 Oil red O 염색으로 확인한 결과, (b) C3H10T1/2세포에서 PRDM4 siRNA (si#1과 si#2) 처리에 의한 유전자의 발현 변화, (c) t37i세포에서, PRDM4 siRNA (si#1과 si#2) 처리에 의한 유전자의 발현 변화를 확인한 결과이다.
도 23은 PRDM4 siRNA와 대조군 (scrambled RNA, scr)을 ip injection을 통하여 주사 하였을 때의 (a) 마우스의 체중 변화 및 (b) fat, spleen, kidney, liver 등의 기관 무게 변화를 나타낸 결과이다.
도 24는 PRDM4 siRNA 가 투여된 마우스의 (a) 항문의 온도 변화, (b) glucose tolerance test, (c) insulin tolerance test 결과를 나타낸 도이다.
도 25는 butein의 유도체를 지방세포로 분화된 C3H10T1/2 세포에 처리하였을 때 UCP-1의 발현량 및 PRDM4의 발현량을 나타낸 결과이다.1 is a result showing changes in the expression levels of PPARγ, aP2 and UCP-1 when C3H10T1/2 cells were induced into adipocytes and then treated with Butein.
2 is a result of comparing the mRNA expression levels of UCP-1, PRDM16, Cidea, and PGC-1a through Oil Red O staining results and real-time PCR in the case of T37i cells differentiated into brown fat and treated with Butein.
3 is a result of comparing the expression levels of UCP-1 in the case of differentiating C3H10T1/2 cells into adipocytes and then treating sulfuretin, fisetin, Butein, resveratrol or genistein.
4 is a result of measuring the expression level of UCP-1 in the case of treatment with Butein in mouse embryonic fibroblast (MEF) cells.
5 is a result of comparing the expression level of UCP-1 after treatment with various anti-obesity physiologically active substances and single substances derived from natural products for 24 hours with anti-obesity efficacy reported on C3H10T1/2 cells with Butein treatment.
6 shows Butein and PBS were injected into the abdominal cavity of a mouse at a dose of 5 mg/kg for 14 days, and then epidydymal fat, which is abdominal adipose tissue, was isolated to separate adipocyte-specific PPARγ, aP2, white adipocyte-specific resistin, Nnmt, and This is the result of comparing the expression levels of specific UCP-1, PRDM16, Cox8b, and Cidea in Beige adipocytes (Ctrl; PBS-administered group (N=6), Butein; Butein-administered group (N=6)).
7 shows Butein and PBS were injected into the peritoneal cavity of a mouse at a dose of 5 mg/kg for 14 days, and then subcutaneous fat was isolated to separate adipocyte-specific PPARγ, aP2, white adipocyte-specific resistin, Nnmt, and This is the result of comparing the expression levels of specific UCP-1, PRDM16, Cox8b, and Cidea in Beige adipocytes.
8 shows Butein and PBS were injected into the abdominal cavity of a mouse at a dose of 5 mg/kg for 14 days, and then brown fat, which is a brown adipose tissue, was isolated to separate adipocyte-specific PPARγ, aP2, white adipose cell-specific resistin, Nnmt, and This is the result of comparing the expression levels of specific UCP-1, PRDM16, Cox8b, and Cidea in Beige adipocytes.
9 is a photograph showing the change in appearance of mice for 8 weeks in an experiment in which Butein was administered to C57BL/6 mice administered a high fat diet (ND, a control group fed a normal chow diet (N=5), HFD, Obesity induction control group fed high fat diet (n= 7); 15, HFD + Butein, group administered by intraperitoneal injection at a dose of 15 mg/kg per day to the group fed high fat diet (n= 7)).
10 is a graph showing changes in body weight for 8 weeks in an experiment in which Butein was administered to C57BL/6 mice administered a high fat diet.
11 is a brown fat (BAT, brown Adipose Tissue), subcutaneous fat (SF, subcutaneous FAT), abdominal fat (AF, abdominal epididymal FAT) in mice administered with Butein for 8 weeks in C57BL/6 mice administered a high fat diet. This is a picture comparing the sizes of ).
12 is a graph comparing the weights of abdominal fat (fat pad) and liver (liver) in mice administered with C57BL/6 mice and Butein for 8 weeks in which obesity was induced by administering a high fat diet.
Figure 13 shows the abdominal fat (AF), subcutaneous fat (SF), and brown fat (BAT) tissues in H&E (Hematoxylin and eosin) tissues in mice administered with obesity-induced C57BL/6 mice and Butein for 8 weeks by administering a high fat diet. ) This is a picture compared by dyeing.
Figure 14 (a) is a result of glucose tolerance test and (b) insulin tolerance test in mice administered with obesity-induced C57BL/6 mice and Butein for 8 weeks by administering a high fat diet.
Figure 15 is a case of treatment with Butein (5, 15mg/kg) targeting obesity-induced C57BL/6 mice, adipocyte-specific PPARγ, aP2, white adipocyte-specific resistin, Nnmt, and in subcutaneous fat, which is a subcutaneous fat tissue. This is the result of comparing the expression levels of specific UCP-1, PRDM16, Cox8b, PGC-1α, CIDEA, COX7a, and Dio2 in Beige adipocytes (obesity induction control group fed HFD, high fat diet (n=7); 15, HFD + Butein, a group that was administered by intraperitoneal injection at a dose of 5mg/kg per day to the group who ingested a high fat diet (n=8), and the group who consumed HFD + Butein, high fat diet 15mg/kg per day. Group administered by intraperitoneal injection as a dose (n=7)).
16 is a case of treatment with Butein (5, 15mg/kg) targeting obesity-induced C57BL/6 mice, adipocyte-specific PPARγ in epididymal fat, abdominal adipose tissue, and UCP-1 specific in beige adipocytes, aP2, This is the result of comparing the expression levels of PGC-1α, CIDEA, COX7a, and Dio2 in PRDM16, Cox8b, white adipocyte-specific resistin, Nnmt, and beige adipocytes.
FIG. 17 is a case of treatment with Butein (5, 15 mg/kg) targeting obesity-induced C57BL/6 mice, adipocyte-specific PPARγ in brown fat, aP2 and beige adipocyte-specific UCP-1, This is the result of comparing the expression levels of PGC-1α, CIDEA, COX7a, and Dio2 in PRDM16, Cox8b, white adipocyte-specific resistin, Nnmt, and beige adipocytes.
18 is a result showing changes in blood glucose, triglycerides, fatty acids, LDL, cholesterol, etc. when Butein was treated (5, 15mg/kg) in obesity-induced C57BL/6 mice.
19 is a schematic diagram of an experiment for confirming the obesity effect by treatment with butein or resveratrol in mice in which obesity was induced by a high fat diet.
20 is a result of comparing the treatment effect of obesity in (a) 20-week-old or (b) 28-week-old mice in which obesity was induced by a high fat diet, and (c) the amount of diet between the three groups by treatment with butein or resveratrol.
21 is a diagram showing the results of (a) anal temperature change, (b) glucose tolerance test, and (c) insulin tolerance test by Butein treatment in mice induced with obesity on a high fat diet.
22 shows the results of confirming the degree of fat accumulation by the treatment of PRDM4 siRNA (
FIG. 23 shows the results of (a) changes in body weight of mice and (b) changes in organ weights such as fat, spleen, kidney, liver, etc. when PRDM4 siRNA and controls (scrambled RNA, scr) are injected through ip injection.
24 is a diagram showing the results of (a) anus temperature change, (b) glucose tolerance test, and (c) insulin tolerance test of a mouse administered with PRDM4 siRNA.
25 is a result showing the expression level of UCP-1 and PRDM4 when the derivative of butein was treated on C3H10T1/2 cells differentiated into adipocytes.
본 발명에서, 뷰테인(Butein)을 처리한 경우, C3H101/2 세포주에서의 베이지 지방세포의 마커인 UCP-1(uncoupling protein-1)의 발현증가 및 T37i세포에서의 갈색 지방세포 마커인 UCP-1, PRDM16, Cidea등의 발현증가를 확인하였다. 또한 고지방 식이로 유도된 마우스에서 Butein 처리에 의한 체중 감소 및 포도당 과 인슐린의 대사 개선을 확인하고, 이에 기초하여 본 발명을 완성하였다.In the present invention, in the case of treatment with Butein, the expression of UCP-1 (uncoupling protein-1), a marker of beige adipocytes in the C3H101/2 cell line, and UCP-, a brown adipocyte marker, in T37i cells. 1, increased expression of PRDM16, Cidea, etc. was confirmed. In addition, weight loss and improvement of glucose and insulin metabolism by Butein treatment in mice induced with a high fat diet were confirmed, and the present invention was completed based on this.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 뷰테인(Butein) 또는 뷰테인(Butein) 유도체, 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는, 백색지방세포로부터 베이지지방세포로의 분화 유도용 조성물을 제공한다.The present invention provides a composition for inducing differentiation from white adipocytes to beige adipocytes, including butein or butein derivatives, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 뷰테인 유도체는 하기 화학식 1로 표시되는 화합물로서, In the present invention, the butane derivative is a compound represented by the following formula (1),
[화학식 1][Formula 1]
상기 화학식 1에서,In
R1은 OH, 또는 C1-C6 알킬이고, R2는 OH, 할로젠, 또는 C1-C6 알콕시이고, R3는 OH, 또는 C1-C6 알콕시이고, R4는 수소 또는 C1-C6 알킬일 수 있으며, 하기 반응식 1에 나타낸 바와 같이, 화합물 C를 프롤린 촉매 하에서 화합물 D와 반응시켜 제조하는 방법으로 상기 화학식 1과 유사한 화학식 B와 화학식 1의 화합물을 제조할 수 있다.R 1 is OH, or C 1 -C 6 alkyl, R 2 is OH, halogen, or C 1 -C 6 alkoxy, R 3 is OH, or C 1 -C 6 alkoxy, R 4 may be hydrogen or C 1 -C 6 alkyl, prepared by reacting compound C with compound D under a proline catalyst as shown in
[반응식 1][Scheme 1]
또한, 본 발명에서 뷰테인 유도체는 하기 화학식 2로 표시되는 화합물로서, In addition, the butane derivative in the present invention is a compound represented by the following formula (2),
[화학식 2][Formula 2]
상기 화학식 2에서, In
Ra, Rb, 및 Rc는 각각 동일하거나 다를 수 있으며, 수소 또는 OH이고, Rd는 OH 또는 C1-C6 알콕시이고, Re는 수소, 할로젠, 또는 C1-C6 알콕시일 수 있으며, 하기 반응식 2에 나타낸 바와 같이, 화합물 E를 산 촉매 하에서 화합물 F와 반응시켜 화학식 2의 화합물을 제조할 수 있다.R a , R b , and R c may each be the same or different, hydrogen or OH, R d is OH or C 1 -C 6 alkoxy, and R e is hydrogen, halogen, or C 1 -C 6 alkoxy As shown in
[반응식 2][Scheme 2]
특히, 상기 화학식 1 또는 2의 화합물은 바람직하게는 2-(3,4-다이하이드록시페닐)-7-하이드로록시크로멘-4-온 (2-(3,4-dihydroxyphenyl)-7-hydroxychroman-4-one); (E)-1-(2,4-다이하이드록시페닐)-3-(4-하이드록시-3-메톡시페닐)프로프-2-엔-1-온 E(()-1-(2,4-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one); 7-하이드록시-2-(4-하이드록시-3-메톡시페닐)크로멘-4-온 (7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)chroman-4-one); (E)-1-(2,4-다이하이드록시페닐)-3-(3-하이드록시-4-메톡시페닐)프로프-2-엔-1-온; ((E)-1-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one); 7-하이드록시-2-(3-하이드록시-4-메톡시페닐)크로멘-4-온 (7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one); (E)-1-(2,4-다이하이드록시페닐)-3-(3-플루오로-4-하이드록시페닐)프로프-2-엔-1-온 ((E)-1-(2,4-dihydroxyphenyl)-3-(3-fluoro-4-hydroxyphenyl)prop-2-en-1-one); (E)-1-(2,4-다이하이드록시페닐)-3-(4-하이드록시페닐)프로프-2-엔-1-온 ((E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one); 2-(3,4-다이하이드록시페닐)-7-하이드록시-3-메틸크로멘-4-온 (2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methylchroman-4-one); 2-(4-플루오로-3-메톡시페닐)-7-하이드록시크로멘-4-온 (2-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-one); (E)-3-(3,4-다이하이드록시페닐)-1-(4-하이드록시페닐)프로프-2-엔-1-온 ((E)-3-(3,4-dihydroxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one); (E)-1,3-비스(3,4-다이하이드록시페닐)프로프-2-엔-1-온 ((E)-1,3-bis(3,4-dihydroxyphenyl)prop-2-en-1-one); 및 (E)-1,3-비스(4-하이드록시페닐)프로프-2-엔-1-온 ((E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one)으로 이루어진 군으로부터 선택될 수 있으나, 이로써, 제한되는 것은 아니다. In particular, the compound of Formula 1 or 2 is preferably 2-(3,4-dihydroxyphenyl)-7-hydroxychromen-4-one (2-(3,4-dihydroxyphenyl)-7-hydroxychroman -4-one); (E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one E(()-1-(2 ,4-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one); 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)chromen-4-one (7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)chroman-4-one); (E)-1-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one; ((E)-1-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one); 7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one (7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one); (E)-1-(2,4-dihydroxyphenyl)-3-(3-fluoro-4-hydroxyphenyl)prop-2-en-1-one ((E)-1-(2 ,4-dihydroxyphenyl)-3-(3-fluoro-4-hydroxyphenyl)prop-2-en-1-one); (E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one ((E)-1-(2,4-dihydroxyphenyl) -3-(4-hydroxyphenyl)prop-2-en-1-one); 2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methylchromen-4-one (2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methylchroman-4-one) ; 2-(4-fluoro-3-methoxyphenyl)-7-hydroxychromen-4-one (2-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-one); (E)-3-(3,4-dihydroxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one ((E)-3-(3,4-dihydroxyphenyl) -1-(4-hydroxyphenyl)prop-2-en-1-one); (E)-1,3-bis(3,4-dihydroxyphenyl)prop-2-en-1-one ((E)-1,3-bis(3,4-dihydroxyphenyl)prop-2- en-1-one); And (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one ((E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1- one) may be selected from the group consisting of, but is not limited thereto.
본 발명에서 사용되는 용어, "약제학적으로 허용 가능한 이의 염"은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 약제학적으로 허용 가능한 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 그의 염을 형성하는 것을 의미한다.The term "pharmaceutically acceptable salts thereof" used in the present invention may be prepared by conventional methods in the art, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid. Salts with inorganic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gastisic acid, fumaric acid, lactobionic acid, salicylic acid, or organic acids such as acetylsalicylic acid (aspirin) Forms salts of these acids that are scientifically acceptable, or reacts with alkali metal ions such as sodium and potassium to form their metal salts, or reacts with ammonium ions to form another form of pharmaceutically acceptable salts thereof. Means to form.
본 발명에서 사용되는 용어, "백색 지방세포"는 중성 지방으로 대량의 지방 에너지를 체내에 축적하는 기능을 갖는 세포로서, 임신말기, 유아기, 사춘기에 집중하여 증식하며, 15배까지 부풀어 올라 지방 비대화 현상의 원인이 되기도 하며, 일반적으로 "지방세포"라 함은 "백색 지방세포"를 의미한다.The term "white adipocytes" as used in the present invention is a cell that has a function of accumulating a large amount of fat energy in the body as triglycerides, and proliferates by concentrating on the end of pregnancy, infancy, and puberty, and swells up to 15 times to enlarge fat. It may cause the phenomenon, and in general, "adipocytes" means "white adipocytes".
본 발명에서 사용되는 용어, "베이지 지방세포"는 백색 지방조직에서부터 유래될 수 있으며, 미토콘드리아에 철분이 존재하여 베이지색을 띄는 세포이다. 갈색지방세포는 백색 지방세포와 비교하여 에너지를 소비하여 열을 발생시킬 수 있는 지방세포이며, 베이지 지방세포 지방을 에너지로 변환하는 기능을 가지고 있으며, 차가운 기온이나 특정 호르몬에 반응하여 UCP-1을 생산한다.The term "beige adipocytes" used in the present invention may be derived from white adipose tissue, and are cells that have a beige color due to the presence of iron in mitochondria. Brown fat cells are fat cells that can generate heat by consuming energy compared to white fat cells, and have the function of converting beige fat cells into energy, and UCP-1 in response to cold temperatures or specific hormones. Produce.
본 발명에서 사용되는 용어, "분화(differentiation)"는 세포가 분열 증식하여 성장하는 동안에 서로 구조나 기능이 특수화하는 현상, 즉 생물의 세포, 조직 등이 각각에게 주어진 일을 수행하기 위하여 형태나 기능이 변해가는 것을 말한다. 일반적으로 비교적 단순한 계(系)가 둘 이상의 질적으로 다른 부분계(部分系)로 분리되는 현상이다. 예를 들면, 개체 발생에서 처음에 동질적이었던 알 부분 사이에 머리나 몸통 등의 구별이 생기거나 세포에도 근세포 또는 신경세포 등의 구별이 생기는 것과 같이 처음에 거의 동질이었던 어떤 생물계의 부분 사이에 질적인 차이가 생기는 것, 또는 그 결과로서 질적으로 구별할 수 있는 부역 또는 부분계로 나누어져 있는 상태를 분화라고 한다.The term "differentiation" used in the present invention refers to a phenomenon in which structures or functions are specialized to each other during the division and proliferation of cells, that is, a form or function in order to perform a task given to each of the cells and tissues of an organism. It says that this is changing. In general, it is a phenomenon in which a relatively simple system is separated into two or more qualitatively different partial systems. For example, in ontogenesis, there is a distinction in the head or trunk between the egg parts that were initially homogeneous, or in the cell there is a distinction between muscle cells or nerve cells. The occurrence of phosphorus difference, or as a result of which it is qualitatively distinguishable, is divided into subregions or sub-systems called differentiation.
본 발명의 조성물은 갈색 지방세포의 활성을 증가시키거나 UCP-1 또는 PRDM4의 발현을 증가시키는 것을 특징으로 한다.The composition of the present invention is characterized by increasing the activity of brown adipocytes or increasing the expression of UCP-1 or PRDM4.
본 발명에서 사용되는 용어, "갈색 지방세포"는 베이지 지방세포와 마찬가지로 지방을 에너지로 변환하는 기능을 갖는 세포로서, 육안으로 보면 황갈색 내지 적갈색을 띈다. 갈색 지방세포가 많을수록 체지방이 감소하며, 성인이 될수록 갈색 지방세포는 감소한다. 갈색 지방세포는 근육세포로 분화하는 줄기세포에 생성되는 반면, 베이지 지방세포는 백색 지방 세포층 안에서 생성된다는 점에서 차이가 있다. The term "brown adipocytes" used in the present invention is a cell having a function of converting fat into energy like beige adipocytes, and has a yellowish brown to reddish brown color when viewed with the naked eye. The more brown fat cells there are, the less body fat is, and the brown fat cells decrease with adulthood. The difference is that brown adipocytes are produced by stem cells that differentiate into muscle cells, whereas beige adipocytes are produced within the white adipose cell layer.
본 발명에서 사용되는 용어, "분화 유도 조성물"은 초기 단계의 세포가 각 조직으로서의 특성을 갖게 되는 과정을 유도할 수 있는 조성물을 의미하며, 본 발명의 목적상 백색 지방세포를 베이지 지방세포로 분화유도를 할 수 있는 조성물을 의미한다.The term "differentiation inducing composition" used in the present invention refers to a composition capable of inducing a process in which cells in an early stage have characteristics as each tissue, and for the purposes of the present invention, white adipocytes are differentiated into beige adipocytes. It means a composition capable of inducing.
본 발명의 베이지 지방세포로의 분화 유도 조성물은 뷰테인 또는 뷰테인 유도체를 전체 조성물 총 중량에 대하여 0.0001 내지 10 중량%, 바람직하게는 0.001 내지 1 중량%의 양으로 존재할 수 있으나, 이에 제한되지는 않는다. The composition for inducing differentiation into beige adipocytes of the present invention may be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight based on the total weight of the total composition, but is not limited thereto. .
본 발명의 일 실시예에서는 뷰테인 (Butein) 처리에 의한 베이지 지방세포의 마커인 UCP-1의 발현 증가를 확인하였으며 (실시예 1 참조), 갈색 지방세포 마커인 PRDM16, Cidea 등의 발현 증가를 확인하였다 (실시예 2 참조). 또한, 다른 항비만 생리활성 유효성분들과 비교하여, 뷰테인 처리에 의한 UCP-1의 발현에 대한 현저한 효과를 확인하였으며 (실시예 3 참조), in vivo 실험 및 고지방식이로 유도된 비만 마우스에서 베이지 또는 갈색 지방세포의 증가 및 비만 개선효과를 확인하였다 (실시예 4 및 5 참조). 본 발명의 다른 실시예에서는 Butein의 생리활성을 유도하는 유전자로 PRDM4을 발견하였으며, PRDM4 발현 억제에 의한 체중 증가 및 포도당 인슐린 대사 억제를 확인하였다 (실시예 6 및 7 참조). 아울러, 뷰테인 유도체를 제조하였으며, 상기 뷰테인 유도체 투여에 의한 UCP-1, 및 PRDM4의 발현량을 증가하였는 바, 본 발명의 베이지 지방세포로의 분화 유도 조성물은 비만의 예방 또는 치료용 약학적 조성물로서 이용될 수 있음을 확인하였다 (실시예 8 및 9 참조).In one embodiment of the present invention, it was confirmed that the expression of UCP-1, a marker of beige adipocytes, was increased by treatment with Butein (see Example 1), and the expression of PRDM16, Cidea, etc., which are brown adipocyte markers, was increased. Confirmed (see Example 2). In addition, compared with other anti-obesity physiologically active active ingredients, a remarkable effect on the expression of UCP-1 by butane treatment was confirmed (see Example 3), in vivo experiments and in obese mice induced by a high fat diet The effect of increasing beige or brown adipocytes and improving obesity was confirmed (see Examples 4 and 5). In another example of the present invention, PRDM4 was found as a gene that induces the physiological activity of Butein, and weight gain and glucose insulin metabolism were suppressed by suppressing PRDM4 expression (see Examples 6 and 7). In addition, a butane derivative was prepared, and the expression levels of UCP-1 and PRDM4 were increased by administration of the butane derivative, and the composition inducing differentiation into beige adipocytes of the present invention is a pharmaceutical composition for preventing or treating obesity. It was confirmed that it can be used as (see Examples 8 and 9).
본 발명의 조성물에 의한 예방 또는 치료 대상 질병인 "비만 (obesity)"은 대사 장애로 인하여 체내에 지방세포가 증식 분화하고, 이로 인하여 지방이 과잉으로 축적된 상태를 의미하며, 에너지 흡수량이 소비량에 비해 상대적으로 증가하는 경우, 지방세포의 수와 부피가 증가되는 과정을 거쳐 결과적으로 지방조직의 질량이 증가된다. 세포 수준에서의 비만은 지방세포의 증식 및 분화의 촉진으로 인한 지방세포의 수와 부피의 증가를 의미한다."Obesity", which is a disease to be prevented or treated by the composition of the present invention, refers to a state in which adipocytes proliferate and differentiate in the body due to metabolic disorders, and thus fat is accumulated excessively, and the amount of energy absorption depends on the consumption amount. In contrast, when it is relatively increased, the mass of adipose tissue increases as a result of the process of increasing the number and volume of adipocytes. Obesity at the cellular level refers to an increase in the number and volume of adipocytes due to promotion of adipocyte proliferation and differentiation.
본 발명의 조성물은 약제학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약제학적으로 허용 가능한 담체는 생리식염수, 폴리에틸렌글리콜, 에탄올, 식물성 오일, 및 이소프로필미리스테이트 등을 포함할 수 있으나, 이에 제한되지는 않는다. 또한 기존에 알려진 줄기세포 배양용 배지, 분화 유도제 등을 더 포함할 수 있다.The composition of the present invention may contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate, but is not limited thereto. In addition, it may further include a previously known stem cell culture medium, a differentiation inducing agent, and the like.
본 발명의 조성물은, 비경구 투여를 위한 수용성 용액으로 제조할 수 있으며, 바람직하게는 한스 용액(Hank's solution), 링거 용액(Ringer's solution) 또는 물리적으로 완충된 염수와 같은 완충용액 등을 사용할 수 있다. 수용성 주입(injection) 현탁액은, 소디움 카르복시메틸셀룰로오스, 솔비톨 또는 데스트란과 같이 현탁액의 점도를 증가시킬 수 있는 기질을 첨가할 수 있다.The composition of the present invention may be prepared as an aqueous solution for parenteral administration, and preferably, a buffer solution such as Hank's solution, Ringer's solution, or physically buffered saline may be used. . In the aqueous injection suspension, a substrate capable of increasing the viscosity of the suspension may be added, such as sodium carboxymethylcellulose, sorbitol or destran.
또한, 본 발명의 조성물의 바람직한 양태는 멸균 주사용 수성 또는 유성 현탁액의 멸균 주사용 제제의 형태일 수 있다. 상기 현탁액은 적합한 분산제 또는 습윤제(ex.트윈 80) 및 현탁화제를 사용하여 이 분야에 공지된 기술에 따라 제형화할 수 있다. 멸균 주사용 제제는 또한 무독성의 비경구적으로 허용되는 희석제 또는 용매 중의 멸균 주사 용액 또는 현탁액 (ex. 1,3-부탄디올 중의 용액)일 수 있다. 본 발명에서 사용될 수 있는 비히클 및 용매로는 만니톨, 물, 링거 용액 및 등장성 염화나트륨 용액 등이 있다. 또한, 멸균 비휘발성 오일이 통상적으로 용매 또는 현탁화 매질로서 사용된다. 상기 목적을 위해 합성 모노 또는 디글리세라이드를 포함하여 자극성이 적인 비휘발성 오일은 그 어느 것이라도 사용할 수 있다.In addition, a preferred embodiment of the composition of the present invention may be in the form of a sterile injectable preparation of an aqueous or oily suspension for sterile injection. Such suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (ex. Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions (ex. solutions in 1,3-butanediol) in non-toxic parenterally acceptable diluents or solvents. Vehicles and solvents that can be used in the present invention include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile nonvolatile oils are commonly used as solvents or suspending media. For this purpose, any irritating nonvolatile oil including synthetic mono or diglycerides may be used.
본 발명의 다른 양태로서, 뷰테인(Butein) 또는 뷰테인(Butein) 유도체, 또는 약제학적으로 허용되는 이의 염을 백색 지방세포에 처리하는 단계를 포함하는, 백색지방으로부터 베이지지방세포로의 분화 유도방법을 제공한다. 본 발명의 방법은 상기 분화 유도용 조성물을 개체에 투여하는 단계를 포함하며, 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐 (mouse), 쥐 (rat), 개, 고양이, 말 및 소 등의 포유류를 의미한다.In another aspect of the present invention, a method for inducing differentiation from white adipose to beige adipocytes, comprising the step of treating white adipocytes with butein or a derivative thereof, or a pharmaceutically acceptable salt thereof. Provides. The method of the present invention includes the step of administering the composition for inducing differentiation to an individual, and in the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, a human or non-human primate , Mouse, rat, dog, cat, horse and cow.
본 발명의 또 다른 양태로서, a) in vitro 상에서 지방세포에 비만 치료 후보 물질을 처리하는 단계; b) 상기 지방 세포의 PRDM4의 유전자의 발현을 측정하는 단계; 및 c) 비처리군에 비해 PRDM4의 유전자의 발현을 증진시키는 물질을 비만 치료물질로 선정하는 단계를 포함하는, 비만 치료물질 스크리닝 방법을 제공한다. In another aspect of the present invention, a) treating adipocytes with a candidate substance for treatment of obesity in vitro; b) measuring the expression of the PRDM4 gene in the adipocytes; And c) selecting a substance that enhances the expression of the PRDM4 gene compared to the non-treatment group as an obesity treatment substance.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
실시예Example 1. 뷰테인( 1.Butane ( ButeinButein )에 의한 )On by 베이지지방세포로의To beige fat cells 분화 유도 확인 Confirmation of differentiation induction
Butein 처리에 의한 베이지지방세포로의 분화 유도를 확인하기 위하여, 생쥐의 배아 섬유 모세포에서 기원한 다능성 줄기세포주인 C3H10T1/2 세포주를 이용하였다. C3H10T1/2 세포주를 6 well plate에 2.5×10⁴/ml의 농도로 지방세포 분화를 위한 1uM dexamethasone, 5ug/ml insulin, 20nM 3-isobutyl-1-methylxanthine(IBMX)과 PPARγ ligand (GW7845)를 함유한 배지를 이용하여 지방세포로 약 7-10일간 분화를 유도하였다. 분화 유도된 지방세포에 Butein을 농도별(5, 10, 20μM)로 24시간동안 처리한 후, 베이지 지방세포에서 발견되는 UCP-1의 발현을 realtime PCR을 통하여 확인하였다.In order to confirm the induction of differentiation into Beige adipocytes by Butein treatment, the C3H10T1/2 cell line, a pluripotent stem cell line originating from mouse embryonic fibroblasts, was used. C3H10T1/2 cell line in a 6 well plate containing 1uM dexamethasone, 5ug/ml insulin, 20nM 3-isobutyl-1-methylxanthine (IBMX) and PPARγ ligand (GW7845) for adipocyte differentiation at a concentration of 2.5×10⁴/ml. Differentiation was induced into adipocytes for about 7-10 days using the medium. After treating the differentiation-induced adipocytes with Butein at different concentrations (5, 10, 20 μM) for 24 hours, the expression of UCP-1 found in Beige adipocytes was confirmed through real-time PCR.
도 1에 나타난 바와 같이, Butein의 농도가 증가함에 따라 UCP-1의 발현이 증가하였으며, 이를 통해 베이지 지방세포로의 분화 증가를 확인하였다. As shown in FIG. 1, as the concentration of Butein increased, the expression of UCP-1 increased, and through this, it was confirmed that the differentiation into beige adipocytes increased.
실시예 2. 뷰테인(Butein)에 의한 갈색지방세포의 증가 확인Example 2. Confirmation of increase in brown adipocytes by Butein
Butein 처리에 의한 갈색지방세포의 증가를 확인하기 위하여, 갈색지방전구세포인 T37i세포를 이용하였다. T37i세포를 5ug/ml insulin, 1nM T3 (triiodothyronine)를 함유한 배지로 2일간 배양하고 이 후, 5ug/ml insulin을 포함한 배지를 이용하여 지방세포로 6-8일간 분화 유도하였다. 분화 유도된 지방세포에 Butein을 농도별(5, 10, 20μM)로 6일간 처리하여, Oil Red O 염색하였으며, 지방세포분화와 관련된 PPARγ, aP2, 그리고 갈색지방세포 마커인 UCP-1, PRDM16, Cidea 유전자의 mRNA 발현량을 realtime PCR을 통하여 확인하였다.In order to confirm the increase of brown adipocytes by Butein treatment, T37i cells, which are brown adipocytes, were used. T37i cells were cultured for 2 days in a medium containing 5 ug/ml insulin and 1nM T3 (triiodothyronine), and then differentiated into adipocytes for 6-8 days using a medium containing 5 ug/ml insulin. Differentiation-induced adipocytes were treated with Butein at different concentrations (5, 10, 20 μM) for 6 days and stained with Oil Red O. PPARγ, aP2 related to adipocyte differentiation, and brown adipocyte markers UCP-1, PRDM16, The mRNA expression level of the Cidea gene was confirmed through real-time PCR.
도 2에 나타난 바와 같이, Butein의 농도가 증가함에 따라 UCP-1의 발현의 증가 및 갈색지방세포의 마커인 PRDM16, Cidea 등의 발현 증가를 확인하였다. As shown in FIG. 2, as the concentration of Butein increased, the expression of UCP-1 and the markers of brown adipocytes, such as PRDM16 and Cidea, were increased.
실시예 3. 뷰테인 (Butein)의 특이적인 UCP-1의 발현 증가 확인 Example 3. Confirmation of increase in expression of specific UCP-1 of Butein
C3H10T1/2 세포를 이용하여, Butein 처리에 의한 UCP-1의 발현량 증가를 지방세포에 영향을 주는 물질로 알려진 sulfuretin, fisetin, resveratrol genistein 처리에 의한 경우와 비교하였으며, mouse embryonic fibroblast (MEF)세포를 이용하여 Butein을 처리에 의한 UCP-1의 발현량 증가를 대조군인 DMSO 처리에 의한 경우와 비교하였다.Using C3H10T1/2 cells, the increase in the expression level of UCP-1 by Butein treatment was compared with that of sulfuretin, fisetin, resveratrol genistein, which are known to affect adipocytes, and mouse embryonic fibroblast (MEF) cells. The increase in the expression level of UCP-1 by treatment with Butein was compared with the case of DMSO treatment as a control.
또한, 분화가 끝난 C3H10T1/2 세포에 항비만 효능을 지닌 것으로 보고된 다양한 항비만 생리활성 물질 및 천연물 유래 단일 물질 등을 24시간 동안 처리한 후의 UCP-1 발현량을 Butein 처리의 경우와 비교하였다.In addition, the expression level of UCP-1 after treatment with various anti-obesity physiologically active substances and single substances derived from natural products reported to have anti-obesity efficacy on differentiated C3H10T1/2 cells for 24 hours was compared with that of Butein treatment. .
도 3 내지 도 4에서 나타난 바와 같이, C3H10T1/2 세포에서, Butein 처리를 한 경우, sulfuretin, fisetin, resveratrol genistein 처리에 의한 경우와 비교하여 3배이상 UCP-1의 발현이 증가하였으며, MEF세포에서, Butein 처리에 의한 경우, 대조군과 비교하여 10배이상 UCP-1의 발현이 증가하였다. 또한, 도 5에서 나타난 바와 같이, 일반적으로 기존에 알려진 항비만 생리활성 물질들을 처리한 경우, UCP-1의 발현량이 증가하지 않은 반면, Butein 처리를 한 경우, UCP-1의 발현량이 특이적으로 현격하게 증가하였다.As shown in FIGS. 3 to 4, in C3H10T1/2 cells, when Butein was treated, the expression of UCP-1 was increased more than 3 times compared to the case by sulfuretin, fisetin, and resveratrol genistein treatment, and in MEF cells , In the case of Butein treatment, the expression of UCP-1 was increased more than 10 times compared to the control group. In addition, as shown in FIG. 5, in the case of treatment with conventionally known anti-obesity physiologically active substances, the expression level of UCP-1 did not increase, whereas in the case of Butein treatment, the expression level of UCP-1 was specifically It increased markedly.
실시예 4. in vivo에서 백색 지방세포 억제 및 베이지와 갈색 지방세포의 증가 확인Example 4. Inhibition of white adipocytes and confirmation of increase in beige and brown adipocytes in vivo
In vivo에서 Butein의 베이지와 갈색 지방세포의 증가 및 백색지방세포의 억제 활성을 검증하기 위해 마우스에 총 14일간 투여하여 지방조직에서 마커의 발현을 측정하였다. 5mg/kg의 용량으로 6마리의 쥐에 복강주사로 투여하였고 대조군으로 용매만을 6마리에 복강에 투여하였다. 14일 후 복부지방 (epididymal fat)과 피하지방 (subcutaneous fat) 그리고 갈색지방 (brown fat)에서 백색지방 및 베이지(갈색)지방 마커의 발현량을 realtime PCR을 통하여 확인하였다. To verify the increase in beige and brown adipocytes and inhibitory activity of white adipocytes of Butein in vivo, it was administered to mice for a total of 14 days to measure the expression of the marker in adipose tissue. Intraperitoneal injection was administered to 6 mice at a dose of 5 mg/kg, and only the solvent was administered intraperitoneally to 6 mice as a control group. After 14 days, the expression levels of white and beige (brown) fat markers in epididymal fat, subcutaneous fat, and brown fat were confirmed by real-time PCR.
도 6 내지 도 8에 나타난 바와 같이, C3H10T1/2 및 T37i세포에서와 유사하게 갈색지방세포 마커인 UCP-1, PRDM16 Cox8b, Cidea의 증가 및 지방세포 마커인 PPARg, aP2, 그리고 백색지방세포 마커인 resistin, Nnmt (nicotinamide N-methyltransferase)의 감소를 확인하였다.6 to 8, similarly to C3H10T1/2 and T37i cells, an increase in brown adipocyte markers UCP-1, PRDM16 Cox8b, Cidea and adipocyte markers PPARg, aP2, and white adipocyte markers Resistin and Nnmt (nicotinamide N-methyltransferase) were decreased.
실시예 5. 고지방식이로 유도된 비만 마우스에서 비만 개선효과 확인Example 5. Obesity improvement effect confirmed in obese mice induced by high fat diet
5.1. PBS 투여군과의 비교실험5.1. Comparative experiment with PBS administration group
뷰테인의 항비만 효과를 확인하기 위하여 C57BL6/J 마우스에 고지방식이로 비만을 유도하여 복강 주사로 투여하였다. 7주된 마우스를 1주간 적응 시킨 후, 고지방식이 (60% fat, Research Diet에서 구입)를 8주간 투여하면서 비만을 유도하였으며, 뷰테인은 하루에 5mg/kg과 15mg/kg의 용량으로 각각 7마리에 투여하였다. 대조군으로는 정상 식이 섭취군 (5마리), 고지방식이 섭취에 PBS 투여군 (7마리)을 사용하였다.In order to confirm the anti-obesity effect of butane, C57BL6/J mice were administered intraperitoneally by inducing obesity on a high fat diet. After acclimating 7-week-old mice for 1 week, obesity was induced by administering a high-fat diet (60% fat, purchased from Research Diet) for 8 weeks. Butane was administered at doses of 5 mg/kg and 15 mg/kg per day for 7 weeks, respectively. It was administered to horses. As a control group, a normal diet intake group (5 mice), and a PBS-administered group (7 mice) in a high fat diet were used.
투여 기간 동안의 체중 증가량 및 각종 장기의 무게를 조사하여 비교하였으며, 8주 후에는 glucose tolerance test (GTT)와 insulin tolerance test (ITT) 를 수행하였으며, 조직 및 혈액학적 분석을 병행하였다.The weight gain during the administration period and the weight of various organs were investigated and compared. After 8 weeks, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed, and tissue and hematologic analysis were performed in parallel.
도 9 내지 도 18에 나타난 바와 같이, 정상식이 대조군에 비해 고지방식이 대조군에서 증가된 몸무게와 간과 내장 지방조직 무게는 뷰테인의 투여에 의해 농도 의존적으로 감소되는 경향을 보였다. 또한, GTT와 ITT에서는 15mg/kg을 투여한 군에서 유의적으로 비만에 의한 포도당과 인슐린의 대사를 개선시켰으며, 베이지 지방세포에서 특이적으로 발현되는 UCP-1, PRDM16, Cox8b, PGC-1α, CIDEA, COX7a, Dio2의 증가를 확인하였다. 혈액 분석에서도 글루코스, 콜레스테롤, 중성지방, HDL, LDL, fatty acid 등이 고용량의 Butein 투여군에서 유의적인 차이를 보였다. As shown in Figs. 9 to 18, the increased body weight and liver and visceral adipose tissue weight in the high-fat diet control group compared to the normal diet control group tended to decrease in a concentration-dependent manner by the administration of butane. In addition, GTT and ITT significantly improved the metabolism of glucose and insulin due to obesity in the group administered with 15 mg/kg, and UCP-1, PRDM16, Cox8b, and PGC-1α were specifically expressed in Beige adipocytes. , CIDEA, COX7a, Dio2 increased. Blood analysis also showed significant differences in glucose, cholesterol, triglycerides, HDL, LDL, fatty acid, etc. in the high-dose Butein group.
5.2. 5.2. PBSPBS 또는 or 레즈베라트롤Resveratrol ( ( ResveratrolResveratrol ) ) 투여군과의With administration group 비교실험 Comparative experiment
뷰테인의 항비만 효과를 확인하기 위하여 C57BL6/J 마우스에 고지방식이로 비만을 유도한 후, Butein 처리에 따른 체중 변화 확인하였다. 구체적으로, 7주된 마우스를 1주간 적응시킨 후, 고지방식이 (60% fat, Research Diet에서 구입)를 12주간 투여하여 비만을 유도하였다. 이 후, 상기 비만이 유도된 마우스에 Butein을 하루에 30 mg/kg의 용량으로 8주간 8마리에 투여하였다. 대조군으로는 PBS 투여군 (7마리)과 항비만 예방 효능이 뛰어나다고 알려진 레즈베라트롤 (Resveratrol) 투여군 (8마리)을 사용하였다.In order to confirm the anti-obesity effect of butane, after inducing obesity in a high fat diet in C57BL6/J mice, the weight change according to Butein treatment was confirmed. Specifically, 7-week-old mice were acclimated for 1 week, followed by administration of a high fat diet (60% fat, purchased from Research Diet) for 12 weeks to induce obesity. Thereafter, Butein was administered to 8 mice for 8 weeks at a dose of 30 mg/kg per day to the obesity-induced mice. As a control group, the PBS-administered group (7 mice) and the Resveratrol-administered group (8 mice), which are known to have excellent anti-obesity prevention efficacy, were used.
8주간의 투여 후 체중 증가량을 조사하여 비교하였으며, 8주 후에는 glucose tolerance test (GTT)와 insulin tolerance test (ITT) 를 수행하였으며, 혈액학적 분석을 병행하였다.After 8 weeks of administration, weight gain was investigated and compared. After 8 weeks, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed, and hematological analysis was performed in parallel.
도 20에 나타난 바와 같이, PBS 투여군에 비해 뷰테인 투여군에서, 체중이 약 10% 가량 감소되는 경향을 보였으며, 종래의 항비만 약물인 레즈베라트롤 (Resveratrol) 투여군에 비해서도 체중 감소효과가 현저히 우수함을 확인하였다. 구체적으로, 28주령 mice 에서 resveratrol 처리된 군에서는 대조군과 비교하여 체중의 변화가 없었던 반면, butein이 처리된 군에서는 체중이 현저하게 감소한 것을 확인하였으며, 이때 식이량에는 세 군간 차이가 없었다. As shown in Figure 20, compared to the PBS-administered group, the butane-administered group showed a tendency to decrease the body weight by about 10%, and the weight reduction effect was significantly superior to the conventional anti-obesity drug Resveratrol-administered group. Was confirmed. Specifically, there was no change in body weight in the resveratrol-treated group in 28-week-old mice compared to the control group, whereas in the butein-treated group, the body weight was significantly decreased. At this time, there was no difference in diet amount between the three groups.
또한, 도 21에 나타난 바와 같이, 뷰테인을 투여한 군(HFD-But)에서 항문의 온도가 증가하였으며, GTT와 ITT에서는 Butein을 투여한 군에서 유의적으로 비만에 의한 포도당과 인슐린의 대사를 개선시킴을 확인하였다 (높은 insulin sensitivity).In addition, as shown in FIG. 21, the anal temperature increased in the group to which butein was administered (HFD-But), and in GTT and ITT, the metabolism of glucose and insulin due to obesity was significantly increased in the group to which Butein was administered. It was confirmed to improve (high insulin sensitivity).
실시예 6. Butein의 생리활성을 유도하는 유전자의 확인 및 발현 억제Example 6. Identification of genes that induce physiological activity of Butein and suppression of expression
Butein의 생리활성을 유도하는 유전자를 확인하기 위해 microarray를 실시 하였으며, 이들 유전자 중에서 약 2배 이상 발현이 증가된 PRDM4 (PR domain-containing protein 4) 유전자를 확인하였다. 구체적으로 Butein의 생리활성 유도여부를 확인하기 위하여, PRDM4 유전자 발현을 siRNA (small interfering RNA)로 억제시킨 후, 백색 지방세포 및 베이지세포 분화 정도를 비교하였다.Microarray was performed to identify the genes that induce the physiological activity of Butein, and among these genes, the PRDM4 (PR domain-containing protein 4) gene, which was expressed more than twice as much, was identified. Specifically, in order to confirm the induction of physiological activity of Butein, PRDM4 gene expression was suppressed with siRNA (small interfering RNA), and then the degree of differentiation of white adipocytes and beige cells was compared.
상기 실시예에서 사용된 두 개의 PRDM4의 siRNA sequences는 다음과 같다.The siRNA sequences of the two PRDM4 used in the above example are as follows.
PRDM4 siRNAPRDM4 siRNA
Sense 5' GAAUUACGCUCAACAGAUAUU 3' (서열번호 1)Sense 5'GAAUUACGCUCAACAGAUAUU 3'(SEQ ID NO: 1)
Antisense 5' UAUCUGUUGAGCGUAAUUCUU 3' (서열번호 2)Antisense 5'UAUCUGUUGAGCGUAAUUCUU 3'(SEQ ID NO: 2)
도 22에 나타난 바와 같이, 분화된 지방세포인 C3H10T1/2에 PRDM4 siRNA를 처리한 경우, UCP-1의 발현량의 감소와 백색 지방세포로의 분화 유도 및 촉진을 확인하였다. 구체적으로 PRDM4 siRNA는 C3H10T1/2 세포에서 백색 지방세포 마커인 Nnmt와 resistin은 증가시켰으며, 갈색 지방세포마커인 UCP-1과 Dio2를 억제하였다. 또한, PRDM4 siRNA는 갈색지방세포인 t37i세포에서, 갈색지방세포 마커인 UCP-1, Cidea, Cox7a1, Dio2의 발현을 감소시켰다. 상기 결과는 PRDM 유전자는 butein 투여에 의한 갈색지방세포 유도 및 백색지방세포 억제와 관련이 있음을 의미한다. As shown in FIG. 22, when PRDM4 siRNA was treated on the differentiated adipocytes C3H10T1/2, it was confirmed that the expression level of UCP-1 was reduced and the induction and promotion of differentiation into white adipocytes. Specifically, PRDM4 siRNA increased white adipocyte markers Nnmt and resistin in C3H10T1/2 cells, and inhibited brown adipocyte markers UCP-1 and Dio2. In addition, PRDM4 siRNA decreased the expression of brown adipocyte markers UCP-1, Cidea, Cox7a1, and Dio2 in t37i cells, which are brown adipocytes. The above results indicate that the PRDM gene is related to the induction of brown adipocytes and suppression of white adipocytes by butein administration.
실시예 7. PRDM4 유전자 발현 억제를 통한 체중 등의 변화 확인Example 7. Confirmation of changes in body weight, etc. through inhibition of PRDM4 gene expression
PRDM4의 생체내 기능을 확인하기 위해 고지방식이를 투여하면서PRDM4 siRNA와 scrambled RNA를 일주일에 두 번씩 각각 25mg/kg으로 6주간 주사하였다. 투여 기간 동안 PRDM4 siRNA 투여군 (si PRDM4)과 대조군인 Scrambled RNA 투여군 (Scr)의 체중 증가량 및 각종 장기의 무게를 조사하여 비교하였으며, 6주 후에는 glucose tolerance test (GTT)와 insulin tolerance test (ITT)를 수행하였다.To confirm the in vivo function of PRDM4, PRDM4 siRNA and scrambled RNA were injected twice a week at 25 mg/kg for 6 weeks while administering a high fat diet. During the administration period, the weight gain and weight of various organs were investigated and compared between the PRDM4 siRNA administration group (si PRDM4) and the control group Scrambled RNA administration (Scr).After 6 weeks, the glucose tolerance test (GTT) and insulin tolerance test (ITT) Was performed.
도 23 내지 도 24에서 나타나 바와 같이, PRDM4 siRNA 투여군은 대조군과 비교하여, 투여 4주 후부터 유의적인 체중 증가를 보였다. 내장지방 (Fat)의 무게도 증가되었으며, 간조직 (Liver) 역시 증가되는 경향성을 보였다. PRDM4 siRNA 투여군에서 나타나는 몸무게의 증가는 GTT와 ITT에서 포도당과 인슐린의 대사를 방해하였으며, 체온도 Butein 투여군과 비교하여, 유의적인 감소를 보였다.As shown in FIGS. 23 to 24, the PRDM4 siRNA administration group showed significant weight gain from 4 weeks after administration compared to the control group. The weight of visceral fat (Fat) was also increased, and liver tissue (Liver) also showed a tendency to increase. The increase in body weight observed in the PRDM4 siRNA-administered group interfered with the metabolism of glucose and insulin in GTT and ITT, and showed a significant decrease in body temperature compared to the Butein-administered group.
실시예 8. 뷰테인(Butein) 및 뷰테인 유도체의 제조 Example 8. Preparation of Butein and Butein Derivatives
화합물의 제조단계는 각각 그에 상응하는 대표적인 예들을 하기에 기재하였다. 치환기가 다른 화합물들의 경우에도 하기와 유사한 단계를 통해 실제로 제조되었으며, 제조된 화합물은 표 1에 구체적으로 나타내었다. In the preparation steps of the compounds, representative examples corresponding to each are described below. In the case of compounds having different substituents, they were actually prepared through steps similar to the following, and the prepared compounds are specifically shown in Table 1.
[표 1][Table 1]
8.1. 뷰테인의 제조8.1. Preparation of Butane
본 발명에 따른 화학식 1-1로 표시되는 뷰테인 화합물은 상기 반응식 3에 따라 제조하였다. The butane compound represented by Formula 1-1 according to the present invention was prepared according to
[반응식 3][Scheme 3]
본 실시예에서 수행된 대표적인 반응예의 반응 조건 등은 하기에 나타내는 바와 같다; (a) 반응조건 및 재료 : 화합물 2 (152 mg, 1 mmol)와 화합물 3 (138 mg, 1 mmol)을 반응 용기에 넣고 EtOH (0.1 ml)와 KOH 수용액 (60% w/w, 1 ml)을 넣어 용해시키고 100℃로 온도를 높여 3시간 동안 반응시켰다. 상온으로 서서히 온도를 낮추면서 HCl로 pH 3이 될 때까지 점적하였다. 반응 용액을 에틸아세테이트 (10 ml)로 희석시킨 후 물로 세척(3 ml, 2회)하고 수집한 유기층을 무수 황산마그네슘으로 건조시켜 여과한 후, 순상 컬럼 조건 (에틸아세테이트 : 헥산 = 1 : 2)으로 정제하여 노란색 고체로서 1-1번 화합물 (102 mg, 수율 40%)을 수득하였으며 이에 대한 NMR 데이터는 다음과 같다; 1H, 400 MHz, DMSO-d6): δ 1H-NMR (CD3OD): δ 7.81 (1H, d, J = 8.9 Hz, H-6′), 7.70 (1H, d, J = 15.3 Hz, H-β), 7.40 (1H, d, J = 15.3 Hz, H-α), 7.15 (1H, d,J = 1.8 Hz, H-2), 7.05 (1H, dd, J = 8.2, 1.8 Hz, H-6), 6.82 (1H, d, J = 8.2 Hz, H-5), 6.40 (1H, dd, J = 8.9, 2.4 Hz, H-5′), 6.33 (1H, d, J = 2.4 Hz, H-3′), LRMs(ESI) m/z = 273.1 (M+H)+.Reaction conditions and the like of representative reaction examples carried out in this example are as shown below; (a) Reaction conditions and materials: Compound 2 (152 mg, 1 mmol) and compound 3 (138 mg, 1 mmol) were put in a reaction vessel and EtOH (0.1 ml) and KOH aqueous solution (60% w/w, 1 ml) Then, the mixture was dissolved and the temperature was increased to 100° C. and reacted for 3 hours. While gradually lowering the temperature to room temperature, dropping was performed with HCl until the pH reached 3. The reaction solution was diluted with ethyl acetate (10 ml), washed with water (3 ml, twice), and the collected organic layer was dried over anhydrous magnesium sulfate and filtered, followed by normal column conditions (ethyl acetate: hexane = 1: 2). Purified with 1-1 as a yellow solid (102 mg, yield 40%), and the NMR data for it are as follows; 1H, 400 MHz, DMSO-d6): δ 1H-NMR (CD3OD): δ 7.81 (1H, d, J = 8.9 Hz, H-6′), 7.70 (1H, d, J = 15.3 Hz, H-β ), 7.40 (1H, d, J = 15.3 Hz, H-α), 7.15 (1H, d, J = 1.8 Hz, H-2), 7.05 (1H, dd, J = 8.2, 1.8 Hz, H-6 ), 6.82 (1H, d, J = 8.2 Hz, H-5), 6.40 (1H, dd, J = 8.9, 2.4 Hz, H-5′), 6.33 (1H, d, J = 2.4 Hz, H- 3′), LRMs(ESI) m/z = 273.1 (M+H)+.
8.2. 화학식 1-2의 화합물의 제조8.2. Preparation of the compound of formula 1-2
본 발명에 따른 화학식 1-2로 표시되는 뷰테인 유도체 화합물은 상기 반응식 4에 따라 제조하였다. The butane derivative compound represented by Formula 1-2 according to the present invention was prepared according to
[반응식 4][Scheme 4]
본 실시예에서 수행된 대표적인 반응예의 반응 조건 등은 하기에 나타내는 바와 같다; Reaction conditions and the like of representative reaction examples carried out in this example are as shown below;
(a) 반응조건 및 재료 : 화합물 4 (152 mg, 1 mmol)와 화합물 5 (152 mg, 1 mmol)를 무수 메탄올 (5 ml)에 녹인 후, 프롤린 (0.5 eq, 0.5 mmol)을 첨가하였다. 80 ℃로 서서히 온도를 올린 후, 3일 동안 교반을 하였다. 화합물 3, 6이 모두 소모된 것을 확인한 후, 에틸아세테이트로 희석시켜 물로 세척하였다. 수집된 유기층을 무수 황산마그네슘으로 건조하여 농축시킨 후 컬럼 크로마토그래피 (에틸아세테이트:헥산 = 1: 2)로 분리정제하였다. 그 결과 노란색 고체인 화합물 1-1 (114 mg, 수득률 36%)과 노란색 고체인 화합물 1-2 (85 mg, 수득률 33%)를 각각 얻었다. 이 때 얻어진 화합물 1-1은 상기 반응의 생성물과 동일하였으며 화합물 1-2에 대한 NMR 데이터는 다음과 같다; 1H NMR (DMSO-d6): 1H-NMR (CD3OD): δ 7.69 (1H, d, J = 8.7 Hz, H-5), 6.87 (1H, d, J = 1.8 Hz, H-2′), 6.77 (1H, d, J =8.2 Hz, H-5′), 6.74 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 6.44 (1H, dd, J = 8.7, 2.2 Hz, H-6), 6.32 (1H, d, J = 2.2 Hz, H-8), 5.22 (1H, dd, J = 13.2, 2.8 Hz, H-2), 2.94 (1H, dd, J = 13.2, 17.0 Hz, H-3a), 2.65 (1H, dd, J = 17.0, 2.8 Hz, H-3b); Ms(ESI) m/z = 273.1 (M+H)+.(a) Reaction conditions and materials: Compound 4 (152 mg, 1 mmol) and compound 5 (152 mg, 1 mmol) were dissolved in anhydrous methanol (5 ml), and then proline (0.5 eq, 0.5 mmol) was added. After gradually raising the temperature to 80 °C, the mixture was stirred for 3 days. After confirming that all of the
8.3. 화학식 1-9의 화합물의 제조8.3. Preparation of the compound of formula 1-9
본 발명에 따른 화학식 1-9로 표시되는 뷰테인 유도체 화합물은 상기 반응식 5에 따라 제조하였다. The butane derivative compound represented by Formula 1-9 according to the present invention was prepared according to
[반응식 5][Scheme 5]
본 실시예에서 수행된 대표적인 반응예의 반응 조건 등은 하기에 나타내는 바와 같다;Reaction conditions and the like of representative reaction examples carried out in this example are as shown below;
(a) 반응조건 및 재료 : 화합물 1-1 (272 mg, 1 mmol)을 무수 메탄올 (5 ml)에 녹인 후 Pd/C (14 mg, 5% g/g)을 넣고 수소 기류 상태를 만들었다. 상온에서 5시간 반응하여 화합물 1-1이 모두 소모된 것을 확인 후 cellite를 이용하여 여과한 후 여과액을 농축시켜 컬럼 크로마토그래피 (에틸아세테이트 : 헥산 = 1:6)을 이용하여 정제하였다. 그 결과 노란 고체인 화합물 1-9 (250 mg, 수득률 91%)를 얻었다. 이 때 얻어진 화합물 1-9에 대한 NMR 데이터는 다음과 같다; (MeOD) 7.72 (1H, d, J = 8.8 Hz), 6.85 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.57 (1H, dd, J = 2.0, 8.0 Hz), 6.35 (1H, dd, J = 2.4, 8.8 Hz), 6.26 (1H, d, J = 2.4 Hz), 3.17 (2H, t, J = 8.0 Hz), 2.86 (2H, J = 8.0 Hz); Ms(ESI) m/z = 275.1 (M+H)+.(a) Reaction conditions and materials: Compound 1-1 (272 mg, 1 mmol) was dissolved in anhydrous methanol (5 ml), and then Pd/C (14 mg, 5% g/g) was added to create a hydrogen stream. After reacting at room temperature for 5 hours and confirming that compound 1-1 was consumed, the filtrate was filtered using cellite, and the filtrate was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:6). As a result, a yellow solid compound 1-9 (250 mg, 91% yield) was obtained. The NMR data for Compound 1-9 obtained at this time are as follows; (MeOD) 7.72 (1H, d, J = 8.8 Hz), 6.85 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.57 (1H, dd, J = 2.0, 8.0 Hz), 6.35 ( 1H, dd, J = 2.4, 8.8 Hz), 6.26 (1H, d, J = 2.4 Hz), 3.17 (2H, t, J = 8.0 Hz), 2.86 (2H, J = 8.0 Hz); Ms(ESI) m/z = 275.1 (M+H)+.
실시예 9. 뷰테인(Butein) 유도체의 항비만 효과 확인Example 9. Confirmation of anti-obesity effect of butein derivatives
뷰테인 유도체의 항비만 효과를 확인하기 위하여, Butein 유도체 (화학식 1-1 내지 1-8, 1-10 내지 1-14) 처리에 의한 UCP-1, 및 PRDM4 발현량 변화를 측정하였다. 분화된 C3H10T1/2 지방세포에 뷰테인 및 유도체 화합물을 24시간 동안 투여한 후 real time PCR을 이용해 UCP-1과 PRDM4의 발현량을 조사하였다.In order to confirm the anti-obesity effect of the butane derivative, changes in the expression levels of UCP-1 and PRDM4 by treatment with the Butein derivative (Chemical Formulas 1-1 to 1-8, 1-10 to 1-14) were measured. After administration of butane and derivative compounds to differentiated C3H10T1/2 adipocytes for 24 hours, the expression levels of UCP-1 and PRDM4 were investigated using real-time PCR.
그 결과, 도 25에 나타낸 바와 같이, 뷰테인 뿐만 아니라 뷰테인 유도체 화합물에서도 유의적인 UCP-1, 및 PRDM4의 발현량 증가를 확인하였다. 특히, 뷰테인 유도체 화합물 1-11 (BD-10), 및 1-12 (BD-11)를 투여한 군의 경우에는, 뷰테인을 투여군 (BFI)보다 UCP-1, 및 PRDM4의 발현량이 현저하게 증가함을 확인하였다.As a result, as shown in FIG. 25, it was confirmed that the expression levels of UCP-1 and PRDM4 were significantly increased not only in butane but also in butane derivative compounds. In particular, in the case of the group administered with the butane derivative compounds 1-11 (BD-10) and 1-12 (BD-11), the expression levels of UCP-1 and PRDM4 were significantly more pronounced than the butane-administered group (BFI). It was confirmed that the increase was increased.
본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative in all respects and are not limiting.
<110> Research and Business Foundation SUNGKYUNKWAN UNIVERSITY <120> Composition for inducing beige and brown fat cells and method of inducing the same <130> MP16-418 <150> 2014/0078275 <151> 2014-06-25 <160> 2 <170> KoPatentIn <210> 1 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> PRDM4 siRNA_sense <400> 1 gaauuacgcu caacagauau u 21 <210> 2 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> PRDM4 siRNA_antisense <400> 2 uaucuguuga gcguaauucu u 21 <110> Research and Business Foundation SUNGKYUNKWAN UNIVERSITY <120> Composition for inducing beige and brown fat cells and method of inducing the same <130> MP16-418 <150> 2014/0078275 <151> 2014-06-25 <160> 2 <170> KoPatentIn <210> 1 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> PRDM4 siRNA_sense <400> 1 gaauuacgcu caacagauau u 21 <210> 2 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> PRDM4 siRNA_antisense <400> 2 uaucuguuga gcguaauucu u 21
Claims (7)
[화학식 2]
상기 화학식 2에서,
Ra, Rb, 및 Rc는 각각 동일하거나 다를 수 있으며, 수소 또는 OH이고, Rd는 OH 또는 C1-C6 알콕시이고, Re는 수소, 할로젠, 또는 C1-C6 알콕시이고;
단, Ra 및 Re는 수소이고, Rb, Rc 및 Rd는 OH인 경우는 제외한다.
A pharmaceutical composition for preventing or treating obesity, comprising a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient.
(2)
In Formula 2,
R a , R b and R c may be the same or different and each is hydrogen or OH, R d is OH or C 1 -C 6 alkoxy and R e is hydrogen, halogen, or C 1 -C 6 alkoxy ego;
Provided that R a and R e are hydrogen and R b and R c And Except that R d is OH.
상기 화학식 2로 표시되는 화합물은 (E)-1-(2,4-다이하이드록시페닐)-3-(4-하이드록시-3-메톡시페닐)프로프-2-엔-1-온; (E)-1-(2,4-다이하이드록시페닐)-3-(3-하이드록시-4-메톡시페닐)프로프-2-엔-1-온; (E)-1-(2,4-다이하이드록시페닐)-3-(3-플루오로-4-하이드록시페닐)프로프-2-엔-1-온; (E)-3-(3,4-다이하이드록시페닐)-1-(4-하이드록시페닐)프로프-2-엔-1-온; (E)-1,3-비스(3,4-다이하이드록시페닐)프로프-2-엔-1-온; 및 (E)-1,3-비스(4-하이드록시페닐)프로프-2-엔-1-온으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
The compound represented by Formula 2 is (E) -1- (2,4-dihydroxyphenyl) -3- (4-hydroxy-3-methoxyphenyl) prop-2-en-1-one; (E) -1- (2,4-dihydroxyphenyl) -3- (3-hydroxy-4-methoxyphenyl) prop-2-en-1-one; (E) -1- (2,4-dihydroxyphenyl) -3- (3-fluoro-4-hydroxyphenyl) prop-2-en-1-one; (E) -3- (3,4-dihydroxyphenyl) -1- (4-hydroxyphenyl) prop-2-en-1-one; (E) -1,3-bis (3,4-dihydroxyphenyl) prop-2-en-1-one; And (E) -1,3-bis (4-hydroxyphenyl) prop-2-en-1-one.
상기 조성물은 갈색 지방세포의 활성을 증가시키는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
Wherein said composition increases the activity of brown adipocytes.
상기 조성물은 UCP-1(uncoupling protein-1)의 발현을 증가시키는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
Wherein the composition increases the expression of UCP-1 (uncoupling protein-1).
상기 조성물은 PRDM4 (PR domain-containing protein 4)의 유전자의 발현을 증가시키는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
Wherein the composition increases the expression of PRDM4 (PR domain-containing protein 4) gene.
A method for inducing differentiation from a white adipocyte into a beige adipocyte, comprising the step of treating the white adipocytes with the composition of claim 1 or 2 in vitro .
상기 유도방법은 갈색 지방세포의 활성을 증가시키는 것을 특징으로 하는, 유도방법. The method according to claim 6,
Wherein said induction method increases the activity of brown adipocytes.
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