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1 J. Exp. Biomed. Sci. 2012, 18(1): 56~62 pissn : Original Article Effects of Long-Term High-Fat Diet Feeding on Gene Expression of Inflammatory Cytokines in Mouse Adipose Tissue Nu Ri Oh, Ae Rang Hwang, Ja In Jeong, Sung Hyun Park, Jin Seok Yang and Yong-Ho Lee Department of Biomedical Science, Catholic University of Daegu, Gyeongsan , Korea This study was to investigate the effects of high-fat diet feeding for a very long period of time on gene expression of inflammatory cytokines in mouse adipose tissue and to determine whether caloric restriction (CR) or insulin sensitizer treatment changes the cytokine gene expressions even in obese mice fed a high-fat diet for a very long term-period. Gene expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were examined by real-time PCR in subcutaneous abdominal adipose tissue (SubQ) from obese and non-obese male C57BL/6 mice at 16, 26, 36, 47, and 77 weeks of age on either normal diet (ND) or high-fat diet (HFD) after starting at 6 weeks of age. In addition, gene expression levels of TNF-α, IL-6 and MCP-1 were determined in SubQ before and after rosiglitazone treatment or CR on 47-week-old obese mice. The results demonstrated that gene expression levels of TNF-α, IL-6 and MCP-1 were significantly increased with aging in SubQ of mice in both groups of diet. MCP-1 gene expression of SubQ in all ages tested was significantly or marginally increased in mice on HFD compared with ND. While TNF-α expression was significantly reduced by rosiglitazone, IL-6 and MCP-1 were significantly decreased by CR. The basic data in this study will be useful for characterizing the C57BL/6 mouse as an animal model of obesity induced by high-fat diet feeding for a very long period of time, and a better understanding of inflammatory cytokine regulation in diet induced obesity which may facilitate the development of new therapeutic strategies to prevent the complications of obesity. Key Words: Obesity, High-fat diet, TNF-α, IL-6, MCP-1, Adipose tissue, C57BL/6, Caloric restriction, Rosiglitazone 서 현대사회는비만화, 고령화사회라고말할수있다. 최근비율이급격히증가하고있는비만은많은만성질환의합병증을야기한다. 현재많은사람들이고지방의서구음식소비의증가로비만인구의급격한증가와이로인하여발생하는만성질환자가더욱증가할것이라예측된다. 비만은인슐린저항, 고혈압, 지질대사이상등을포함하는대사증후군을나타내며제2형당뇨, 심혈관질환, 암및호흡기계질환등의합병증유발위험성을높인다 * Received: 30 December, 2011 / Revised: 30 March, 2012 Accepted: 30 March, 2012 Corresponding author: Yong-Ho Lee. Department of Biomedical Science, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk , Korea. Tel: , Fax: ylee325@cu.ac.kr C The Korean Society for Biomedical Laboratory Sciences. All rights reserved. 론 (Pi-Sunyer, 2002). 최근많은연구들은비만과전신의저준위만성적염증상태와의연관성을보여주고있다. 비만은혈액에서염증마커들의농도증가와관련이있는것으로알려져있다 (Kershaw and Flier, 2004; Rajala and Scherer, 2003). 건강한남녀에서비만도와공복기혈장의 interleukin-6 (IL-6) 농도의직접적인연관성이밝혀졌다 (Vozarova et al., 2001). 다른연구들에서도 IL-6 (Kershaw and Flier, 2004; Rajala and Scherer, 2003) 와 tumor necrosis factor (TNF)-α (Hotamisligil and Spiegelman, 1994) 가비만과연관되어있음을보여주었다. 또한당뇨, 고혈압, 동맥경화증등의비만합병증들도혈액의염증성사이토카인농도의증가와관련이있음이알려졌다 (Hotamisligil and Spiegelman, 1994). 한편, 지방조직은단순한수동적인에너지저장고로의역할을넘어체중조절과대사작용에중요한역할을하는많은신호물질을분비하는조직으로재조명되고있다

2 (Ronti et al., 2006). 지방조직에대한지난주요연구들은지방에대한인식을변화시켰는데, 특히지방조직은에너지저장고의역할뿐만아니라대사작용이왕성한조직으로써일종의내분비기관으로작용하여음식섭취, 에너지소모와대사작용및면역기능을조절하는분자등다양한신호분자를합성, 분비하는기관으로알려지게되었다 (Kershaw and Flier, 2004; Lee et al., 2005; Lee and Pratley, 2005, 2007; Lyon et al., 2003; Rajala and Scherer, 2003). 비만과비만에의한당뇨병등의합병증과의연결기전에대해괄목할만한연구가이루어져왔으며, 그중지방조직이주요한역할을하는것으로알려졌다. 지방조직은 TNF-α, IL-6, IL-1, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) 과 macrophage inflammatory protein (MIP)-1 등여러염증성사이토카인을분비하는것으로알려져있고 (Kershaw and Flier, 2004; Rajala and Scherer, 2003), 이들사이토카인은 adipokine으로도불리며, 비만인에서이상발현이전신의저준위염증상태를동반하며결국비만의합병증발병의주요요인으로작용한다 (Hotamisligil and Spiegelman, 1994; Shoelson et al., 2006). 실험동물을이용해비만에의한지방조직염증성사이토카인의합성과이들의역할에관한연구도많이진행되어왔는데, Hotamisligil과 Spiegelman (Hotamisligil and Spiegelman, 1994), 그리고 Hotamisligil 등 (Hotamisligil et al., 1993) 은지방조직유래의염증성사이토카인 TNF-α 가비만성인슐린저항발병에기능하고있음을처음으로보고하였다. 그들은비만및당뇨에대한여러실험모델동물들에서지방조직의 TNF-α mrna 발현증가와혈액의 TNF-α 단백질농도증가를관찰하였으며, TNF-α 농도를감소시킨비만쥐모델에서인슐린민감성이회복됨을보고하였다 (Hotamisligil et al., 1993). 또한, Xu 등 (Xu et al., 2003) 에의해유전적인비만생쥐모델과고지방식이로유도된비만생쥐모델에서지방조직에존재하는대식세포가주요한역할을하고있으며 MIP-1, MCP-1, MAC-1 등의유전자발현이비만에의한인슐린저항성유발에역시주요한역할을하고있음이알려졌다. 이와유사하게, Weisberg 등 (Weisberg et al., 2003) 은유전적비만생쥐모델 (ob/ob) 의지방조직에서증가된대식세포를관찰하였고지방조직유래의 TNF-α와 IL-6 등의주요염증성사이토카인의상당량의발현을담당하고있음을보고하였다. 본연구에서는사람의식습관이매우긴기간유지되 는점을감안하여장기간의고지방음식섭취의영향을실험동물모델을통해조사하고자하였다. 이를위해장기간고지방식이섭취로비만화를유도한비만생쥐의지방조직에서염증성사이토카인의유전자발현량을조사하였고, 매우긴기간동안의고지방섭취에의한비만화후에도입한식이제한과인슐린민감성을증진시키는약물에의한염증성사이토카인의유전자발현의변화를조사하였다. 재료및방법실험동물수컷 4주령실험용생쥐 (C57BL/6) 를구입하여 (Hyochang Science, Daegu, Korea) 2주동안적응기간을거친후 6주령때부터일반식이 (normal diet, ND; fat 4 kcal%, Rodent NIH-31 Open Formula Auto, Zeigler Bros, inc, Gardners, PA, USA) 로사육한일반비-비만생쥐그룹과고지방식이 (high-fat diet, HFD; fat 45 kcal%, Feedlab Korea Co, Ltd, Korea) 로비만화를유도한생쥐 (DIO mice) 그룹으로나누어사육하였다. 각그룹의생쥐들을 16주, 26주, 36주, 47주, 또는 77주령까지장기간사육하여실험대상조직적출에사용하였다. Rosiglitazone 섭취와칼로리제한고지방식이로비만화를장기간유도한후에염증성사이토카인발현에대한 insulin sensitizer의영향을조사하기위해, 6주령부터 47주령까지고지방식이로비만화를유도한 DIO mice에 carboxymethyl cellulose 용액을 vehicle로사용하여 10 mg/kg body weight의 rosiglitazone 을매일 2주간경구투여하였다 (Higuchi et al., 2010). 대조군 (control) 은 vehicle만경구투여한 DIO mice들을사용하였다. 고지방식이로비만화를유도한후칼로리제한 (CR) 의영향을알아보기위해 47주령까지고지방식이로비만을유도한생쥐를사용하였다. 칼로리제한군 (CR) 은대조군 (CC) 섭취칼로리의 70% 해당하는일반식이로 6주간식이제한하였으며, 대조군 (CC) 은같은기간내고지방식이를자유급식으로하였다. cdna 합성 16주, 26주, 36주, 47주, 77주령까지일반식이, 고지방식이로키운생쥐와 rosiglitazone 또는 vehicle 투여생쥐

3 및칼로리제한실험에이용된실험군생쥐들을 sodium pentobarbital로마취시키고흉강을열어심장채혈후복부피하지방조직 (subcutaneous abdominal adipose tissue) 등실험대상조직을적출하였다. 적출한각생쥐의지방조직약 300 mg을 RNeasy Lipid Tissue Mini Kit (Qiagen, Valencia, CA, USA) 를이용하여 total RNA를추출하였다. RNA 추출과정중에 DNase I (RNase-free DNase set, Qiagen) 를처리하여 DNA의오염이없는순수 RNA만추출하였다. 각 total RNA 시료 500 ng을 High Capacity cdna Reverse Transcription Kit와 96-well GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA, USA) 을사용하여 cdna를합성하였다. Real-time PCR TNF-α, IL-6, MCP-1과 normalizing gene으로사용된 house keeping 유전자의하나인 GAPDH의 RNA transcript 발현량을측정하기위해 quantitative Real-Time PCR을기존의표준곡선방식대로수행하였다 (Kim and Lee, 2010; Lee et al., 2008). 이를위해 mouse TaqMan Gene Expression Assays (assay ID: TNF-α Mm _m1, IL-6 Mm _m1, MCP-1 Mm _m1, Applied Biosystems) 를사용하여 Real-Time PCR System 7500 (Applied Biosystems) 에서 real-time PCR을수행하였다. Normalizing gene으로 Mouse GAPDH Endogenous Control (FAM/MGB Probe, Non-Primer Limited, part # E) 을 Applied Biosystems로부터구입하여사용하였다. 각각의 plate well 에 10 ng의 total RNA에해당하는 cdna를포함하는반응용액 20 μl에서측정하였다. Real-time PCR 조건은 50 에서 2분, 95 에서 10분반응후 95 에서 15초와 60 에서 1분을 40회반복하는것으로증폭하였다. 각각의사이토카인 mrna 발현량은 GAPDH mrna 발현량에대해 normalization 되었으며, 발현량은임의적인상대적인값 (arbitrary values) 이며, 평균과표준편차 (SD) 또는표준오차 (SEM) 로결과를나타냈고, student t-test로유의성을검정하였으며, P<0.05인것을유의한결과라판단하였다. 결과및고찰최근서구화된고지방식사에따른영향으로비만인구의급증과, 비만화에따른고지혈증, 심혈관질환, 제2형당뇨병의발병빈도가증가하고있다. 비만화에따른지방 조직의증가와지방조직에서발현분비되는염증성사이토카인이전신에악영향을미치며합병증유발의매개자역할을하는것으로연구되어왔다 (Ronti et al., 2006). 이에따라, 본연구에서는사람의식습관이매우긴기간유지되는점을감안하여장기간고지방식이섭취로비만화를유도한비만생쥐의지방조직에서염증성사이토카인의유전자발현량을조사비교하였으며, 일반적으로비만의합병증이나인슐린저항성의개선방법으로알려진칼로리제한이나 rosiglitazone 섭취에의한지방조직의주요염증성사이토카인으로알려진 TNF-α, IL-6와 MCP-1 유전자들의변화를조사하였다. 생쥐 (C57BL/6) 를이용하여고지방식이섭취에의한비만화와지방조직에서의염증화및염증성사이토카인발현에대한연구가많이진행되어왔다. 하지만, 본연구에서처럼생쥐 6주령에서식이를시작하여 16, 26, 36, 47, 및 77주령까지매우긴기간동안각기일반식이와고지방식이로사육하여염증성사이토카인의유전자발현의변화양상을비교조사한연구는아직없었다. 염증성사이토카인 (TNF-α, IL-6, MCP-1) 의발현양상 Real-time PCR을이용하여각실험군생쥐의지방조직에서의염증성사이토카인 mrna 발현량을조사한결과, TNF-α mrna의발현량은주령이증가함에따라증가하는양상을보였다 (Fig. 1A). 특히, 47주령과 77주령에서크게증가한 TNF-α의발현이관찰되었다. ND로사육한 77주령생쥐의복부피하지방조직 TNF-α mrna의발현량 (393 ± 68; mean ± SEM, arbitrary number) 은 ND군의 16 주령 (54 ± 7), 26주령 (53 ± 21), 36주령 (42 ± 8), 47주령 (158 ± 48) 보다유의하게 (P<0.05) 증가하였다. ND 군의 47주령 TNF-α 발현도 16주령, 26주령, 36주령에비해증가하였다 (P<0.05). HFD군의생쥐들에서의 TNF-α 발현은 16주령 (40 ± 9), 26주령 (34 ± 8), 36주령 (24 ± 7) 에비해 47주령 (208 ± 39) 에서유의하게증가하였으나 (P<0.05), 47주령과 77주령 (206 ± 21) 사이에서는변화가없었다 (Fig. 1A). IL-6의발현량조사의결과는 TNF-α의경우와매우유사하게나타났다 (Fig. 1B). ND군과 HFD군모두에서 47 주령과 77주령에서의발현량이 16주령, 26주령, 36주령의발현량보다크게증가하는양상이관찰되었다 (P<0.05). TNF-α와 IL-6의 mrna 발현양상에서공통적으로특이하게주목할점은통계적으로유의하지는않지만전반적으로 HFD군의생쥐에비해 ND군의생쥐에서조금

4 높게발현되는것이관찰되었다. 또한 77주령의생쥐에서는 ND군의 TNF-α 발현량이 HFD군보다통계적으로유의하게높은 (P<0.05) 발현을보였다. 기존의연구결과 (Hotamisligil et al., 1993; Shoelson et al., 2006) 를감안하면고지방식이에의해비만화된생쥐의지방조직은일반식이를섭취한생쥐의지방조직보다높은 TNF-α와 IL-6의발현을예상할수있다. 그러나최근의연구들에서장기간의고지방식섭취에의한비만생쥐에서 TNF-α 와 IL-6 를포함하는여러염증성사이토카인이감소되는것이 A B TNF-α (TNF-α/GAPDH) 관찰보고되고있어 (Altintas et al., 2011) 이들연구들과같은결과를보이고있다. 이런점은단기간 (Alkhouri et al., 2010) 또는장기간의고지방식이를섭취한비만생쥐가지방조직염증성사이토카인의발현에다른특성을보인다고추측되며, 이런불확실한발현특성이정리되고그원인탐색이필요하겠다. MCP-1의발현도 TNF-α와 IL-6의경우처럼, 주령증가에따라발현량이증가하는양상을보였다 (Fig. 1C). 47 주령 (ND 118 ± 27, HFD 241 ± 61) 과 77주령 (ND 275 ± 77, HFD 357 ± 31) 에서의발현이 16주령 (ND 19 ± 5, HFD 59 ± 6), 26주령 (ND 27 ± 11, HFD 51 ± 10) 과 36 주령 (ND 14 ± 2, HFD 20 ± 2) 에비해크게증가하였다 (P<0.05). 또한, HFD군의 16주령, 36주령, 47주령의생쥐에서 MCP-1의발현량이 ND군에비하여통계적으로높게나타났다 (P<0.001, P<0.05, and P<0.05, respectively). 또한통계적으로유의하지는않지만 26주령과 77주령의 HFD군생쥐가 ND군의생쥐보다높은발현을보였다. 이 MCP-1의발현양상은기존에알려진비만화에따른지방조직발현양상과일치하는것으로비만쥐의지방조직으로의높은대식세포침투를의미한다. 이상의세가지사이토카인의발현양상들은 aging에따라비교적비슷한패턴으로변화되는것으로나타났다. 즉, 식이따른변화보다는주령에따른변화양상이더욱크게나타나는경향을보였다. 몇주정도의단기간의고지방식이섭취에따른지방조직에서의사이토카인의발현양상은많이확인되어왔으나짧게는 10여주에서길 C Fig. 1. Gene expression levels of TNF-α (A), IL-6 (B), and MCP-1 (C) in adipose tissue of C57BL/6 mice fed either a normal diet or a high-fat diet for various period of time. Data are given as mean ± SEM. ND, mice fed on a normal diet; HFD, mice fed on a high-fat diet. *P<0.05, **P<0.001 Table 1. Body weight of C57BL/6 mice at the time of sacrifice and duration of feeding either a normal diet or a high-fat diet. Age (weeks) n Body weight at sacrifice (g) Diet ± 2.1 ND * Duration of diet (weeks) 16 w ± 2.9 HFD ** 10 w 26 w ± 2.1 ND ± 1.9 HFD 20 w 36 w ± 2.3 ND ± 5.5 HFD 30 w 47 w ± 2.4 ND ± 4.9 HFD 41 w 77 w ± 3.4 ND ± 6.5 HFD 71 w Data are means ± SD. * ND, normal diet; ** HFD, high-fat diet

5 A Relative TNF-α gene expression (TNF-α/GAPDH) D Relative TNF-α gene expression (TNF-α/GAPDH) B E C F Fig. 2. Effect of caloric restriction (A~C) and rosiglitazone (ROS) treatment (D~F) on gene expression of inflammatory cytokines in subcutaneous abdominal adipose tissue of C57BL/6 mice. CR, mice fed calorically restricted normal diet; CC, control mice fed high-fat diet. Data are given as mean ± SEM. 게는 71주간의장기간동안의고지방식이섭취에의한지방조직사이토카인의변화양상은거의조사되지않았었다. 따라서본연구에서의변화양상을직접비교하기는어려우나, HFD군의생쥐에서두드러진사이토카인발현증가를확인하지못한이유에대해서는추가적인확인과정이필요하겠으나현단계에서저자들은장기간에걸친식이에의한대사적적응에의한것이라추측하고있다. 식이제한과 rosiglitazone 섭취에따른염증성사이토카인의발현량변화장기간에걸쳐이미비만화가진행되어대사특성이달라진생쥐에서도식이제한과 insulin sensitizer에의해지방조직의염증성사이토카인의발현양상변화가있는지관찰하기위해, 6주령부터 47주령까지 41주동안고지방식이만을섭취한비만생쥐를식이제한그룹 (CR) 과대조군 (CC) 으로나누어식이제한실험을 6주간수행하였

6 으며, 또한 rosiglitazone 섭취그룹과 vehicle만섭취한대조군으로나누어 rosiglitazone 섭취에의한영향확인실험을 2주간수행하였다. 각실험군과대조군에 8~9마리의비만생쥐 (47주령) 를사용하였고처리후의대조군과실험군의사이토카인발현량을서로비교하였으며, 또한 HFD군의 47주령에희생시킨생쥐 (Table 1, Fig. 1) 들을처리전의대조군으로삼아처리후발현량의비교에사용하였다 (Fig. 2). 칼로리제한실험의결과, 칼로리제한군 (CR) 의사이토카인발현량이통계적유의성은약하나처리전의 HFD군의 47주령생쥐에비해감소하는경향을보였고, 식이제한후의실험군 (CR) 과식이제한대조군 (CC) 과의비교에서는 IL-6 (CR 82 ± 12 vs. CC 171 ± 37, P<0.05) 와 MCP-1 (CR 137 ± 25 vs. CC 292 ± 59, P=0.01) 이통계적으로크게감소하는결과를나타냈다 (Fig. 1A~1C). 칼로리제한군 (CR) 의생쥐에서의이런사이토카인의발현감소는칼로리제한을통한체중감량에크게기인하는것으로사료된다 (CR 전 48.2 ± 2.2 vs. 후 41.6 ± 2.7 g, P<0.0001). 가장최근의한연구에서 Lijne et al. (Lijnen et al., 2012) 은본연구와매우유사한결과를보고하였다. 이들도 C57BL/6 생쥐를 50주동안 HFD로비만화시키고 6주동안식이제한결과복부피하지방조직에서 IL-6 는유의하게감소하였으나 TNF-α는변화되지않았다 (Lijnen et al., 2012). 이결과는매우유사한조건에서수행한본연구와매우동일한결과를나타내는것으로보아이조건에서식이제한이 TNF-α와 IL-6 발현에미치는영향으로재현성있는결과라여길수있겠다. PPARgamma agonist로써 insulin sensitizer 기능을하는 (Staels and Fruchart, 2005) rosiglitazone를섭취시킨결과 (Fig. 2D~2F), IL-6와 MCP-1의발현량은처리전의 HFD 군생쥐에비해처리후의 rosiglitazone 섭취군과 vehicle 섭취군의발현이동시에감소하는경향을보였으나통계적으로유의한변화는아니었으며, TNF-α의발현량의경우는 rosiglitazone 섭취군 (60 ± 6) 이 vehicle 섭취군 (208 ± 64) 과처리전의 47주령 HFD군 (208 ± 39) 에비해크게감소하였다 (P=0.006 and P=0.001, respectively). 이상의식이제한과 rosiglitazone 섭취에의한사이토카인발현변화는기존의연구결과들을토대로한예상과일치하며, 특히 TNF-α 발현은 rosiglitazone 섭취에의해더욱크게감소하였으며, IL-6와 MCP-1은칼로리제한에더욱크게변화하는경향을보였다. 이는 TNF-α가 IL-6 나 MCP-1에비해인슐린민감성에더욱민감하게조절 됨을나타내며, 41주동안고지방식이로비만화가유도된 47주령의비만생쥐에서도비교적짧은기간의식이제한이나 insulin sensitizer 섭취방법에의해염증성사이토카인의발현량감소로개선될수있음을나타낸다. 최근에비만과염증, 대사이상증후군과의복잡한관계를밝히는연구들이진행되고있다. 현재까지의연구결과들은비만은일종의염증상태이며이런염증상황이인슐린저항, 제2형당뇨, 고혈압, 동맥경화증등의많은비만합병증들의유발과깊이연관되어있음을보여주고있다. 그러나, 비만에서의이런염증상태의유발원인은복잡하며지방세포의사이토카인뿐만아니라지방조직에침투한대식세포도크게기여하는것으로보이나자세한사항은아직명료하지않다. 비만에따른지방조직의사이토카인조절에대한이해는비만합병증유발의예방과치료방법의개선발전에기여할것으로사료된다. 감사의글이연구는학부교육선진화선도대학지원사업에의해지원되었으며이에감사드립니다. REFERENCES Alkhouri N, Gornicka A, Berk MP, Thapaliya S, Dixon LJ, Kashyap S, Schauer PR, Feldstein AE. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem : Altintas MM, Rossetti MA, Nayer B, Puig A, Zagallo P, Ortega LM, Johnson KB, McNamara G, Reiser J, Mendez AJ, Nayer A. Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice. Lipids in Health and Disease : 198. Higuchi A, Ohashi K, Shibata R, Sono-Romanelli S, Walsh K, Ouchi N. Thiazolidinediones reduce pathological neovascularization in ischemic retina via an adiponectin-dependent mechanism. Arterioscler Thromb Vasc Biol : Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science : Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes : Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract