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1 J Korean Med Obes Res 2017;17(2): pissn , eissn JKOMOR Original Article 비만형동물모델에서복합한약추출물 CAPA 의비만및당대사개선효능 송미영 동국대학교한의과대학한방재활의학교실 The Mixed Herbal Extract, CAPA, Prevents Obesity and Glucose Intolerance in Obese Mice Miyoung Song Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Dongguk University Received: November 14, 2017 Revised: November 30, 2017 Accepted: December 1, 2017 Correspondence to: Miyoung Song Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Korea Tel: Fax: Copyright 2017 by The Society of Korean Medicine for Obesity Research Objectives: This study investigated the effects of the mixed herbal extract from Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx (CAPA) on obesity and glucose tolerance in obese mice. Methods: Animals were divided in 6 groups, normal diet, high fat diet (HFD), HFD with CAPA 100 mg/kg (CAPA 100), CAPA 300 mg/kg (CAPA 300), and metformin 200 mg/kg or lorcaserin 10 mg/kg as positive controls, and treated for 16 weeks. Body weight, food intake, fasting blood glucose, and body temperature were checked every week and then organs, blood serums were collected after treatment. The oral glucose tolerance test was also carried out after treatment. Results: Compared to HFD, CAPA extract treated mice showed significant decreases in body weight, adipose tissue weight, lipid accumulations in liver and serum lipid levels without a reduction of food intake. And fasting glucose and glucose tolerance were all improved in the CAPA treated mice. Conclusions: Our results suggest that CAPA extract can prevent diet induced obesity and glucose intolerance without a reduction of energy intake in obese mice. Key Words: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, Aconitum carmichaeli Debx, Obesity, Glucose 서론 비만의유병률은가파르게상승하고있으며, 최근발표된 2016년국민건강조사에의하면, 국내성인남성의비만율이처음으로 40% 를넘은것으로조사되었다 1). 세계보건기구 (World Health Organization) 는비만을 21세기의새로운전염병으로명시하고전세계가비만과의전쟁을선포하였음에도불구하고, 비만인구는급속도로증가하고있다 2). 비만유병률의급격한증가에도불구하고현재비만치료제시장은매출규모가작고침체되어있는데, 그이유는기대 이하의효과및높은부작용으로이하여극소수의환자가단기간만비만치료제를사용하기때문으로분석되고있다 3). 비만은에너지섭취와소비의불균형으로생기는질환이므로비만치료는에너지섭취 (energy intake) 를억제시키거나에너지소비 (energy expenditure) 를증가시키는두가지로크게나뉘는데, 현재 Food and Drug Administration (FDA) 에서승인된비만치료제는모두식이제한을통한에너지섭취억제제이다 4). 이들은대부분중추신경계에작용하는식욕억제제인데, 2010년 sibutramine ( 상품명 Reductil) 이심혈관계부작용으로철수 5) 한이후비만제약 119

2 시장은침체기를걸으며신약이허가되지못하다가 13년만에 lorcaserin ( 상품명 Belviq) 이미국 FDA 허가를받은후 3종의약물이추가로신규허가를받았으나모두식욕억제제로전혀다른새로운기전의약물은아니다 4). 인체의항상성조절기전으로인해섭식제한으로만체중을감량하게되면에너지효율을증가시키기위해기초대사율을떨어뜨리게되어장기적으로는체중감량이더디어지고, 체중의재증량이쉽게오게된다. 따라서효과적이며안전한비만치료를위해서는생체에너지대사촉진을통해에너지소비를증가시킬수있는약물개발이필요하다 6). 이에저자는서양의학에서미토콘드리아작용으로생산되는에너지의개념이추동, 온후작용으로대표되는한의학에서의기의개념과유사하므로 7,8), 보기, 보양제가에너지대사조절을통해항비만효능을나타낼수있을것이라는연구가설을세우고보기, 보양약물을중심으로에너지대사조절을통한항비만및인슐린저항성조절효능약물을탐색하여왔다. 그결과백출, 부자및육계의관련효능을확인할수있었는데 7-12), 백출및백출의주요성분인 atractylenolide III는각각골격근세포에서미토콘드리아기능조절과지방산, 당대사를증가시켰으며 9,10), 육계는비만형동물모델에서골격근내에너지대사조절과항비만효능을나타내었다 11). 또한부자는비만형동물모델에서체중감소효능은없었지만혈당및내당능장애를개선시킴을알수있었으며 12), 골격근세포에서에너지대사조절효능을확인할수있었다 13). 한편이상의보기, 보양약물외에갈근이비만형동물모델에서골격근내에너지대사조절과항비만, 내당증장애개선효능을나타냄을확인하였다 14). 이상과같은선행연구를통하여백출, 육계, 부자및갈근 4종의약물을각각도출하였으며, 약효향상을위하여 4종약물을복합한추출물을조제한후비만형동물모델에서복합추출물의항비만효능을평가하였다. 재료및방법 2; Sigma-Aldrich, St. Louis, MO, USA) 로여과한후잔류물에동량의물을첨가하여동일방법으로 2차추출하였다. 모든추출액을합하여회전식감압농축기 (Buchi Rotavapor R-114 system) 로감압농축한후동결건조 (Freeze Dryer FD5508A; Ilsin Lab., Dongducheon, Korea) 하여물추출물건조분말을제조하였다. 수득률은 23.7% 였다. 2. 실험동물및모델제작실험동물은 5주령 C57BL/6 수컷마우스를 ( 주 ) 샘타코바이오코리아 (Samtako Bio Korea, Osan, Korea) 로부터구입하였다. 모든실험동물은동물보호법 13조규정에따라관리하였으며, 실험기간동안항온, 항습이가능한사육장에서실내온도 22 C±2 C, 습도 55%±5%, 명암 12시간 (day light 06:00 18:00) 을주기로실험종료시까지일정한사육조건환경을유지하였다. 구입후 1주동안적응기간을둔후, 다음과같이총 6개의군으로나누었다. 정상식이군 (normal diet group, ND), 고지방식이군 (high fat diet group, HFD), 고지방식이를공급하면서실험약물을각각 100 mg/kg (Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx [CAPA] 100), 300 mg/kg (CAPA 300) 의농도로투여한 2종의실험군, 고지방식이를공급하면서대조약물인 metformin (MF) 200 mg/kg 및 lorcaserin (LC) 10 mg/kg을투여한 2종의양성대조군으로나누어각 5마리씩무작위배정하였다. ND를제외한나머지 5개의군은고지방식이를약물투여없이 1주간섭취시키고, ND에비해서 10% 이상의체중증가가유도된것을확인한후, HFD에는생리식염수를투여하였으며, 실험군및양성대조군에는정해진농도에따른약물을 16주간경구투여하였다. 정상식이사료는 2018S (Envigo, Alconbuly Huntington, UK) 를사용하였고, 고지방식이사료는 60 kcal% 의지방을함유한 D12492 (Research Diets, New Brunswick, NJ, USA) 를사용하였다. 1. 약재육계, 백출, 갈근, 포부자 ( 광명당제약, Ulsan, Korea) 각 50 g씩총 200 g에약재증류수 2 L를가하여 2시간동안 100 C에서환류추출하고, 전액을여과지 (Whatman No. 3. 체중, 섭식량, 혈당및기초체온측정체중은실험기간동안매주 1회측정하였고, 또한실험기간동안 3일간격으로섭식량을측정하였다. 혈당은매주 1 회 12시간이상절식시킨후모든동물의꼬리정맥으로부 120

3 송미영 : 비만형동물모델에서복합한약추출물 CAPA 의비만및당대사개선효능 터혈액을수집하여혈당측정기 (Accu-Check; Roche Diagnostics, Basel, Switzerland) 를이용하여측정하였다. 또한기초체온은매주 1회오후 3시에직장체온을 thermocouple probe (Physitemp, Clifton, NJ, USA) 를이용하여측정하였다. 4. 경구내당능측정경구내당능검사 (oral glucose tolerance test, OGTT) 는약물투여마지막날 12시간이상모든동물을금식시키고실시하였다. 포도당용액을체중 (kg) 당 2 g씩경구투여한다음 0, 30, 60, 90, 120분에각각실험동물의꼬리정맥으로부터혈액을수집하고혈당측정기 (Accu-Check) 를이용하여혈당변화를측정하였다. 절하여조직슬라이드를제작하였다. 조직슬라이드를 Oil red O로염색한후, 광학현미경 (Leica DM 500; Leica, Wetzlar, Germany) 으로관찰하였다. 8. 통계분석각실험모든측정값은평균 ± 표준오차 (means±standard errors of the mean) 로표시하였고통계적분석은 GraphPad Prism Program ver 5.0 (GraphPad Software, La Jolla, CA, USA) 을이용하여 one-way ANOVA (Tukey s post hoc test) 를사용하여각군간의차이를분석하였으며, P값이 0.05 미만인경우통계적으로유의한것으로판정하였다. 결과및고찰 5. 혈청지질및간효소측정약물투여종료후최소 12시간이상절식시킨후모든동물을희생시키고복대정맥으로부터혈액을수집하였다. 수집된혈액은 6,000 rpm에 15분간원심분리하여혈청을분리하였으며, 자동혈액분석기 (FDC7000i; Fujifilm Co., Tokyo, Japan) 를이용하여혈청내 glutamic oxaloacetic transaminase (GOT), glutamate pyruvate transaminase (GPT), 총콜레스테롤 (total cholesterol), 중성지방 (triglyceride), high-density lipoprotein-cholesterol (HDL-C) 및 lowdensity lipoprotein-cholesterol (LDL-C) 의농도를측정하였다. 6. 조직무게측정모든실험동물을희생시키고심장으로부터생리식염수를관류하여혈액을제거한후백색지방은부위별 ( 부고환지방, 신장주위지방, 장간막지방 ) 로적출하였으며, 간, 췌장및비복근역시적출하였다. 적출된조직은생리식염수로세척한다음여과지로수분을제거한후무게를측정하였다. 체중대비골격근비율은한쪽비복근의무게를체중으로나눈값으로계산하였다. 7. 간조직의 Oil red O 염색적출한간을 10% 의 paraformaldehyde 에담가고정하고, 조직절편기 (microtome) 를이용하여 10 m 두께로박 1. 체중및에너지효율총 17주간의고지방식이및약물투여후, HFD의체중이 ND에비해서유의하게증가한것을확인할수있었다. HFD의최종체중은 44.1±1.6 g이었으며, CAPA 100은 41.0±4.2 g, CAPA 300은 37.6±3.3 g으로 CAPA 투여시체중이농도의존적으로유의하게감소하였다 (Fig. 1A, B). 식이섭취량은 CAPA 투여군에서는 HFD에비해서유의한차이가없었으나 MF 투여군에서는유의하게감소하였으며, LC 투여군에서는섭취량의변화가나타나지않았다 (Fig. 1C). MF의식욕억제효능은이전연구에서밝혀진바로, MF은중추신경계에작용하여식욕억제효능을나타내는것으로보고된바있다 15,16). LC 역시식욕억제제이나 17) 식욕억제효과가비교적약한약물로알려져있으며 18), 본연구에서식이제한효과는관찰되지않았다. 에너지배출증가, 즉에너지대사촉진을통한항비만효능을평가하기위하여에너지섭취량에따른체중변화를나타내는에너지효율과기초체온을측정하였다. 기초체온은에너지대사를간접적으로평가할수있는지표로, 기초체온이상승할수록에너지배출및산소소비가높아지는것으로보고된바있다 19,20). CAPA 투여군 (300 mg/kg) 에서고지방식이대조군에비해서에너지효율이감소하고, 기초체온이증가한것으로나타났다 (Fig. 1D, E). 이상의결과를통해 CAPA는식욕억제효과없이에너지대사를증가시켜체중감소효과를나타내는것으로추측된다

Fig. 1. Effects of CAPA extract on body weight. (A) Body weight changes by period, (B) body weight differences, (C) food intake, (D) energy efficiency, (E) body temperature.

4 Fig. 1. Effects of CAPA extract on body weight. (A) Body weight changes by period, (B) body weight differences, (C) food intake, (D) energy efficiency, (E) body temperature. Results are presented as means± standard errors of the mean (n=5). CAPA: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx, MF: metformin, LC: lorcaserin. ***P< vs. the normal chow fed controls (normal diet [ND] group); ### P<0.001, ## P<0.01, # P<0.05 vs. the high fat diet (HFD) fed mice (HFD group). Table 1. White Adipose Tissue and Organ Weights Variable ND HFD CAPA 100 CAPA 300 MF LC Epididymal adipose tissue 0.46± ±0.16** 1.18±0.21 # 1.10± ± ±0.09 ## Perirenal adipose tissue 0.16± ± ± ± ± ±0.06 Mesenteric adipose tissue 0.38± ±0.12*** 0.92±0.33 # 0.63±0.17 ### 0.77±0.32 ### 0.94±0.18 ## Total white adipose tissue (g) 0.99± ±0.21*** 2.57± ±0.36 # 2.19±0.21 ## 2.56±0.17 Liver (g) 1.34± ± ± ± ± ±0.17 Pancreas (g) 0.33± ± ± ± ± ±0.08 MW/BW (%) 0.53± ±0.09* 0.44± ± ± ±0.06 Values are presented as mean±standard error of the mean (n=5). CAPA: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx, MF: metformin, LC: lorcaserin, MW: muscle weight, BW: body weight. ***P<0.001, **P<0.01, *P<0.05 vs. normal chow fed controls (normal diet [ND] group); ### P<0.001, ## P<0.01, # P<0.05 vs. the high fat diet (HFD) fed mice (HFD group). 2. 백색지방조직및주요조직무게백색지방중피하지방보다는내장지방이비만으로인한대사증후군의발생과관련이깊다 21). 마우스에서내장지방은부고환지방, 신장주위지방및장간막지방으로이루어져있는데 22), 이들의무게변화를측정하였다. 부고환지방의경우 HFD에비해서 CAPA 약물치료군에서증가하는경향을나타내었으나, 전체내장지방무게를합산할결과고지방식이에비해서 CAPA 300군에서유의하게무게가감 소하였으며, 양성대조군인 MF와 LC 처치군에서도감소를나타내었다. 간과췌장의고지방식이대조군과 CAPA 실험군및양성대조군간에유의한차이가없었으며, 체중대비골격근비율은 ND에비해서 HFD가유의하게감소하여비만으로인한골격근비율감소를확인할수있었으며, CAPA 투여군에서증가하는경향을나타내었으나통계적유의성은없었다 (Table 1). 이상을결과를통해 CAPA가고지방식이로증가한내장지방의무게를유의하게감소시킴 122

5 송미영 : 비만형동물모델에서복합한약추출물 CAPA 의비만및당대사개선효능 Fig. 2. Effects of CAPA extract on serum lipids. (A) Total cholesterol, (B) triglyceride, (C) high-density lipoprotein-cholesterol (HDL-C), (D) lowdensity lipoprotein-cholesterol (LDL-C). Results are presented as means± standard errors of the mean (n=5). CAPA: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx, MF: metformin, LC: lorcaserin. ***P< vs. the normal chow fed controls (normal diet [ND] group); ### P< 0.001, ## P<0.01, # P<0.05 vs. the high fat diet (HFD) fed mice (HFD group). 을확인할수있었다. 3. 혈청지질총콜레스테롤및 LDL-C는 CAPA 투여군에서 HFD에비해유의하게감소하였으며, 양성대조군인 MF 및 LC 투여군에서도유사한경향을나타내었다. 그러나중성지방과 HDL-C는고지방식이대조군에비해서유의한개선효능이나타나지않았다 (Fig. 2). 4. 간의지질축적및간기능평가간조직의지질축적상태를 Oil red O 염색을통해평가하였다. ND에비해 HFD에서지질축적을확인할수있었다. CAPA 투여군에서지질축적이현저하게감소한것으로나타났으며, 양성대조군이 LC에비해서도지질축적도가감소한것으로관찰되었다 (Fig. 3A). 또한간기능평가를위해서가장일반적인혈청검사항목인 GOT, GPT의혈청농도를측정하였다. GOT의경우 HFD에비해서 CAPA 투여시감소하는경향을나타내었으나, 통계적인유의성은없었다. GPT 항목은 ND보다 HFD에서확연히증가하였으며, CAPA 투여시유의하게감소하는결과를나타내었다 (Fig. 3B). 5. 혈당및내당능장애본연구의실험동물인 C5BL mice는고지방식이로비만뿐만아니라고혈당증, 내당능장애를유발하기에적합한동물모델로알려져있으며, 고지방식이기간별로유발양상을분석했을때, 16주동안고지방식이급여시에 8주및 12 주보다확연한내당능장애가유발되는것으로보고된바있다 23). 본연구에서 17주동안고지방식이를투여한후 OGTT를통해내당능장애를평가한결과 ND에비해 HFD에서내당능장애가유발되었음을곡선하면적을통해서알수있었으며, CAPA 투여군에서곡선하면적이농도의존적으로유의하게감소함을알수있었다. 공복혈당은 ND에비해 HFD에서유의하게상승하였다. CAPA 100, 300에서 HFD에비해농도의존적으로유의하게감소하였다. 또한 2종의양성대조군역시 OGTT와공복혈당에서고지방식이대조군에비해서유의한효과를나타내었다 (Fig. 4). 이상의결과를종합하여 CAPA 추출물이고지방식이로유도된비만형동물모델에서체중증가를억제시키고혈중지질과간의지질축적을감소시킴을확인할수있었다. 또한비만으로인한고혈당증및내당능장애를개선시킴을알수있었다. 본실험에서는실험약물의엄격한효능평가를위하여 2종의양성대조군을사용하였다. MF는에너지대 123

Fig. 3. Effects of CAPA extract on lipid accumulations in livers. (A) Oil red O stained liver tissues ( 200), (B) glutamic oxaloacetic transaminase (GOT), (C) glutamate pyruvate transaminase (GPT).

6 Fig. 3. Effects of CAPA extract on lipid accumulations in livers. (A) Oil red O stained liver tissues ( 200), (B) glutamic oxaloacetic transaminase (GOT), (C) glutamate pyruvate transaminase (GPT). Results are presented as means±standard errors of the mean (n=5). CAPA: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx, MF: metformin, LC: lorcaserin. **P <0.01 vs. the normal chow fed controls (normal diet [ND] group); ## P<0.01 vs. the high fat diet (HFD) fed mice (HFD group). Fig. 4. Effects of CAPA extract on glucose tolerance. (A) Oral glucose tolerance test (OGTT), (B) area under curve in OGTT, (C) fasting blood glucose. Results are presented as means±standard errors of the mean (n=5). CAPA: Cinnamomum cassia Blume, Atractylodes macrocephala Koidzumi, Pueraria lobata Benth, and Aconitum carmichaeli Debx, MF: metformin, LC: lorcaserin. ***P< 0.001, **P<0.01 vs. the normal chow fed controls (normal diet [ND] group); ### P<0.001, ## P<0.01, # P <0.05 vs. the high fat diet (HFD) fed mice (HFD group). 사를조절하는센서인 adenosine monophosphate-activated protein kinase (AMPK) activator로서가장대표적인 2형당뇨병에 1차로사용되며 24), 항비만효능및식욕억제작용역시알려져있다 15,16). 또한 LC는선택적 5- HT2C 세로토닌효능제로작용하여식욕억제효능을나타내는항비만치료제 17) 로 2014년국내에출시되어바로이듬해부터국내비 만치료제판매 1위를기록한치료제이다 25). 기존약물에비해서장기간사용할수있다는장점이있지만식욕억제효능및체중감소효능은다소약하다는평가가일반적이다 18). 이들대조약물과비교시특히주목할점은 CAPA가식욕억제를통한사료섭취량의감소없이항비만효능을나타내었다는점이며, 이는고지방식이대조군에비해서에너지 124

7 송미영 : 비만형동물모델에서복합한약추출물 CAPA 의비만및당대사개선효능 효율이감소하고, 기초체온이증가한결과와도연결되는내용이다. 즉 CAPA는식욕억제작용이아닌에너지배출촉진을통한항비만효능이기대되는약물이다. 이전연구에서 CAPA의구성약물인백출, 갈근, 육계가골격근세포배양모델및비만형동물모델에서미토콘드리아기능조절및에너지대사조절의핵심인자인 PGC1 26) 및 AMPK 27) 의발현량을증가시키는것을확인할수있었다 9-11,14). CAPA의에너지대사조절효능및기전을구체적으로평가하기위해서는골격근, 갈색지방및간등에너지대사의핵심기관에서 PGC1, AMPK, UCP 1 28) 등에너지및열대사관련조절인자들의발현도를평가하는분자생물학적연구가이뤄져야하겠다. 결론 고지방식이로유도된 C57BL/6 마우스비만형동물모델에육계, 백출, 갈근, 부자로구성된복합한약추출물 CAPA (100, 300 mg/kg) 를 16주간투여한결과, 에너지섭취량의변화없이체중, 지방조직무게, 간지질축적도및혈청지질수치에서유의한항비만효능을확인할수있었다. 또한공복혈당및 OGTT에서도유의한개선효능을발견하였다. 복합한약추출물 CAPA는에너지대사촉진통한항비만효능이기대되는약물이며, 이와관련하여구체적인작용기전을밝히기위해추후연구가필요하다. 감사의글 본연구는 2017년도미래창조과학부의재원으로한국연구재단의지원을받아수행된기초연구사업임 (No. NRF- 2017R1A1A1A ). References 1. Korea Centers for Disease Control and Prevention (KCDC). Korea national health and nutrition examination survey [Internet]. Cheongju: KCDC; [cited 2017 Oct 29]. Available from: 2. World Health Organization (WHO). Obesity and overweight fact sheet [Internet]. Geneva: WHO; [cited 2017 Oct 29]. Available from: fs311/en/. 3. Biological Research Information Center (BRIC). Future prospect of development of obesity treatment based on global industry trend [Internet]. Pohang: BRIC; [cited 2017 Oct 20]. Available from: &id= Daneschvar HL, Aronson MD, Smetana GW. FDA-approved anti-obesity drugs in the united states. Am J Med ; 129(8) : 879.e European medicines agency (EMA). European Medicines Agency recommends suspension of marketing authorisations for sibutramine [Internet] London: EMA; [cited 2017 Oct 20]. Available from: 6. Tseng YH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov ; 9(6) : InTechOpen. Why is qi-invigorating therapy in chinese medicine suitable for mitochondrial diseases? [Internet]. London: InTech; [cited 2017 Oct 22]. Available from: n-chinese-medicine-suitable-for-mitochondrial-diseases-a-bioe nergeti. 8. Wallace DC. Mitochondria as chi. Genetics ; 179 : Song MY, Kang SY, Oh TW, Kumar RV, Jung HW, Park YK. The roots of atractylodes macrocephala koidzumi enhanced glucose and lipid metabolism in C2C12 myotubes via mitochondrial regulation. Evid Based Complement Alternat Med ; 2015 : Song MY, Jung HW, Kang SY, Park YK. Atractylenolide III enhances energy metabolism by increasing the SIRT-1 and PGC1 expression with AMPK phosphorylation in C2C12 mouse skeletal muscle cells. Biol Pharm Bull ; 40(3) : Song MY, Kang SY, Kang A, Hwang JH, Park YK, Jung HW. Cinnamomum cassia prevents high-fat diet-induced obesity in mice through the increase of muscle energy. Am J Chin Med ; 45(5) : Song MY. Evaluation of efficacy of aconitum carmichaeli debx extract on obesity and glucose tolerance in diet induced obese mice. J Korean Med Obes Res ; 17(1) : Song MY. Effect of aconitum carmichaeli debx on energy metabolism in C2C12 skeletal muscle cells. J Korean Med Obes Res ; 16(2) : Jung HW, Kang AN, Kang SY, Park YK, Song MY. The root extract of pueraria lobata and its main compound, puerarin 125

8 prevent obesity by increasing the energy metabolism in skeletal muscle. Nutrients ; 9(1) : E Rouru J, Huupponen R, Pesonen U, Koulu M. Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese zucker rats. Life Sci ; 50(23) : Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, et al. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res ; 1444 : Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther ; 325(2) : Kumar RB, Aronne LJ. Obesity (Silver Spring). Efficacy comparison of medications approved for chronic weight management ; 23 Suppl 1 : S Landsberg L, Young JB, Leonard WR, Linsenmeier RA, Turek FW. Is obesity associated with lower body temperatures? Core temperature: a forgotten variable in energy balance. Metabolism ; 58(6) : Jurgens HS, Schurmann A, Kluge R, Ortmann S, Klaus S, Joost HG, et al. Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiol Genom ; 25(2) : Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb ; 18(8) : Nagai M, Komiya H, Mori Y, Ohta T, Kasahara Y, Ikeda Y. Estimating visceral fat area by multifrequency bioelectrical impedance. Diabetes Care ; 33(5) : Williams LM, Campbell FM, Drew JE, Koch C, Hoggard N, Rees WD, et al. The development of diet-induced obesity and glucose intolerance in C57BL/6 mice on a high-fat diet consists of distinct phases. PLoS One ; 9(8) : e Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et. al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest ; 108(8) : Economic review. Obesity drug market in Korea. [Internet] Seoul: Economic review; [cited 2017 Oct 20]. Available from: Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ ; 30(4) : O'Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol ; 366(2) : Kim SH, Plutzky J. Brown fat and browning for the treatment of obesity and related metabolic disorders. Diabetes Metab J ; 40(1) :

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α α α α α α α α 太陰調胃湯加減方 dbdb 마우스 肝에 대한 아디포사이토카인 및 발현에 미치는 영향 SREBPs 와 섞어서 하고 마커 또한 하여 전기 영동을 하였다 전기영동을 한 후에 에 를 쪼여서 각 를 확인하였다 이 를 프로그램을 이용해 수치화하 여 분석하였다 肝 조직 동결 절편 분리한 조직은 로 시간 동안 고정 시킨 후 에 세척한 후 물기를