JJCAM. 2018 September;15 (2)：121-125

【Short Communication】 Effect of japonicum Thunb on Body Composition and Biochemical Examination of Blood

Miki SAKAUE1,*, Asuka YASUEDA1, Toshinori ITO2, Satoshi OHNO1

1Department of Integrative Medicine, Osaka University Graduate School of Medicine 2 Osaka Center for Cancer and Cardiovascular Disease Prevention

【ABSTRACT】 INTRODUCTION Peucedanum japonicum Thunb (PJT) Metabolic syndrome is defined as a condition has reported the effect of lipid characterized by obesity due to visceral fat and glucose metabolism at some accumulation and ≥2 of the following symptoms: in vivo and in vitro study. In this hyperglycemia, hypertension, and dyslipidemia1). study, 21 subjects with dyslipidemia Metabolic syndrome may trigger arteriosclerotic border zone took PJT for 12 weeks. diseases such as diabetes, hypertension, dyslipidemia, The changes over time of body heart disease, and stroke. Therefore, prevention and composition and biochemical test treatment of metabolic syndrome are urgent issues. were examined. The values of HbA1c Since it has been reported that excessive nutrient were significantly reduced compared intake and unhealthy lifestyles may contribute to to the values before intake. For metabolic syndrome, various approaches have body fat percentage, the value been introduced into the medical administration at 8 weeks after intake showed a system and performed; for example, preventive and significant decrease compared with therapeutic dietary counseling and nutritional therapy the value before intake. Adiponectin for the purpose of reducing of visceral fat. Recently, was significantly increase after 8 the pharmacological effects of foods have been noted weeks in obese subject. These results and a study on "functional foods" has been promoted suggested PJT may improvement of in countries worldwide. glucose metabolism. It has been reported that approximately 60% of Japanese adults routinely use functional foods 【Key words】 with expectations of health maintenance, disease functional food, Peucedanum prevention, or the amelioration of symptoms2). japonicum Thunb, chlorogenic acid, However, it is limited functional foods of which effect glucose metabolism, adiponectin on improvement of metabolic syndrome has been demonstrated by clinical trials in human3). Therefore, it is thought that the evidence of functional foods should be established immediately.

Accepted Date: August 7, 2018 2-2, Yamadaoka, Suita, Osaka 565-0871, Tel: +81-6-6879-3498 Fax: +81-6-6879-3499 E-mail: [email protected] 122 M. Sakaue, et al.

In our laboratory, a screening method for adiponectin [Inclusion and exclusion criteria] secretagogue using human fat stem cells has been The inclusion criteria were as follows: age between developed4). Adiponectin is an adipocytokine specifically 20 and 80 years; LDL cholesterol level from borderline secreted by adipocytes. It is an important factor for the to mild (120-159 mg/dL), or TG level from normal prevention and improvement of metabolic syndrome, to moderately high (120-199 mg/dL). The exclusion and provides benefits such as improvement of insulin criteria were as follows: a person with an underlying resistance and prevention of hypertension and disease (i.e., diabetes, hepatic disorder, renal disease, arteriosclerosis5). Based on this screening method, PJT and heart disease) that requires medical treatment; promoted adiponectin secretion. person of irregular habits; a person with a history of PJT is a perennial of the family, and food allergy. is found primarily in the area between South Kyushu and Okinawa in Japan. In Okinawa, PJT is traditionally [Test Schedule] consumed as a vegetable or medicinal herb. It has The method of intake is as follows: take 3 g of been reported that PJT exhibits an anti-obesity effect lyophilized powder of PJT dissolved in approximately in mice, and its mechanism of action is believed to 150 ml of water, 3 times per day (3 g * 3 times; total of be associated with chlorogenic acid, which is an 9 g) for 12 weeks. After the initiation of administration, ingredient of PJT6, 7). Moreover, it has recently been the subjects underwent body composition measurements reported that pteryxin, which is another ingredient of and blood tests every 4 weeks (Fig. 1). PJT, inhibits synthesis of TG8). Furthermore, in vitro study of glucose metabolism indicated that PJT extract [Ethic review] has alpha-glucosidase inhibitory activity9). This study was conducted after obtaining the approval This study aimed to examine the effects of PJT on of the ethical review board of Osaka University dyslipidemia border zone that contributes to metabolic Hospital (UMIN000021962). And this study based on syndrome in human clinical trials. Helsinki Declaration.

MATERIALS AND METHODS RESULTS

[Study food] The subjects consisted of 10 men and 11 women (total Lyophilized powder of PJT (KANEHIDE BIO Co., of 21 subjects; age, 52.6 ± 12.4 years [mean ± standard Ltd., Okinawa, Japan) was used as the study food. No deviation, SD]). The value of body fat at 8 weeks after health hazard of PJT has been reported officially, and intake had decreased significantly compared with the its safety has been confirmed in an animal experiment value before intake. There was no change in total and a long-term intake study involving human subjects cholesterol, LDL cholesterol, and TG (indicator of lipid (3 months). The intake was set at 9 g/day (3 g * 3 in blood). The value of HbA1c, which is an indicator times) based on a previous study10). of blood glucose, showed a significant decrease compared with the value before intake. There was no

Fig. 1 Test schedule Consent was obtained from the subjects. After the initiation of administration, the subjects underwent body composition measurements and blood tests every 4 weeks. Effect of Peucedanum japonicum Thunb on Human Body 123 change in fasting blood glucose. Although the value chlorogenic acid, its inhibitory effect on obesity11, 12) and of adiponectin tended to elevate over time, there was promotion effect of adiponectin secretion13) have been no significant difference. However, stratified analysis reported. In addition, an anti-obesity effect of pteryxin of obese subjects with BMI of ≥25 showed a significant has been shown by a fundamental experiment8). increase at 8 weeks after intake compared to the value Moreover, in the present human clinical trial, no of adiponectin before intake (Table 1). subject exhibited a statistical significant change in blood adiponectin level (n=21). However, when DISCUSSION the analysis was conducted of only obese subjects (BMI ≥25; n=7), a significant increase was found at The subjects took PJT for 12 weeks, and their data of 8 weeks after intake. It has been reported that blood body composition and change in blood were analyzed adiponectin level decreases in patients with obesity, every 4 weeks. 14) diabetes, or coronary artery disease . The results of With respect to body composition, no change was this study suggest that adiponectin level might have found in body weight throughout the 12 weeks, while increased in the subjects whose adiponectin secretion body fat percentage at 8 weeks after intake showed was inhibited due to obesity. It seems that there are a significant decrease compared with the percentage two factors for this mechanism. First, chlorogenic acid before intake. The decrease in body fat percentage in PJT acts on adipocyte directly, which might have was consistent with the results of previous animal promoted adiponectin secretion through activated experiments. It has been reported that accumulation nuclear hormone receptors and peroxisome proliferator- of visceral and subcutaneous fat is reduced taken PJT 15, 16) activated receptorγ(PPARγ) . Second, adiponectin is administered to high-fat diet compared to no taken secretion might have been promoted by reduction it in mice6). The ingredients that are thought to be of enlarged adipocyte. This mechanism is based involved are chlorogenic acid, which is a polyphenol, on a previous study that reported various "bad" and pteryxin, which is a coumarin compound. For adipocytokines such as bioactive proteins including

Table 1 Body Composition and Blood Test Results

Before ingestion After 4 weeks After 8 weeks After 12 weeks

Age 52.6 ± 12.4

Gender (men/women) 10/11

Height (cm) 164.8 ± 8.2

Weight (kg) 62.7 ± 10.3 62.8 ± 10.5 62.8 ± 10.3 63.1 ± 10.6

BMI (kg/m2) 23.0 ± 3.0 23.0 ± 3.0 23.1 ± 3.0 23.2 ± 3.0

Body fat percentage (8%) 25.1 ± 6.8 24.9 ± 6.9 24.5 ± 6.7* 24.9 ± 6.7

Total cholesterol (mg/dl) 230.6 ± 39.1 227.5 ± 32.8 227.4 ± 28.2 226.7 ± 33.3

HDL cholesterol (mg/dl) 61.9 ± 15.5 61.8 ± 14.4 61.6 ± 15.1 61.7 ± 16.0

LDL cholesterol (mg/dl) 140.3 ± 28.7 136.2 ± 27.4 138.4 ± 23.1 136.9 ± 25.4

TG (mg/dl) 114.0 ± 44.9 140.4 ± 83.0* 131.7 ± 73.7 133.0 ± 68.7

Glucose (mg/dl) 84.8 ± 8.9 85.1 ± 11.3 83.4 ± 8.3 84.2 ± 9.4

HbA1c (%) 5.5 ± 0.3 5.5 ± 0.3 5.4 ± 0.2** 5.4 ± 0.3*

Adiponectin (μg/ml) 9.7 ± 4.8 10.0 ± 4.0 10.0 ± 4.6 10.1 ± 4.3

Adiponectin of obese subjects (μg/ml) 8.4 ± 3.9 8.9 ± 3.6 9.2 ± 4.3* 9.2 ± 4.5 n = 7

BMI: Body mass index, HDL Cholesterol: High Density Lipoprotein Cholesterol, LDL Cholesterol: Low Density Lipoprotein Cholesterol, TG: triglyceride ＊ : p < 0.05 ＊＊: p < 0.01 124 M. Sakaue, et al.

human tumor necrosis factor-α(TNF-α) or interleukin-6 program (NCEP) expert panel on detection, evaluation, (IL-6) are secreted when adipocytes are enlarged17-19), and treatment of high blood cholesterol in adults (adult while adiponectin secretion as "good" adipocytokine is treatment panel III) final report. Circulation. 2002; 106: increased when enlargement of adipocyte is reduced. 3143-3421. Considering that the body fat percentage decreased at 2) Kamohara S. Prospects for the appropriate use of the 8 weeks after intake in this clinical study, these results dietary supplements in geriatric medicine. Nihon Ronen are consistent with the previous data. Igakkai Zasshi. 2014; 51: 141-143. In addition, the mechanism that caused HbA1c to 3) Yasueda A, Ito T, Maeda K. Review: Evidence-based clinical research of anti-obesity supplements in Japan. decrease significantly can be shown in vitro study. It Immunol Endocr Metab Agents Med Chem. 2013; 13: has been reported that 3T3-L1 cells as preadipocyte to 185-195. which cis-3',4'-diisovalerylkhellactone as extract of PJT 4) Inomata-Kurashiki Y, Maeda K, Yoshioka E, et al. was added showed an increase of alpha-glucosidase Measurement of adiponectin production from inhibitory activity and elevation of glucose uptake in differentiated metabolic stem cells. Horm Metab Res the cells, in comparison with the cells to which it is 2010; 42: 318-323. not added9). In other words, in this clinical study, cis- 5) Matsuzawa Y, Funahashi T, Kihara S, et al. Adiponectin 3',4'-diisovalerylkhellactone included in PJT may have and metabolic syndrome. Arterioscler Thromb Vasc provided alpha-glucosidase inhibitory activity and Biol. 2004; 24: 29-33. decreased HbA1c level. 6) Okabe T, Toda T, Nukitrangsan N, et al. Peucedanum This study is the limit because it was a clinical trial japonicum Thunb inhibits high-fat diet induced obesity without a control group. In the future, a randomized in mice. Phytother Res. 2011; 25: 870-877. controlled trial using placebo is required. 7) Nukitrangsan N, Okabe T, Toda T, et al. Effect of Peucedanum japonicum Thunb extract on high-fat diet- CONCLUSION induced obesity and gene expression in mice. J Oleo sci. 2012; 61: 89-101. In this study, it was found that intake of lyophilized powder 8) Nugara RN, Inafuku M, Takara K, et al. Pteryxin: a of PJT for 12 weeks reduced body fat percentage and coumarin in Peucedanum japonicum Thunb leaves HbA1c level, which may contribute to improvement of exerts antiobesity activity through modulation of glucose metabolism. adipogenic gene network. Nutrition. 2014; 30: 1177- 1184. GRANTS 9) Choi RY, Nam SJ, Ham JR, et al. Anti-adipogenic and This study was supported by the Grant of Project for anti-diabetic effects of cis-3',4'-diisovalerylkhellactone formation of life science network (health food field) from isolated from Peucedanum japonicum Thunb leaves in Okinawa Prefectural Government. vitro. Bioorg Med Chem Lett. 2016; 26: 4655-4660. 10) Maeda K, Sakaue M, Ohno S, et al. Examination of adiponectin promoting effect in Okinawa food ACKNOWLEDGMENTS (Peucedanum japonicum, wild ). JJIM. 2016; 9: We appreciate KANEHIDE BIO Co., Ltd. for providing 188-192. us the hot air drying powder of PJT manufactured 11) Cho AS, Jeon SM, Kim MJ, et al. Chlorogenic acid by the Grant of Project for Formation of Life Science exhibits anti-obesity property and improves lipid Network (Health Food Field) from Okinawa Prefectural metabolism in high-fat diet-induced-obese mice. Food Government. The authors owe deepest gratitude Chem Toxicol. 2010; 48: 937-943. to Tamaki Matsuyama, Azusa Sawauchi for their 12) Ghadieh HE, Smiley ZN, Kopfman MW, et al. tremendous supports. Chlorogenic acid/chromium supplement rescues diet- induced insulin resistance and obesity in mice. Nutri

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要 旨

沖縄産長命草（ボタンボウフウ）摂取による体組成および血液生化学的検査に及ぼす影響

阪上未紀 1，安枝明日香 1，伊藤壽記 2，大野 智 1

1 大阪大学大学院医学系研究科 統合医療学寄附講座 2 大阪がん循環器病予防センター

ボタンボウフウ (PJT) は，脂質及び糖代謝の改善効果が動物・細胞実験で報告されている．本研究は，脂質異常 境界域の方に PJT を 12 週間摂取させ，体組成，生化学検査の経時的変化を検討した．その結果，HbA1c は摂取前 と比較して有意に低下し，体脂肪率は摂取 8 週後で有意に減少した．アディポネクチンは肥満者 (n=7) において， 摂取前と比較して摂取 8 週後に有意に上昇した．これらの事から，PJT は，耐糖能改善作用改善効果の可能性が示 唆された．

キーワード：機能性食品，ボタンボウフウ，クロロゲン酸，糖代謝，アディポネクチン