농림수산식품부장관귀하 이보고서를 팥의대사성질환개선및기능성규명 에관한연구의최종보고서로제출 합니다 년 2 월 11 일 - 1 -

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1 농림수산식품부장관귀하 이보고서를 팥의대사성질환개선및기능성규명 에관한연구의최종보고서로제출 합니다 년 2 월 11 일 - 1 -

2 연구기관명 : 부산대학교 연구책임자 : 정명호 연구원 : 손용해 연구원 : 장민경 - 2 -

3 Ⅰ. 제목 팥의대사성질환개선및기능성규명 Ⅱ. 연구개발의목적및필요성 팥의대사성질환개선소재발굴과그기능성을과학적으로증명하기위해, 팥의당뇨, 비만및비알코올성지방간질환의개선과이에관련된분자적기전을세포및동물모델에서규명하고자하였다. Ⅲ. 연구개발내용및범위 농진청에서재배한팥 (Vigna nakashimae IT17864) 의추출물 (total extract, water 층, organic 층 ) 이당뇨, 비만, 비알코올성지방간질환에대한개선효능이있는지를알기위해, 1) 세포수준에서각질환의분자적표적들 ( 당뇨 : AMPK 활성화, PPARγ 활성화, 염증및스트레스억제, 비만 : 지방세포분화저해, 비알코올성지방간질환 : 지방축적관련대사조절효소, 지방합성조절신호등 ) 을측정하였고, 또한 in vivo ( 질환모델동물, HFD mice 및 db/db) 에서그기능성을검증하였다. Ⅳ. 연구개발결과 팥의항비만기능성규명 - 팥추출물은지방세포의분화에필수적인 PPARγ의발현을억제하고지방세포분화를저해하는것으로알려진 AMPK의활성을촉진함으로써지방세포 3T3-L1 세포의분화를억제하였다. - 팥추출물은 HFD로비만을유도한 micce에서 HFD로인한체중및지방조직의무게증가를감소시켰으며, 지방세포의크기도감소시켜항비만의효능을확인하였다. 또한팥추출물은비만으로인해증가하는혈중지질, free acid, inflammatory cytokine TNFα, IL-6을감소시켰으며, 비만에의해감소하는 adiponectin의양은증가시켰다. - 팥추출물을식이한 HFD mice의지방조직에서 PPARγ의발현억제와 AMPK 활성촉진을확인하였다. 팥의비알코올성지방간개선기능성규명 - HFD로유도한지방간 mice에서팥추출물은 HFD로인해증가하는간무게, 간조직에서의 fat accumulation, triglyceride양을감소시켜지방간개선효능을나타내었다 - 팥추출물은지방간을억제함으로써 HFD로인한간독성, 간조직에서의염증생성및산화적스트레스 (oxidative stress) 를억제하였다. - 팥추출물은 LXR-SREBP-1c의 pathway을저해하여 hepatic lipogenesis을억제하였다

4 팥의항당뇨기능성규명 - 팥추출물은이미알려진 α-glucosidase inhibitor로서의활성이외에인슐린저항성과관련된분자적표적즉 AMPK 활성을촉진하고, 항염증및 ER stress을억제함으로써항당뇨효능을나타냄을확인하였다. - 팥추출물은골격근육세포 C2C12에서 glucose uptake를증가시키고, 간세포 HepG2에서는 gluconeogenic genes의발현을억제하여 glucose production을억제하였다. 또한팥추출물은 ER stress에의한 insulin signaling 억제를개선시켰다 - 팥추출물 (water층과 organic 층 extract) 의항당뇨효능을 db/db mice에서검증하였다. Ⅴ. 연구성과및성과활용계획 연구성과 - 팥의항비만효능에관한연구결과를 SCI저널인 Biosci. Biotechnol. Biochem. (77: , 2013) 에발표하였음 - 팥의지방간개선에관한연구결과를 SCI저널에투고예정 성과활용계획 - 팥의대사성질환개선에관한기능성홍보에활용 - 팥의기능성식식품으로서의개발에활용 - 대사성질환개선성분을규명함으로써대사성질환의약품소재개발에활용 - 4 -

5 SUMMARY ( 영문요약문 ) In this study, we evaluated the antiobesity effects of Vigna nakashimae (VN) extract and elucidated the underlying mechanisms. VN extract suppressed adipocyte differentiation and significantly attenuated the expression of adipogenic genes in 3T3-L1 cells. It decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes in fully differentiated 3T3-L1 cells. Moreover, it enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC), and increased the expression of fatty acid oxidation genes. In high-fat diet (HFD) fed mice, VN extract suppressed HFD-induced increases in body weight, epididymal fat tissue weight, and hepatic lipid levels, and decreased the plasma levels of triacylglycerols, fatty acid, total cholesterol, and inflammatory cytokines. Consistently with in vitro study results, VN extract prevented HFD-induced increases in the expression of PPARγ and its target genes, and restored the decrease in the phosphorylation of AMPK and ACC in epididymal fat and liver tissues. These findings suggest that Vigna nakashimae prevents obesity through suppression of PPARγ expression and activation of AMPK, and that it might be a useful dietary supplement for the prevention of obesity. Furthermore, we investigated the potential of VN extract to inhibit high fat diet (HFD)-induced hepatic steatosis and underlying mechanism. VN extract treatment attenuated fat accumulation and induction of lipogenic genes in the liver of HFD-fed mice. Blood biochemical analyses and histopathologic examinations showed that VN extract prevented liver injury with the inhibition of oxidative stress, as evidenced by thiobarbituric acid reactive substances formation and nitrotyrosinylation. Moreover, VN extract treatment inhibited LXRα agonist (T )-mediated SREBP-1c activation. VN extract was found to activate AMP-activated protein kinase (AMPK). Our results demonstrate that VN extract has an effect of activating AMPK, contributing to the prevention of SREBP-1c-mediated hepatic lipogenesis via the inhibition of LXRα activity. We also investigated antidiabetic activity of VN extract. While VN extract activated AMPK in C2C12 cells, it inhibited TNF-α-stimulated IKKβ/NFkB signaling and attenuated ER stress in HepG2 cells. The db/db mice treated with the extract showed reduced fasting blood glucose and HbA1c levels, and significantly decreased plasma free fatty acid, triglyceride and total cholesterol

6 팥의대사성질환개선및기능성규명 Anti-metabolic diseases activity of Vigna nakashimae 팥의대사성질환개선소재발굴과그기능성을과학적으로증명하기위해, 팥의당뇨, 비만및비알코올성지방간질환의개선과이에관련된분자적기전을세포및동물모델에서규명하고자하였다. 팥의항비만기능성규명 - 팥추출물은지방세포의분화에필수적인 PPARγ의발현을억제하고지방세포분화를저해하는것으로알려진 AMPK의활성을촉진함으로써지방세포 3T3-L1 세포의분화를억제하였다. 또한팥추출물은 HFD로비만을유도한 micce에서 HFD로인한체중및지방조직의무게증가를감소시켰으며, 지방세포의크기도감소시켜항비만의효능을확인하였다. 한편팥추출물은비만으로인해증가하는혈중지질, free acid, inflamatory cytokine TNFα, IL-6을감소시켰으며, 비만에의해감소하는 adiponectin 을증가시켰다. 팥의비알코올성지방간개선기능성규명 - HFD로유도한지방간 mice에서팥추출물은 HFD로인해증가하는간무게, 간조직에서의 fat accumulation, triglyceride양을감소시켜지방간개선효능을나타내었다. 또한팥추출물은지방간을억제함으로써 HFD로인한간독성, 간조직에서의염증생성및산화적스트레스 (oxidative stress) 를억제하였다. 팥추출물은 LXR-SREBP-1c 의 pathway을저해하여 hepatic lipogenesis을억제하였다. 팥의항당뇨기능성규명 - 팥추출물은이미알려진 α-glucosidase inhibitor로서의활성이외에인슐린저항성과관련된분자적표적즉 AMPK 활성을촉진하고, 항염증및 ER stress을억제함으로써항당뇨효능을나타냄을확인하였다. - 팥의대사성질환개선에관한기능성홍보에활용 - 팥의기능성식식품으로서의개발에활용 - 대사성질환개선성분을규명함으로써대사성질환의약품소재개발에활용 - 6 -

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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