REVIEW Adiponectin 의임상적의미 서울대학교의과대학내과학교실, 분당서울대학교병원 임수 장학철 Clinical Implication of Adiponectin Soo Lim, Hak Chul Jang Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital Abstract Adipose tissue is now considered as an active hormone-secreting organ, which secretes a number of biologically active adipokines such as free fatty acids, leptin, tumor necrosis factor alpha (TNFα), interleukin-6, plasminogen activator inhibitor-1, adiponectin and retinol binding protein 4 (RBP4). Among these, adiponectin has attracted considerable attention as an adipokine that has important role in the development of type 2 diabetes, atherosclerosis and cardiovascular diseases. Adiponectin was discovered to be the most abundant adipose-specific transcript. Many epidemiological and clinical studies have demonstrated that serum levels of adiponectin are inversely associated with body weight, especially abdominal visceral fat accumulation. Studies among Japanese and Pima Indians have reported lower concentrations of adiponectin in patients with type 2 diabetes than in those with normal glucose tolerance. A low level of adiponectin was found to be a significant risk factor for the development of cardiovascular events in the Korean patients with type 2 diabetes. We recently published that exercise, having an insulin-sensitizing effect, could be a good therapy to prevent or delay diabetes and cardiovascular diseases in middle-aged women through the modification of adiponectin. These results suggest that the clinical implication of adiponectin. A number of studies have been conducted to clarify the biological role of adiponectin. Recent studies have showed that adiponectin has anti-inflammatory, anti-atherogenic, and glucose-lowering properties. Taken together, it is conceivable that adiponectin plays as a backbone of metabolic syndrome. Finally, pleiotropic functions of adiponectin may possibly serve to prevent and treat atherosclerosis, type 2 diabetes and cardiovascular diseases. Furthermore, enhancement of adiponectin secretion or action may be a good therapeutic target for preventing type 2 diabetes or cardiovascular diseases. (KOREAN DIABETES J 32:85-97, 2008) Key Words: Adipokine, Adiponectin, Atherosclerosis, Insulin resistance, Metabolic syndrome 서론비만, 특히복부비만은고지혈증, 당뇨병, 고혈압, 심혈관계질환의중요한위험인자이다. 하지만비만이어떻게이러한질환을유발하는지에대해서는잘알려지지않고있다. 일본의오사카대학의 Matsuzawa 교수연구진은지방조직의특성을규명하기위하여사람의피하지방과내장지방에 서유전자발현특성에대한연구를시행하였다 1). 이를통해약 1,000개의지방특이적인유전자를규명하였는데그중약 60% 는이미잘알려진유전자였으며나머지 40% 는새로운것들이었다 2). 당시만해도지방조직은에너지를저장하는수동적인기관으로생각되었는데놀랍게도매우많은유전자들이혈중으로유리되는분비단백을표지하고있었다 3). 피하지방에서는발현되는유전자의약 20% 가분비 85
Fig. 1. Structure of adiponectin. This 244-amino-acid protein contains a signal sequence, and a collagen-like domain at the N-terminus and a C1q-like globular domain at the C-terminus. Some units of the trimer of adiponectin are bound in a bouquet-like formation in plasma. [Reproduced with permission from Matsuzawa et al. (2004) Arterioscler Thromb Vasc Biol 24:29-33] 되는단백이었으며내장지방에서는그빈도가약 30% 까지증가하였다 2,3). 이러한지방조직에서유래되어타기관에서활성을갖는단백질들을 Adipocytokine이라고명명하였다 3). Matsuzawa 교수연구진이발견한이단백질은신호단백 (signal protein) 과콜라겐모티프 (collagen motif) 를갖고있었는데이단백질이아디포넥틴 (Adiponectin) 이라고명명되었다 (Fig. 1). 아디포넥틴은유사한시기에 Nakano 등에의하여사람혈중에서 gelatin-binding protein-28이라는단백질로분리되기도하였다 4). 또한생쥐에서는 ACRP30과 AdipoQ라는이름으로동정되기도하였다 5,6). 하지만당시로써는이새로운단백질의임상적인중요성에대해서별로알려진것이없었다. 이후 ELISA 방법을이용하여혈중아디포넥틴농도를측정하는방법을개발하였고이를통하여아디포넥틴의임상적의의를규명할수있게되었다 7). 1. 구조 아디포넥틴의구조적특성 (Structure of Adiponectin) 아디포넥틴을표지하는유전자는 3번염색체장완 27에위치하며이부위는광범위유전체연관성연구를통하여당뇨병의위험을증가시키는곳으로최근에보고되고있다 8,9). 이단백질은 244개의아미노산으로구성되어있으며신호서열 (signal sequence), N-말단 (N-terminal) 에위치한 collagen-like domain과 C-말단 (C-terminal) 에위치한 C1q -like globular domain을포함하고있다 (Fig. 1). Globular domain은 collagen VIII, X, complement factor C1q와서 열이유사하다. 두개의중요한소중합체 (oligomer) 형태는육합체 (hexamer) 와 400-kDa의고분자복합체 (HMW complex) 이다. 고분자복합체는저분자복합체 (LMW complex) 보다더활성이높은것으로알려져있다 10). 아디포넥틴은 globular domain을포함하는더작은단위로분해되기도한다 11). 전체길이를갖는아디포넥틴보다 globular domain을갖는소단위가더활성이높다고보고되고있다. 하지만생리학적인수준에서어느소단위가얼마나많은부분을차지하며생물학적인활성이얼마나되는지에대해서는아직많은연구가필요하다. 2. 위치아디포넥틴의 mrna는지방조직에서만발현되는것으로알려져왔으나 1,6), 최근연구에의하면골수, 조골세포, 태아조직, 근육세포, 심근세포, 타액선상피세포에서도일부발현되는것으로보고되고있다 12). 하지만성인에서아디포넥틴이가장많이생성되는곳은지방세포이다. 성인에서혈중아디포넥틴의농도는약 3~30 μg/ml 정도이다. 태아의배꼽정맥에서측정한아디포넥틴의농도는 30 μg/ml 정도이다 13). 3. 분비여러대사경로에 Adipocytokine이중요함에도불구하고어떻게이들이분비되는지에대하여는잘알려지지않았다. 세포내에서아디포넥틴은주로골지체 (Golgi apparatus) 혹은골지간네트워크 (trans-golgi network, TGN) 에위치한다 14). 3T3-L1 지방세포에골지체이후이동경로 (post -Golgi trafficking pathway) 를억제하는 brefeldina (BFA) 를투여 86
임수외 1 인 : Adiponectin 의임상적의미 할경우아디포넥틴의분비가현격히감소하였다 15). 아마도아디포넥틴을골지체 /TGN으로부터세포막으로이동시키는경로가존재할것으로생각된다. 더군다나분획분석 (fractional analysis) 결과아디포넥틴의분획은 transferrin receptor-positive membrane 분획과중복되는것으로나타났고이는아디포넥틴의분비가 transferrin receptor-positive endosomal system을이용할가능성을보여준다 16). 4. 수용체 2003년에두개의아디포넥틴수용체가밝혀졌다 17). AdipoR1은골격근육에서발현이많으며 globular 아디포넥틴의수용체이다. AdipoR2는주로간에서발현되며전체길이의아디포넥틴의수용체이다. AdipoR1과 AdipoR2는시상하부에서도발현되며특히에너지대사에관여하는 paraventricular nucleus (PVN) 에서는 AdipoR2의발현이증가되어있었다 18). 이수용체들은 seven-transmembranespaning G protein-coupled receptor에속한다. 이들수용체의생리학적인기능및신호전달체계에대한연구는아직부족하다. 흥미로운것은혈중아디포넥틴의농도는통상의싸이토카인에비하여월등히높다. 따라서아디포넥틴의작용중일부는수용체를통하지않고나타날수있을것이다. 즉아디포넥틴의저친화성거대분자상호작용 (low affinity macromolecular interaction) 에의해그기능을수행할가능성이있다. 아디포넥틴의임상적중요성및역할 (Clinical Meaning and Role of Adiponectin) 1. 비만 현재까지아디포넥틴의혈중농도와다양한질병과의상관관계에대한많은논문이보고되었다. 그중에서가장두드러진것은혈중아디포넥틴의농도가체질량지수와음의상관관계를갖는다는것이다 7). 더욱이체중감량은혈중아디포넥틴의농도를증가시키는것으로나타났다 19). 아디포넥틴과비만이갖는음의상관관계는피하지방보다는내장지방과더욱명확하다 20,21). 내장지방이증가된사람에서어떠한기전으로아디포넥틴이감소하는지는아직밝혀지지않았다. 하지만한가지가능한설명은아디포넥틴유전자의프로모터를강력히억제할수있는 TNFα의발현이내장지방이축적할수록증가한다는것이다 22). 2. 대사증후군현재아디포넥틴은대사증후군의가장중요한요소로평가되고있으며, 대사증후군은심혈관계질환을예방하기위하여개선해야할목표로인식되고있다. 중년의성인에서저아디포넥틴혈증은대사질환유무와관련이있는것으로나타났다 23). 한국노인을대상으로한전향적연구에서는아디포넥틴이대사증후군발병에미치는영향이증명되기도하였다 24). 661명의일본성인을대상으로한연구에서는대사증후군의구성요소가증가할수록아디포넥틴의농도가감소하는것으로나타났다 25). 유전자연구를통하여아디포넥틴과관련된유전자변이 4종류가발견되었다. 이러한변이들중에 1164T 변이는현격한저아디포넥틴혈증을일으켰다. 특히 1164T 변이가있는경우대부분이고혈압과고지혈증을보였으며전원이당뇨병을포함하는당대사의장애를보였다 26). 이러한결과들은유전적으로아디포넥틴의농도가감소되어있는사람들이유전적으로대사증후군을갖게될가능성이높다는것을시사한다. 3. 당뇨병일본의 Matsuzawa Y. 그룹은당뇨병환자에서대조군에비하여유의하게아디포넥틴농도가감소되어있다는것을관찰하였다 27). 또한비만과당뇨병의유병률이피마인디언들을대상으로한연구에의하면아디포넥틴농도가높았던사람들은아디포넥틴농도가낮았던사람들에비하여당뇨병으로진행할확률이낮은것으로나타났다 28). 상기연구에서고아디포넥틴혈증은낮은복부둘레, 공복시혈당, 식후 2시간째혈당, 공복시인슐린농도보다당뇨병발병의위험을낮추는데중요한요인인것으로나타났다. 인도및서양인에서도저아디포넥틴혈증이향후당뇨병발병을예측할수있는것으로보고되고있다 29,30). 비만과당뇨병이동시에있는원숭이를대상으로한연구에따르면아디포넥틴농도의감소는당뇨병발병에선행하였으며인슐린감수성과평행하게감소하였다 31). 이러한결과들은아디포넥틴이당뇨병발병에중요하다는점을분명히해주고있다. 임상적으로중요한점은아디포넥틴이인슐린감수성을증가시키는역할을한다는것이다. 아디포넥틴을정맥으로주입하면간에서포도당신생성과관련된효소를억제함으로써혈당의상승을억제하였다 32). 아디포넥틴중에서도특히 globular domain이인슐린감수성을증가시키는데더효과적이었다 11,32-35). 아디포넥틴은근육및간에서 AMPK를자극함으로써혈당의이용및지방산산화를증가시키고궁극적으로인슐린감수성을증가시킬것으로생각된다 35,36). 87
Fig. 2. Effect of exercise on adiponectin concentration and relationship with insulin resistance. [Reproduced with permission from Lim et al. (2008) J Clin Endocrinol Metab. Epub ahead of print] 아디포넥틴유전자제거생쥐 (KO mice) 에서정상적인사료를먹였을때는특이한형질을보이지않았으나고지방고슈크로스 (sucrose) 사료를먹였을때는혈당및인슐린농도가상승하고인슐린저항성이증가하였는데, 이생쥐들에게아디포넥틴을투여하면다시인슐린저항성이호전되는것을볼수있었다 37). 본연구진은젊은여성 30명과, 중년여성 30명을대상으로 10주간유산소운동을시행하고시행전후의아디포넥틴농도의변화및인슐린민감도지표와의관련성을조사하였다. 결과적으로양군에서모두유의하게아디포넥틴의농도가증가하였으며, 이러한증가정도는인슐린저항성지표와유의한상관성을보여주었다 (Fig. 2) 38). 이러한결과는운동의인슐린감수성개선효과에있어서아디포넥틴이적어도매개역할을할것을시사한다 39). 또한당뇨병쥐의간에 AdipoR1과 AdipoR2를과발현시키면각각 AMPK 활성과 peroxisome proliferatoractivated receptor-α 신호를증가시키는것으로나타났다. AdipoR1 혹은 AdipoR2가제거된생쥐들은인슐린저항성을보였다. 이러한결과들은인슐린저항성이나타나는데아디포넥틴수용체도일정부분관여한다는사실을보여준다 40). 아디포넥틴은수용체에결합하여 AMPK 경로를활성화하며이는 IRS의 serine 인산화를억제하고 tyrosine 인산화를촉진하여인슐린감수성을증가시킨다 41). 4. 심혈관계질환아디포넥틴이갖는임상적중요성중의하나는허혈성심장질환을갖는사람들에서감소되어있다는점이다 42). 말기신부전환자를 4년간추적해본결과아디포넥틴의농도가감소되어있었던사람들은심혈관계질환으로사망할가능성이유의하게증가되어있었다 43). 이러한자료들은저아디토넥틴혈증이죽상동맥경화증의중요한위험인자임을시 Fig. 3. Cumulative hazard rates for primary outcome (MI, stroke, unstable angina, CABG or PCI) in 42 months follow-up: comparison of quartiles of adiponectin at baseline [Reproduced with permission from Lim et al. (2008) Atherosclerosis 196:398-404 사한다. 더욱이, 전향적인연구에서도혈중아디포넥틴의농도가높았던사람들은혈중아디포넥틴농도가중간혹은낮았던사람들에비하여유의하게심혈관질환의발생을경험할확률이감소되어있었다 44). 본연구진은한국인제2형당뇨병환자 343명을대상으로 42개월간전향적연구를진행한결과, 기저아디포넥틴농도가낮으면심혈관계질환의발생이유의하게높음을보고하였다 (Fig. 3) 45). 이러한상관관계는전통적인심혈관위험인자인고혈압혹은당뇨병의유무와독립적이었다 44,45). 또한여러단면연구 (cross sectional study) 에서도아디포넥틴의농도와심혈관계질환이관련되어있다는것이보고되었다 27,46). 그리고이러한차이는당뇨병, 고지혈증, 고혈압, 흡연, 비만등다른요인을보정을한 88
임수외 1 인 : Adiponectin 의임상적의미 후에도유의한것으로나타났다 42). 저아디포넥틴혈증은심혈관계질환뿐만아니라경동맥의죽상경화증과도상관관계를보였다 47). 관상동맥죽상반의취약성은급성관동맥증후군 (acute coronary syndrome) 이발병하는데중요한요소이다. 혈중아디포넥틴의농도는급성관동맥증후군환자에서안정성협심증 (stable angina) 환자에비하여유의하게낮게측정되었다. 다변량분석결과저아디포넥틴혈증은급성관동맥증후군이나타나는데독립적인위험요인인것으로밝혀졌다 48). 더우기, 남성에서는관상동맥질환이복합적일수록아디포넥틴농도가감소되어있는것도보고되었다 49). 이러한자료들은아디포넥틴이죽상반의취약성에있어서매우중요한역할을한다는것을시사한다. 5. 고혈압최근의연구들은저아디포넥틴혈증이고혈압에도중요함을보여주고있다. 한환자대조군연구에의하면고혈압환자에서혈중아디포넥틴이낮게측정되었으며아디포넥틴농도는평균, 수축기, 이완기혈압과유의한음의상관관계를갖고있었다 50). 758명의고혈압과정상인을대상으로한연구에서다변량회귀분석을시행하였을때혈중아디포넥틴농도는고혈압의독립적인위험인자였다 51). 특히남성에서는혈압정도와아디포넥틴농도간에유의한상관관계를보였다 52). 고혈압에있어서아디포넥틴이중요하다는사실은생쥐를이용한실험에서도밝혀진바있다. 비만한생쥐에서아데노바이러스를이용하여아디포넥틴을과발현시키면혈압이감소되었던것이다. 이러한기전으로 endothelial NO synthase (enos) and prostaglandin I(2) synthase의감소를들수있으며, 이러한결과는저아디포넥틴혈증이적어도일부분에서는직접적으로고혈압을일으킬수있음을시사하고있다 53). 6. 고지혈증아디포넥틴이고지혈증과관련이있다는사실도잘밝혀져있다 21,23,54-56). 혈중아디포넥틴농도는 HDL-C 농도와양의상관관계를보였으며중성지방및 apolipoprotein (Apo) B-100과는음의상관관계를보였다. 그리고이러한상관관계는비만과관련된변수들을보정한이후에도유의하였다. 최근의연구는아디포넥틴이간세포에직접작용함으로써지질대사에영향을준다는사실을밝혀냈다 56). 고분자복합체 (HMW) 아디포넥틴은간세포에서 ApoB와 ApoE 의유리를감소시켰으며 ABCA1 및 ApoA-I에는영향을미치지않았다. 더군다나, 고분자복합체 (HMW) 아디포넥틴은 hepatic nuclear factor 4-α (HNF4-α) 유전자및 HNF4-α에 의해영향을받는 ApoB 유전자의발현을감소시켰다 57). 이러한기전은내장지방축적시간문맥정맥에서고지혈증과저아디포넥틴혈증이관찰되는사실을설명해줄수있을것이다. 임상적으로매우중요한점은아디포넥틴이고혈압, 고지혈증및심혈관계질환에있어서보호효과가있다는것이알려지고있다. Shimomura 그룹에의해서혈중아디포넥틴이혈관벽으로침투할수있다는사실을관찰하였다. 렛드 (Rat) 의경동맥을면역화학염색하였을때는아디포넥틴을검출할수없었다. 하지만풍선에의한경동맥손상 (balloon -injured vascular wall) 을유발한이후에는아디포넥틴이검출되었다 58). 또한아디포넥틴은 collagen V, VIII, X 같은내피하콜라겐에부착하였다. 혈관내피의손상이발생하면이를통하여아디포넥틴이침투하고내피하의콜라겐에부착하는것으로생각된다. 아디포넥틴은혈관내피세포, 대식세포, 혈관평활근세포에이롭게작용하여동맥경화증을억제할것이다. 아디포넥틴농도감소는내피세포기능의저하에도영향을미친다 59). 아디포넥틴농도는정상인및당뇨병환자에서내피세포의존적혈관확장 (endothelium dependent vasodilation) 과음의상관관계를가졌다 60). 강력한혈관확장인자인 nitric oxide (NO) 가아디포넥틴의혈관에대한효과를매개하는것으로보인다 61). 아디포넥틴은산화 LDL (oxldl) 이 endothelial NO synthase (enos) 의활성을억제하는것을완화하여준다. 또한아디포넥틴은 AMPactivated protein kinase (AMPK) 에의한 enos의인산화과정에관여하는 phosphatidylinositol 3-kinase (PI3K) 경로를통하여 NO 생성을촉진한다 61). 흥미롭게도 Adiponectin 유전자가제거된생쥐 (knockout mice) 에서는내피세포의존적인혈관확장이현저히줄어들었다 62). 이외에도내피세포표면의결합분자들 (adhesion molecules) 은대식세포가혈관벽에부착하는데중요하다. TNF-α에의해이러한결합분자들의발현이증가하는현상은아디포넥틴에의해억제되었으며이러한반응은용량의존적이었다 46). 대식세포에서 scavenger receptor class A-1 (SR-A) 는 oxldl의흡수와 foam cell의형성에관여하는데아디포넥틴은이 SR-A의발현을억제한다 63). Foam cell은다양한 matrix metalloproteinases (MMP) 를생성하며이는죽상반을취약하게만들어서심혈관질환의발생을촉진한다 64). 또한아디포넥틴은 IL-10을통하여 tissue inhibitor of MMP (TIMP) 의발현과분비를촉진하여 MMP의기능을억제한다. 궁극적으로아디포넥틴은죽상반이파열되는것을막는 89
Fig. 4. Antiatherogenic effects of adiponectin. [Reproduced with permission from Matsuzawa et al. (2004) Arterioscler Thromb Vasc Biol 24:29-33] 데일정역할을할것으로생각된다. 직접적으로아디포넥틴은동맥경화의진행에중요한혈관평활근세포의분열과이동을억제한다. 이과정은아디포넥틴이경쟁적으로 platelet-derived growth factor (PDGF) -BB 수용체에결합하여 extracellular signal-related kinase (ERK) 를억제함으로써나타난다 65). 아디포넥틴은또한 heparin-binding epidermal growth factor-like growth factor (HB-EGF) 를자극함으로써평활근의분열과이동을억제하였다. 염증반응의신호, oxldl, 산화스트레스등이내피세포의손상을가져올수있는데아디포넥틴은손상된내피세포로이동하여염증반응의신호를억제하고동맥경화를예방하는기능을한다 (Fig. 4) 66). 7. 염증반응 (Inflammation) 염증반응이심혈관계질환을예측한다는사실은잘알려져있다. 염증반응은심혈관계질환뿐만아니라대사증후군의중요한병태생리기전으로이해되고있다. 여러연구에서심혈관계질환및대사증후군환자뿐만아니라정상인에서도아디포넥틴농도가염증반응의척도인 TNF-α, interleukin 6, C-reactive protein (CRP) 과음의상관관계가있다는것이보고되고있다 67-70). 흥미롭게도지방조직에서 CRP가발현된다는사실이알려졌으며지방세포내아디포넥틴의양과 CRP는음의상관관계가있음을관찰하였다 68). 아디포넥틴이동맥경화발생과정중에항염증효과를갖는다는것이여러연구들에서입증되었다. Nuclear transcription factor B (NF-kB) 는염증반응과정중에서싸이토카인과부착단백 (adhesion molecule) 의발현을증가시킨다. 아디포넥틴은 TNF-α에의한 NF-kB의활성화를억제 하였으며이것은 TNF-α에의한다른인산화신호들과는독립적으로발생하였다 71). 동맥경화가잘생기는 apolipoprotein E-deficient mice 모델에아디포넥틴을투여한결과동맥경화를줄였다 38). 또한아디포넥틴유전자가제거된생쥐에아데노바이러스를이용하여아디포넥틴을발현시키면지방조직에서 TNF-α의발현이감소하였으며혈중 TNF-α의농도도감소하였다 37). TNF-α 외에산화스트레스도염증반응을유발한다. 아디포넥틴은 oxldl에의한세포분열을억제하며세포내활성산소의발생을억제한다 72). 최근의연구에의하면아디포넥틴은 calreticulin 관련경로를통하여사멸단계의초기에있는세포들을제거하는것으로나타났다 73). 아디포넥틴이복합체를형성하는것이 NF-kB 경로를활성화하는데중요한것으로보인다 74). 아디포넥틴의임상적적용 (Clinical Application of Adiponectin) 아디포넥틴이임상적으로이용될가능성은우선동물모델에서시험되었다. 아디포넥틴유전자가제거된생쥐 (KO mice) 는동맥혈관손상시신생내막 (neointima) 이과도하게증가한다 75,76). 이러한생쥐에아데노바이러스를이용하여아디포넥틴을과발현시키면혈관내평활근의증식이억제되고신생내막 (neointima) 의증식도감소한다 76). 이결과는아디포넥틴을증가시키면혈관성형술이후에동맥의재협착이발생하는것을억제할수있을가능성을제시해준다. 평활근이외에 foam cell도동맥경화병변의주요구성요소이다. Apolipoprotein E 유전자가제거된생쥐 (KO mice) 는 foam cell의증가를동반한동맥경화증의좋은동물모델이다. 이생쥐들에아데노바이러스를이용하여아디포넥틴을과발현시킨결과, 바이러스주입 2주후죽상반의면적이대조군에비하여감소하였다 38). 또한동맥경화가발생한병변에포함된지방입자의크기도감소하였다. 면역조직화학염색을시행한결과아데노바이러스를통해과발현된아디포넥틴은 fatty streak lesion에집중되어있었다. 이러한결과들은혈중아디포넥틴의농도를상승시키는것이심혈관질환을예방하는데좋은방법이될것이라는가설을뒷받침해준다. PPARγ 경로는아디포넥틴발현을증가시키는데중요하다. 실제로 PPARγ 작용제인 thiazolidinedione은혈중아디포넥틴을상승시킨다 76-78). 트로글리타존 (troglitazone) 은경도의비만을보이며당불내성을보이는사람들에서혈중아 90
임수외 1 인 : Adiponectin 의임상적의미 Fig. 5. Status and role of adiponectin in metabolic syndrome and related disorders. 디포넥틴의농도를약 3배증가시켰다 22). 이러한효과는당뇨병환자, 마른정상인및비만한정상인에서도관찰되었다 22,77). 다른연구에서당뇨병환자를대상으로한무작위위약대조군연구에서로지글리타존 (rosiglitazone) 의투여는아디포넥틴의농도를약 2배이상증가시켰다 78). 아울러피오글리타존 (pioglitazone) 은고분자복합체 (HMW) 대총아디포넥틴의비율을증가시켰으며이것은간에서인슐린감수성을증가시키는것과관련이있었다 79). PPARγ 작용제는지방조직에서아디포넥틴 mrna의발현을증가시켰으며 3T3-L1 지방세포에서는투여용량과시간에비례하여아디포넥틴의발현과분비를증가시켰다 22). 사람과생쥐에서피오글리타존은고분자복합체아디포넥틴의분비만을촉진하며저분자형태의아디포넥틴에는영향이없었다 80). PPARγ 작용제뿐만아니라 fibrate들도아디포넥틴을상승시키는데유용하다. 대조군에비하여 bezafibrate를투여받은사람들에서아디포넥틴의농도가유의하게증가하였다 81). Bezafibrate와 fenofibrate는생쥐와 3T3-L1 지방세포에서아디포넥틴을증가시켰다. 또한 fibrate에의한아디포넥틴발현의증가는 PPAR responsive element (PPRE) 를통해서나타난다는사실이밝혀졌다 81). 더군다나, 사람에서는 AdipoR2가 PPARγ 및 PPARα agonist에의하여발현이증가하였다 82). 아디포넥틴의발현을상승시키는방법으로아디포넥틴유전자의 promoter를활성화시킬수있다. 아디포넥틴유전자의 promoter 영역에는두가지의반응요소 (responsive element) 가있는데, 하나는 PPAR responsive element (PPRE) 이고다른하나는고아핵수용체 (orphan nuclear receptor) 인 liver receptor homolog-1 (LRH-1) 이었다. LRH-1은 PPARγ에의 한아디포넥틴의발현을증폭시켰다 83). 이러한결과는 PPAR γ와 LRH-1이각각 PPRE와 LRH-RE를통해아디포넥틴유전자의발현을증가시키는데매우중요한역할을한다는것을시사한다. 결론지방조직에특이적인단백을찾는과정에서발견된아디포넥틴은다양한종류의질환과관련되어있었다. 특히지방세포에서분비된다는점에서비만과의연관성에관심을가지게되었으며, 내장지방의축적은혈중아디포넥틴의농도를감소시켰다. 또한아디포넥틴은비만관련질환및동맥경화증에직접적인영향을갖는것으로밝혀졌다. 따라서아디포넥틴은대사증후군의발병에핵심적인역할을하는것으로여겨진다 (Fig. 5). 아디포넥틴이갖는다양한기능은이것이비만관련질환및심혈관계질환의예방및치료에사용될가능성이있음을보여준다. 아디포넥틴의분비를촉진하거나그활성을증가시킬수있는방법을찾는것은대사관련질병을극복하는데중추적인역할을할것으로기대된다. 참고문헌 1. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K: cdna cloning and expression of a novel adipose specific collagen-like factor, apm1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221:286-9, 1996 91
2. Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K: Analysis of an expression profile of genes in the human adipose tissue. Gene 190:227-35, 1997 3. Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y: Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 38:202-6, 1999 4. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M: Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 120:803-12, 1996 5. Hu E, Liang P, Spiegelman BM: AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697-703, 1996 6. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746-9, 1995 7. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79-83, 1999 8. Takahashi M, Arita Y, Yamagata K, Matsukawa Y,Okutomi K, Horie M, Shimomura I, Hotta K, Kuriyama H, Kihara S, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord 24:861-8, 2000 9. Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Haring H: Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 51:37-41, 2002 10. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE: Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem 278:9073-85, 2003 11. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF: Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005-10, 2001 12. Pineiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, Dieguez C, Gualillo O, Gonzalez-Juanatey JR, Lago F: Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett 579:5163-9, 2005 13. Corbetta S, Bulfamante G, Cortelazzi D, Barresi V, Cetin I, Mantovani G, Bondioni S, Beck-Peccoz P, Spada A: Adiponectin expression in human fetal tissues during mid- and late gestation. J Clin Endocrinol Metab 90:2397-402, 2005 14. Bogan JS, Lodish HF: Two compartments for insulinstimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4. J Cell Biol 146: 609-20, 1999 15. Feng L, Arvan P: The trafficking of alpha 1- antitrypsin, a post-golgi secretory pathway marker, in INS-1 pancreatic beta cells. J Biol Chem 278:31486-94, 2003 16. Clarke M, Ewart MA, Santy LC, Prekeris R, Gould GW: ACRP30 is secreted from 3T3-L1 adipocytes via a Rab11-dependent pathway. Biochem Biophys Res Commun 342:1361-7, 2006 17. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T: Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762-9, 2003 18. Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S, Snead DR, Hoggart B, O'Hare JP, McTernan PG, Kumar S: Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin 92
임수외 1 인 : Adiponectin 의임상적의미 receptors in the human hypothalamus. J Clin Endocrinol Metab 92:1129-36, 2007 19. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM: Weight reduction increases plasma levels of an adiposederived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86:3815-9, 2001 20. Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, Nakai Y, Ishibashi S: Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 52:1274-8, 2003 21. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE: Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459-69, 2003 22. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y: PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094-9, 2001 23. Hulthe J, Hulten LM, Fagerberg B: Low adipocytederived plasma protein adiponectin concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study. Metabolism 52:1612-4, 2003 24. Choi KM, Lee J, Lee KW, Seo JA, Oh JH, Kim SG, Kim NH, Choi DS, Baik SH: Serum adiponectin concentrations predict the developments of type 2 diabetes and the metabolic syndrome in elderly Koreans. Clin Endocrinol (Oxf) 61:75-80, 2004 25. Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T: Adiponectin as a biomarker of the metabolic syndrome. Circ J 68:975-81, 2004 26. Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K, Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y: Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol 43:1195-200, 2004 27. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y: Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595-9, 2000 28. Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J: Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360:57-8, 2002 29. Snehalatha C, Mukesh B, Simon M, Viswanathan V, Haffner SM, Ramachandran A: Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians. Diabetes Care 26:3226-9, 2003 30. Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, Tataranni PA: Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 51:1884-8, 2002 31. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y: Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126-33, 2001 32. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L: Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108: 1875-81, 2001 33. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota 93
N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama -Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941-6, 2001 34. Stefan N, Stumvoll M, Vozarova B, Weyer C, Funahashi T, Matsuzawa Y, Bogardus C, Tataranni PA: Plasma adiponectin and endogenous glucose production in humans. Diabetes Care 26:3315-9, 2003 35. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288-95, 2002 36. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB: Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-coa carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 99:16309-13, 2002 37. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y: Diet-induced insulin resistance in mice lacking adiponectin/acrp30. Nat Med 8:731-7, 2002 38. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y: Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106:2767-70, 2002 39. Lim S, Choi SH, Jeong IK, Kim JH, Moon MK, Park KS, Lee HK, Kim YB, Jang HC: Insulin-sensitizing Effects of Exercise on Adiponectin and Retinol Binding Protein-4 Concentrations in Young and Middle-aged Women. J Clin Endocrinol Metab, 2008 40. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T: Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332-9, 2007 41. Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, Dong LQ, Liu F: Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem 282:7991-6, 2007 42. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y: Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23:85-89, 2003 43. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y: Adiponectin, metabolic risk factors, and cardiovascular events among patients with end -stage renal disease. J Am Soc Nephrol 13:134-41, 2002 44. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB: Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291:1730-7, 2004 45. Lim S, Koo BK, Cho SW, Kihara S, Funahashi T, Cho YM, Kim SY, Lee HK, Shimomura I, Park KS: Association of adiponectin and resistin with cardiovascular events in Korean patients with type 2 diabetes: the Korean atherosclerosis study (KAS): a 42-month prospective study. Atherosclerosis 196: 398-404, 2008 46. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, 94
임수외 1 인 : Adiponectin 의임상적의미 Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100:2473-6, 1999 47. Kojima S, Funahashi T, Maruyoshi H, Honda O, Sugiyama S, Kawano H, Soejima H, Miyamoto S, Hokamaki J, Sakamoto T, Yoshimura M, Kitagawa A, Matsuzawa Y, Ogawa H: Levels of the adipocyte -derived plasma protein, adiponectin, have a close relationship with atheroma. Thromb Res 115:483-90, 2005 48. Nakamura Y, Shimada K, Fukuda D, Shimada Y, Ehara S, Hirose M, Kataoka T, Kamimori K, Shimodozono S, Kobayashi Y, Yoshiyama M, Takeuchi K, Yoshikawa J: Implications of plasma concentrations of adiponectin in patients with coronary artery disease. Heart 90:528-33, 2004 49. Otsuka F, Sugiyama S, Kojima S, Maruyoshi H, Funahashi T, Matsui K, Sakamoto T, Yoshimura M, Kimura K, Umemura S, Ogawa H: Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease. J Am Coll Cardiol 48:1155-62, 2006 50. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y: Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 16:72-5, 2003 51. Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi T, Rakugi H, Matsuzawa Y, Ogihara T: Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 43:1318-23, 2004 52. Mallamaci F, Zoccali C, Cuzzola F, Tripepi G, Cutrupi S, Parlongo S, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y: Adiponectin in essential hypertension. J Nephrol 15:507-11, 2002 53. Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I: Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47:1108-16, 2006 54. Zietz B, Herfarth H, Paul G, Ehling A, Muller-Ladner U, Scholmerich J, Schaffler A: Adiponectin represents an independent cardiovascular risk factor predicting serum HDL-cholesterol levels in type 2 diabetes. FEBS Lett 545:103-4, 2003 55. Schulze MB, Rimm EB, Shai I, Rifai N, Hu FB: Relationship between adiponectin and glycemic control, blood lipids, and inflammatory markers in men with type 2 diabetes. Diabetes Care 27:1680-7, 2004 56. Matsubara M, Maruoka S, Katayose S: Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 87:2764-9, 2002 57. Neumeier M, Sigruener A, Eggenhofer E, Weigert J, Weiss TS, Schaeffler A, Schlitt HJ, Aslanidis C, Piso P, Langmann T, Schmitz G, Scholmerich J, Buechler C: High molecular weight adiponectin reduces apolipoprotein B and E release in human hepatocytes. Biochem Biophys Res Commun 352:543-8, 2007 58. Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y: An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32:47-50, 2000 59. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T, Ueda S, Shimomura I, Funahashi T, Matsuzawa Y: Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88:3236-40, 2003 60. Tan KC, Xu A, Chow WS, Lam MC, Ai VH, Tam SC, Lam KS: Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 89:765-9, 2004 61. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ: Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278:45021-6, 2003 62. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Nagasawa A, 95
Kobayashi H, Hiraoka H, Komai N, Kaibe M, Rakugi H, Ogihara T, Matsuzawa Y: Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42:231-4, 2003 63. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y: Adipocyte -derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103:1057-63, 2001 64. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y: Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin -10 expression in human macrophages. Circulation 109:2046-9, 2004 65. Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y: Adipocyte -derived plasma protein adiponectin acts as a platelet -derived growth factor-bb-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105:2893-8, 2002 66. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I: Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 24:29-33, 2004 67. Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, Mohlig M, Pfeiffer AF, Luft FC, Sharma AM: Association between adiponectin and mediators of inflammation in obese women. Diabetes 52:942-7, 2003 68. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y: Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107: 671-4, 2003 69. Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC, Lindsay RS: Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care 26:1745-51, 2003 70. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G: Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52:1779-85, 2003 71. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Adiponectin, an adipocyte -derived plasma protein, inhibits endothelial NF -kappab signaling through a camp-dependent pathway. Circulation 102:1296-301, 2000 72. Motoshima H, Wu X, Mahadev K, Goldstein BJ: Adiponectin suppresses proliferation and superoxide generation and enhances enos activity in endothelial cells treated with oxidized LDL. Biochem Biophys Res Commun 315:264-71, 2004 73. Takemura Y, Ouchi N, Shibata R, Aprahamian T, Kirber MT, Summer RS, Kihara S, Walsh K: Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J Clin Invest 117:375-86, 2007 74. Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF: Oligomerization state-dependent activation of NFkappa B signaling pathway by adipocyte complementrelated protein of 30 kda (Acrp30). J Biol Chem 277:29359-62, 2002 75. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863-6, 2002 76. Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara 96
임수외 1 인 : Adiponectin 의임상적의미 S, Nagai R, Funahashi T, Matsuzawa Y: Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277:37487-91, 2002 77. Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M, Olefsky JM: The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968-74, 2002 78. Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM: Synthetic peroxisome proliferator-activated receptor -gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25:376-80, 2002 79. Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C, Scherer PE, Hawkins M: Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 53:1621-9, 2004 80. Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ: Pioglitazone increases secretion of high-molecular-weight adiponectin from adipocytes. Am J Physiol Endocrinol Metab 291:E1100-5, 2006 81. Hiuge A, Tenenbaum A, Maeda N, Benderly M, Kumada M, Fisman EZ, Tanne D, Matas Z, Hibuse T, Fujita K, Nishizawa H, Adler Y, Motro M, Kihara S, Shimomura I, Behar S, Funahashi T: Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level. Arterioscler Thromb Vasc Biol 27:635-41, 2007 82. Chinetti G, Zawadski C, Fruchart JC, Staels B: Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR. Biochem Biophys Res Commun 314:151-8, 2004 83. Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I: Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52:1655-63, 2003 97