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Cite This: J. Agric. Food Chem. 2018, 66, 9989−9994
Antiobesity Effect of Tricin, a Methylated Cereal Flavone, in HighFat-Diet-Induced Obese Mice Dabeen Lee and Jee-Young Imm*
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Department of Foods and Nutrition, Kookmin University, 861-1, Jeongneung-dong, Seongbuk-gu, Seoul 02-707, Korea ABSTRACT: The antiobesity potential of tricin, a methylated cereal flavonoid, was examined using a high-fat-diet-induced obese mice model. The body weight (P < 0.01) and body fat mass (P < 0.05) were significantly decreased in the high-dose tricin supplementation group (TH: 200 mg/kg diet) in comparison to the high fat diet control group (CON) after a 12-week feeding trial. The serum (60.9 ± 2.09 mg/dL) and hepatic triglyceride levels (45.3 ± 4.42 nmol/mg protein) in the TH group were significantly decreased in comparison to the CON group (78.3 ± 5.09 mg/dL, 76.3 ± 8.10 nmol/mg protein), respectively. This antiobesity effect was attributed to a decrease in the expression of lipogenic markers crucial for fat synthesis in the liver (fatty acid synthase, stearoyl-CoA desaturase 1, elongation of long-chain fatty acids family member 6, glycerol-3-phosphate acyltransferase, and diglyceride acyltransferase) and suppressed expression of transcription factors associated with adipocyte differentiation (peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α). These lipid-lowering effects are mediated by the activation of adenosine 5′-monophosphate-activated protein kinase. KEYWORDS: tricin, de novo lipogenesis, adipogenesis, molecular mechanism, obese mice
1. INTRODUCTION
2. MATERIALS AND METHODS
Obesity arises from positive energy balance and leads to excessive fat accumulation in the body. The prevalence of obesity has continuously increased, and approximately 40% of adults in USA alone were obese (BMI ≥ 30 kg/m2) in 2015− 2016.1 Abdominal obesity is highly linked with elevated risk of metabolic diseases, such as diabetes mellitus, hypertension, and cardiovascular diseases.2 Antiobesity medications, which control energy intake and appetite, have been developed, but most of them are limited in their use because of undesirable side effects, such as dry mouth, diarrhea, and dyspepsia.3,4 Thus, demands for safe and effective compounds are increasing. Dietary phenolic compounds are good sources for developing potential antiobesity agents.5 Tricin (5,7,4′-trihydroxy-3′,5′-dimethoxyflavone) is a flavonoid found in various edible plant resources, including cereals, bamboo, and sugar cane juice. Tricin is dominantly present in free or conjugated forms as 7-O-β-D-glucopyranoside.6 Bran of Njavara rice is a rich source of tricin, and it contains 1930 mg tricin/kg in its dry weight form.7 Winter wheat hull (770 mg tricin/kg tricin) has been suggested as a more economical source of tricin.8 Various bioactivities of tricin, including antioxidant activity,9 anti-inflammatory activity,10,11 anticancer activity,12 antiangiogenic activity,13 and antidiabetic activity, have been reported.14 In terms of safety, no sign of toxicity was observed in mice after being fed 1 g tricin/kg diet for 5 consecutive days.15 Previously, we demonstrated that tricin isolated from oat hulls effectively decreased fat accumulation in 3T3-L1 preadipocytes (Lee et al., 2015), and tricin-mediated antiadipogenic effects were exerted via AKT and mTOR cell signaling in 3T3-L1 preadipocytes.16,17 The present study aimed to verify the antiobesity effect of tricin in a high-fat-dietinduced obese mice model.
2.1. Materials. The purified tricin (99.6% purity, Dalton Pharma Services, Toronto, Canada) was used for animal study. The antibodies for phospho-AMP-activated protein kinase alpha (p-AMPKα, Thr 172), AMPKα, phospho-acetyl-CoA carboxylase (p-ACC, Ser 79), ACC, fatty acid synthase (FAS), elongation of very long-chain fatty acids protein 6 (ELOVL 6), stearoyl-CoA desaturase-1 (SCD1), peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer-binding protein alpha (C/EBP-α), TATA-binding protein (TBP), and β-actin were from Cell Signaling Technology (Danvers, MA, USA). Glycerol-3-phosphate acyltransferase (GPAM), diglyceride acyltransferase (DGAT), and sterol regulatory elementbinding protein 1 (SREBP-1) antibodies were bought from Santa Cruz Biotechnology (Santa Cruz, CA, USA). 2.2. Animals and Diets. Male C57BL/6 mice (4-week-old, Daehan Bio Link, Chungbuk, Korea) were housed in a temperature and humidity controlled cage (24 °C, 50% ± 10% relative humidity) with a 12 h light:dark cycle. After a 1-week acclimation period, the mice were randomly divided into five groups (12 mice in each group) as follows: 1) normal diet control group (ND, 6.2% calories from fat, Envigo, Huntingdon, UK), 2) high-fat diet control group (CON, 45% calories from fat, Research Diets, Inc., NJ, USA), 3) CON + 50 mg tricin/kg diet (TL), 4) CON + 200 mg tricin/kg diet (TH), and 5) CON + 500 mg Xenical/kg diet (XE). The dose was selected based on the colon carcinogenesis study of tricin.18 The mice were given free access to food and water, and weight change and feed intake were measured weekly. The animal experiments continued for 12 weeks, and all experimental protocols used in this study were approved by Kookmin University Institutional Animal Care and Use Committee (KMUIACUC-2016-05). 2.3. Body Composition Measurement. The mice were fasted for 4 h and then were anesthetized by intraperitoneal injection of ketamine (100 mg/kg BW) and xylazine (10 mg/kg BW). The body
© 2018 American Chemical Society
Received: Revised: Accepted: Published: 9989
June 24, 2018 August 19, 2018 September 2, 2018 September 2, 2018 DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
Article
Journal of Agricultural and Food Chemistry composition, including fat and lean mass of mice, was analyzed every 4 weeks using dual energy X-ray absorptiometry (DEXA) (Medikors, Gyeong-Gi, Korea). 2.4. Biochemical Analyses of Serum. The mice were sacrificed after 15 h of fasting, and blood was collected. Blood was kept in ice for 15 min, and the serum was obtained by centrifugation at 1,500 × g for 15 min at 4 °C. Serum TG, total cholesterol, LDL cholesterol, glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were determined using a blood analyzer Toshiba TBA-40FR (Toshiba, Tochigi-ken, Japan). 2.5. Hepatic Triacylglycerol (TG) Accumulation. Mice livers were homogenized in NP-40 solution (5%, Sigma−Aldrich, MO, USA) and extracted for 50 min using a tube shaker (Thermo Scientific, Rockford, IL, USA). Samples were centrifuged and heated at 95 °C for 5 min to collect the supernatant and then cooled down to room temperature. The heating and centrifugation step was repeated to solubilize TG. The assay kit (Abcam, Cambridge, MA, USA) and bicinchoninic acid method19 were used for the quantification hepatic TG and protein content, respectively. 2.6. Western Blot Analysis. The liver and white adipose tissue (WAT) were homogenized in radioimmunoprecipitation assay buffer using a bullet blender (Next Advance, Troy, NY, USA). The cell supernatant was obtained after centrifugation (4,000 × g, 15 min) at 4 °C. In the case of SREBP-1 expression, a nuclear extract was isolated using NE-PER nuclear extraction reagents (Thermo Scientific, Rockford, IL, USA). After filtration, the equal amounts of total cellular proteins were separated by SDS-PAGE (10%) and transferred onto polyvinylidene fluoride membranes (Millipore, Billerica, MA, USA) at 0.2 A for 90 min and then blotted as described previously.11 Protein bands in the membranes were visualized by enhanced chemiluminescence detection kits (BioRad, Hercules, CA, USA), and the relative band densities of proteins were determined using Image Lab software 5.1 (Biorad) after normalization to β-actin (or TBP). 2.7. Statistical Analysis. All data were expressed as mean ± standard error. Statistical analysis was done using Prism 6 software (GraphPad Software, Inc., CA, USA). When data showed significant differences (P < 0.05) in one-way ANOVA, Duncan’s multiple comparisons test was done to find significant differences between the group means, with the exception of the ND group.
3. RESULTS 3.1. Effects of Tricin Supplementation on Body Weight and Composition. The administration of a high fat diet significantly increased the body weight of C57Bl/6J mice in comparison to the ND group (P < 0.05). Significant difference was observed in body weight between the TH and CON groups after 9 weeks (P < 0.01), remaining until the end of the feeding experiment [Figure 1(A)]. The effect of highdose tricin supplementation (TH: 200 mg/kg diet) on body weight was comparable to the effect of Xenical supplementation (500 mg/kg diet), which was used as a positive control. However, significant difference was not detected in body weight between the CON and TL groups. The analysis of body composition using DEXA indicated that body fat was significantly decreased in the TH group in comparison to the CON group at 12 weeks (P < 0.05), whereas no difference was observed in lean mass [Figure 1(B) and 1(C)]. Therefore, decreased body weight in the TH group was due to reduction of body fat. Figure 1(D) is a representative image of DEXA scans from each group. The accumulation of fat, indicated in red in the central region, is reduced in the TH group. These results suggest that abdominal fat, an emerging cardiovascular risk factor, was effectively reduced by high-dose tricin supplementation. Body weight gain was significantly decreased in the TH group without affecting feed intake and feed efficiency ratio (Table 1). This result
Figure 1. Effects of tricin supplementation on (A) body weight, (B) fat tissue, and (C) lean mass in mice and its (D) representative DEXA image. ND, normal diet group; XE, high-fat diet + Xenical (500 mg/ kg diet); CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/kg diet) supplementation group. Each value represents mean ± standard error (n = 12). *P < 0.05, **P < 0.01 compared with the CON group.
indicates that body weight and body fat reductions in the TH group were not attributed to decreased feed intake or appetite. 3.2. Effect of Tricin Supplementation on Serum Biochemical Parameters. The serum levels of total cholesterol, LDL cholesterol, and glucose were not significantly changed, but TG levels in the TH group was significantly decreased (P < 0.05, Table 2). This result indicates that tricin exerted a significant effect on fat accumulation rather than on cholesterol metabolism. Serum AST and ALT levels were measured as indices of liver function. The serum AST levels 9990
DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
Article
Journal of Agricultural and Food Chemistry Table 1. Weight Gain, Food Intake, and Feed Efficiency Ratio of the Experimental Groupsa group
ND
CON
TL
TH
weight gain (g/week) food intake (g/week) FER
1.15 ± 0.04 23.8 ± 0.07 4.86 ± 0.17
1.62 ± 0.2 21.3 ± 0.19 7.59 ± 0.54
1.75 ± 0.1 21.2 ± 0.22 8.28 ± 0.46
1.31 ± 0.12* 20.6 ± 0.41 5.86 ± 0.63
a
ND, normal diet group; CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/kg diet) supplementation group. Each value represents mean ± standard error (n = 12). *P < 0.05, compared with the CON group. Food efficiency ratio (FER) = (weight gain/food intake) × 100.
Table 2. Effect of Tricin Supplementation on Serum Biochemical Markersa group TG (mg/dL) TC (mg/dL) LDL-c (mg/dL) glucose (mg/dL) ALT (U/L) AST (U/L)
ND 61.2 117 45.3 178 38.5 83.7
± ± ± ± ± ±
1.94 2.51 1.51 8.93 3.7 3.76
CON 78.3 150 52.6 202 95.6 156
± ± ± ± ± ±
TL
5.09 4.74 7.36 183 11.8 17.8
79.8 155 54.6 184 65.3 121
± ± ± ± ± ±
1.47 2.59 2.23 1.78 8.24* 17.7
TH 60.9 139 53.7 185 58.1 118
± ± ± ± ± ±
2.09** 4.45 2.6 4.97 4.83** 7.99
a
ND, normal diet group; CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/kg diet) supplementation group. Each value represents mean ± standard error (n = 12). *P < 0.05, **P < 0.01 compared with the CON group. TG, triacylglycerol; TC, total cholesterol; LDL c, low-density lipoprotein cholesterol; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
(ACC1), a rate-controlling enzyme in de novo lipogenesis, showed a decreasing trend by tricin supplementation, but there were no significant differences detected among the groups. The expression of FAS, an enzyme catalyzing the final step of fatty acid biosynthesis, was significantly decreased in the TL (P < 0.01) and TH groups (P < 0.001). In comparison to the CON group, the TH group exhibited a significant decrease in SCD1 (P < 0.001) and ELOVL6 (P < 0.05). GPAM was significantly decreased in the TH group (P < 0.01), and DGAT was significantly decreased in the TL (P < 0.05) and TH groups (P < 0.01). The expression of sterol regulatory element-binding protein 1 (SREBP1), which regulates lipogenic genes associated with lipid formation, significantly decreased in both the TL (P < 0.05) and TH groups (P < 0.01). 3.5. Effect of Tricin Supplementation on Adipogenesis in White Adipose Tissue. PPARγ and C/EBPα are two master transcription factors governing adipogenesis.22,23 In order to examine possible mechanisms associated with reduction in fat mass through the PPARγ and C/EBPα pathway, the expressions of these two adipogenic transcriptional factors in WAT were analyzed. As shown in Figure 4, the expressions of PPARγ significantly decreased in the TH group (P < 0.05). In addition, the expression of C/EBPα significantly decreased in a dose-dependent manner (P < 0.001) compared with the expression observed in the CON group.
did not show a difference among groups, but ALT levels were significantly decreased in the TL (P < 0.05) and TH groups (P < 0.01). ALT is a more precise predictor of liver damage because ALT is mainly localized in the liver, whereas AST is present in the liver, muscles, and kidneys.20 The normal range of ALT and AST in C57BL/6J male mice (20-week-old) was 51.1 ± 26.7 and 68.0 ± 31.7 U/L, respectively.21 Based on this result, tricin supplementation attenuated impairment of liver function caused by a high fat diet. 3.3. Effect of Tricin Supplementation on TG Accumulation in the Liver. Figure 2 indicates the amount of TG
Figure 2. Effect of tricin supplementation on hepatic TG accumulation in mice. ND, normal diet group; CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/ kg diet) supplementation group. Each value represents mean ± standard error (n = 12). ***P < 0.001 compared with the CON group.
4. DISCUSSION Tricin is a cereal flavone bearing 3 −OH groups (4′, 5, and 7) and two −OCH3 groups at the 3′ and 5′ positions. Tricin is frequently found in the leaves and stems of herbaceous and cereal plants and occurs in free, tricin-glycoside, or tricin-lignan forms.24 Methoxy groups in dietary polyphenols have a greater permeability to cell membranes than their hydroxylated forms during absorption, thus limiting extensive modification in the metabolism of polyphenols.25 The number of methoxy groups in flavones also affects biological activities, and their anticancer potency increased in the decreasing order of pentamethoxyflavone, tricin, and apigenin.26
accumulation in the liver. No significant difference was found in the hepatic TG level between the CON and TL groups, but TG accumulation in the TH group was effectively reduced by 40% (P < 0.001). 3.4. Effect of Tricin Supplementation on Lipogenic Enzymes in the Liver. The expression of hepatic lipogenic enzymes was analyzed to elucidate the underlying mechanisms of tricin-mediated reduced TG accumulation. As shown in Figure 3, the phosphorylation of acetyl-CoA carboxylase 1 9991
DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
Article
Journal of Agricultural and Food Chemistry
Figure 4. Effect of tricin supplementation on the expression of adipogenic transcriptional factors in visceral adipose tissue of mice. ND, normal diet group; CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/kg diet) supplementation group. The protein expression levels of PPAR-γ and C/EBP-α were analyzed by Western blot using β-actin as an internal control. Each value represents mean ± standard error (n = 6). *P < 0.05, **P < 0.01, compared with the CON group. PPAR-γ, peroxisome proliferatoractivated receptor gamma; C/EBP-α, CCAAT/enhancer-binding protein α.
Obesity is closely associated with development of nonalcoholic fatty liver disease.28 The CON group showed a significantly higher hepatic TG level and serum ALT level in comparison to the TH group. These results suggest that tricin supplementation was effective in suppressing the development of a fatty liver. ALT was closely associated with abdominal fat distribution and suggested as a credible indicator to monitor even mild stages of steatosis.29,30 The TH group exhibited a significantly lower serum ALT level than that in the CON group. The reduced hepatic fat accumulation was consistent with the Western blot results of lipogenic enzymes in the liver. The expression levels of FAS, ELOVL6, SCD1, GPAM, and DGAT were significantly decreased in the TH group in comparison to the CON group (Figure 4). However, tricin supplementation significantly increased the phosphorylation of adenosine 5′monophosphate (AMP)-activated protein kinase (AMPK). AMPK modulates energy balance and lipid metabolism in adipose tissue, liver, and skeletal muscle and has been suggested as a promising molecular target for alleviating metabolic syndrome, including obesity.31 The action of AMPK on target organs occurs via direct phosphorylation of metabolic enzymes, such as ACC1 and FAS, for acute control. It also regulates the gene expression for fat oxidation in mitochondria for long-term control.32 Although active compounds are not clearly indicated, Sasa quelpaertensis extract containing pcoumaric acid and tricin showed an antiobesity effect by restoring decreased AMPK activity in high-fat-diet-induced obese mice.33 ACC converts acetyl-CoA to malonyl-CoA, a key molecule which initiates fatty acid metabolism.34 Tung et al.35 reported that 5-acetoxy-6,7,8,3′,4′-pentamethoxyflavone suppressed adi-
Figure 3. Effect of tricin supplementation on the expression of hepatic de novo lipogenesis enzymes. ND, normal diet group; CON, high-fat diet group; TL, high fat diet + low dose tricin (50 mg/kg diet) supplementation group; TH, high fat diet + high dose tricin (200 mg/ kg diet) supplementation group. The protein expression levels of SREBP1 and other lipogenesis enzymes were analyzed by Western blot using TBP and β-actin as an internal control, respectively. Each value represents mean ± standard error (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the CON group. AMPKα, AMPactivated protein kinase α; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL 6, elongation of very long-chain fatty acids protein 6; SCD1, stearoyl-CoA desaturase-1; GPAM, glycerol-3phosphate acyltransferase; DGAT, diglyceride acyltransferase; SREBP-1, sterol regulatory element-binding protein 1; TBP, TATAbinding protein.
The antiadipogenic effect of tricin in vitro was studied previously using 3T3-L1 preadipocytes. Fat accumulation in adipocytes was significantly suppressed at 5 μM through the AKT/mTORC1/SREBP-1 pathway.17 Herein, the dietary supplementation of tricin (200 mg/kg diet) resulted in significant reduction in weight gain and the levels of TG in the serum and liver of high-fat-diet-induced obese mice. There was no significant difference in food intake among the groups. Similar to the antiobesity effect of tricin, the oral administration of nobiletin (100 mg/kg), a hexamethoxyflavone found in citrus fruit, significantly reduced weight gain and body fat accumulation and improved insulin resistance in mice fed a high fat diet.27 In our previous study, tricin resulted in promoted glucose uptake in C2C12 muscle cells and lowered blood glucose levels during an oral glucose tolerance test.14 9992
DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
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Journal of Agricultural and Food Chemistry ORCID
pogenesis via the AMPKα/SREBP1/FAS pathway in obese mice, but there were no significant differences in the phosphorylation of ACC1, similar to the result of the present study. After fatty acids are synthesized from malonyl-CoA, they combine with glycerol to form triglycerides. The reduction in the hepatic TG level occurred with the inhibition of TG synthesis enzymes, such as DGAT1 and GPAM. The DGAT enzymes, DGAT1 and DGAT2, catalyze the final step of TG synthesis. Both enzymes are responsible for the accumulation of fat in the liver. DGAT1 is more ubiquitous than DGAT2 and is primarily involved in the delivery of exogenous fatty acids taken up by cells to the liver. On the other hand, DGAT2 plays an important role in the incorporation of endogenously synthesized monounsaturated fatty acids into TG.36 Based on this context, DGAT1 is closely associated with high-fat-dietmediated steatosis. DGAT1 is also significantly increased in the human liver and in patients with nonalcoholic fatty liver disease.37 This result suggests that dietary supplementation of tricin, especially at high doses, effectively suppresses lipogenic protein expression and enzyme activities in livers. ELOVL6 and SCD-1 are involved in the modification of hepatic fatty acids composition. ELOVL6 catalyzes the conversion of palmitate to stearate, and SCD-1 forms oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA.38,39 The inhibition of ELOVL6 and SCD-1 diminishes diet-induced insulin resistance and hepatic steatosis.38,40 SREBP is another key modulator for lipid homeostasis. Increased SREBP-1c expression leads to FAS expression and TG accumulation in the liver.41 Adopogenesis refers to the differentiation, mitotic clonal expansion, and maturation of adipocytes. PPARγ and C/ EBPα are major transcriptional factors regulating the adipogenic transcriptional cascade via a positive feedback loop.42 Tricin supplementation actively blocked adipogenesis in high-fat-diet-induced obese mice, in accordance with the result of 3T3-L1 preadipocytes.16 Liou et al.24 reported that a methylated flavone and acacetin suppressed lipid accumulation in both 3T3-L1 cells and adipose tissue in high-fat-dietinduced obese mice by inhibiting C/EBPα and SREBP1c expressions. The current study hypothesized that tricin is a potent bioactive compound against high-fat-diet-induced obesity in vivo. Physical phenotype (body fat mass) and metabolic phenotype (serum TG level) improved following the administration of high dose tricin (TH). Subsequently, the molecular phenotypes were explored in the liver and white adipose tissue. Hepatic de novo lipogenesis and adipogenesis in visceral adipose tissues significantly decreased. Administration of low dose of tricin (TL) retarded the activities of lipogenic and adipogenic enzymes (i.g. FAS, DGAT, and C/ EBPα) in part; however, the treatment failed to rescue physical and metabolic phenotypes. Therefore, only TH showed a series of antiobesity fallouts, which is clearly explained via the AMPK pathway. The previously reported in vitro antiobesity effect of tricin was confirmed in a high-fat-diet-induced obese animal model.
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Jee-Young Imm: 0000-0003-3152-7051 Funding
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (2014R1A2A2A01007169). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Hales, C. M.; Fryar, C. D.; Carroll, M. D.; Freedman, D. S.; Ogden, C. L. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007−2008 to 2015−2016. JAMA 2018, 319 (16), 1723−1725. (2) Kopelman, P. G. Obesity as a medical problem. Nature 2000, 404 (6778), 635−643. (3) Kang, J. G.; Park, C.-Y. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab. J. 2012, 36 (1), 13−25. (4) Rodgers, R. J.; Tschöp, M. H.; Wilding, J. P. Anti-obesity drugs: past, present and future. Dis. Models & Mech. 2012, 5 (5), 621− 626. (5) Sergent, T.; Vanderstraeten, J.; Winand, J.; Beguin, P.; Schneider, Y.-J. Phenolic compounds and plant extracts as potential natural anti-obesity substances. Food Chem. 2012, 135 (1), 68−73. (6) Zhou, J.-M.; Ibrahim, R. K. Tricina potential multifunctional nutraceutical. Phytochem. Rev. 2010, 9 (3), 413−424. (7) Mohanlal, S.; Parvathy, R.; Shalini, V.; Helen, A.; Jayalekshmy, A. Isolation, characterization and quantification of tricin and flavonolignans in the medicinal rice Njavara (Oryza sativa L.), as compared to staple varieties. Plant Foods Hum. Nutr. 2011, 66 (1), 91−96. (8) Moheb, A.; Grondin, M.; Ibrahim, R. K.; Roy, R.; Sarhan, F. Winter wheat hull (husk) is a valuable source for tricin, a potential selective cytotoxic agent. Food Chem. 2013, 138 (2), 931−937. (9) Parvathy, R.; Mohanlal, S.; Pushpan, C.; Helen, A.; Jayalekshmy, A. Antioxidant properties, anti-inflammatory effects, and bioactive constituents of the Indian medicinal rice Njavara yellow compared with staple varieties. Food Sci. Biotechnol. 2014, 23 (5), 1379−1388. (10) Duarte-Almeida, J. M.; Novoa, A. V.; Linares, A. F.; Lajolo, F. M.; Genovese, M. I. Antioxidant activity of phenolics compounds from sugar cane (Saccharum officinarum L.) juice. Plant Foods Hum. Nutr. 2006, 61 (4), 187−192. (11) Lee, D.; Imm, J. Y. AMP Kinase Activation and Inhibition of Nuclear Factor-Kappa B (NF-κB) Translocation contribute to the anti-Inflammatory effect of tricin. J. Food Biochem. 2017, 41 (2), e12293. (12) Cai, H.; Boocock, D. J.; Steward, W. P.; Gescher, A. J. Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties. Cancer Chemother. Pharmacol. 2007, 60 (2), 257−266. (13) Han, J. M.; Kwon, H. J.; Jung, H. J. Tricin, 4’, 5, 7-trihydroxy-3′, 5′-dimethoxyflavone, exhibits potent antiangiogenic activity in vitro. Int. J. Oncol. 2016, 49 (4), 1497−1504. (14) Kim, S.; Go, G.-W.; Imm, J.-Y. Promotion of glucose uptake in C2C12 myotubes by cereal flavone tricin and its underlying molecular mechanism. J. Agric. Food Chem. 2017, 65 (19), 3819−3826. (15) Verschoyle, R. D.; Greaves, P.; Cai, H.; Borkhardt, A.; Broggini, M.; D’Incalci, M.; Riccio, E.; Doppalapudi, R.; Kapetanovic, I. M.; Steward, W. P. Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone. Cancer Chemother. Pharmacol. 2006, 57 (1), 1−6. (16) Lee, D.; Park, H. Y.; Kim, S.; Park, Y.; Bang, M.-H.; Imm, J.-Y. Anti-adipogenic effect of oat hull extract containing tricin on 3T3-L1 adipocytes. Process Biochem. 2015, 50 (12), 2314−2321. (17) Lee, D.; Go, G.-W.; Imm, J.-Y. Tricin, a methylated cereal flavone, suppresses fat accumulation by downregulating AKT and mTOR in 3T3-L1 preadipocytes. J. Funct. Foods 2016, 26, 548−556.
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*Phone: 82-2-910-4772. Fax: 82-2-910-5249. E-mail: jyimm@ kookmin.ac.kr. 9993
DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
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Journal of Agricultural and Food Chemistry
steatosis due to exogenous fatty acids. Hepatology 2009, 50 (2), 434− 442. (38) Matsuzaka, T.; Shimano, H. Elovl6: a new player in fatty acid metabolism and insulin sensitivity. J. Mol. Med. 2009, 87 (4), 379− 384. (39) Paton, C. M.; Ntambi, J. M. Biochemical and physiological function of stearoyl-CoA desaturase. Am. J. Physiol.-Endoc. M. 2009, 297 (1), E28−E37. (40) Narce, M.; Bellenger, J.; Rialland, M.; Bellenger, S. Recent advances on stearoyl-Coa desaturase regulation in fatty liver diseases. Curr. Drug Metab. 2012, 13 (10), 1454−1463. (41) Browning, J. D.; Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 2004, 114 (2), 147−152. (42) Ali, A. T.; Hochfeld, W. E.; Myburgh, R.; Pepper, M. S. Adipocyte and adipogenesis. Eur. J. Cell Biol. 2013, 92 (6−7), 229− 236.
(18) Oyama, T.; Yasui, Y.; Sugie, S.; Koketsu, M.; Watanabe, K.; Tanaka, T. Dietary tricin suppresses inflammation-related colon carcinogenesis in male Crj: CD-1 mice. Cancer Prev. Res. 2009, 2 (12), 1031−1038. (19) Smith, P. K.; Krohn, R. I.; Hermanson, G.; Mallia, A.; Gartner, F.; Provenzano, M.; Fujimoto, E.; Goeke, N.; Olson, B.; Klenk, D. Measurement of protein using bicinchoninic acid. Anal. Biochem. 1985, 150 (1), 76−85. (20) Thapa, B.; Walia, A. Liver function tests and their interpretation. Indian J. Pediatr. 2007, 74 (7), 663−671. (21) Zhou, X.; Hansson, G. K. Effect of sex and age on serum biochemical reference ranges in C57BL/6J mice. Comparative Med. 2004, 54 (2), 176−178. (22) Darlington, G. J.; Ross, S. E.; MacDougald, O. A. The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 1998, 273 (46), 30057−30060. (23) Grimaldi, P. A. The roles of PPARs in adipocyte differentiation. Prog. Lipid Res. 2001, 40 (4), 269−281. (24) Liou, C.-J.; Wu, S.-J.; Chen, L.-C.; Yeh, K.-W.; Chen, C.-Y.; Huang, W.-C. Acacetin from traditionally used Saussurea involucrata Kar. et Kir. suppressed adipogenesis in 3T3-L1 adipocytes and attenuated lipid accumulation in obese mice. Front. Pharmacol. 2017, 8, 589. (25) Gao, S.; Hu, M. Bioavailability challenges associated with development of anti-cancer phenolics. Mini-Rev. Med. Chem. 2010, 10 (6), 550−567. (26) Cai, H.; Sale, S.; Schmid, R.; Britton, R. G.; Brown, K.; Steward, W. P.; Gescher, A. J. Flavones as colorectal cancer chemopreventive agentsphenol-O-methylation enhances efficacy. Cancer Prev. Res. 2009, 2 (8), 743−750. (27) Lee, Y.-S.; Cha, B.-Y.; Choi, S.-S.; Choi, B.-K.; Yonezawa, T.; Teruya, T.; Nagai, K.; Woo, J.-T. Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. J. Nutr. Biochem. 2013, 24 (1), 156−162. (28) Fabbrini, E.; Sullivan, S.; Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010, 51 (2), 679−689. (29) Chang, H.-C.; Huang, C.-N.; Yeh, D.-M.; Wang, S.-J.; Peng, C.H.; Wang, C.-J. Oat prevents obesity and abdominal fat distribution, and improves liver function in humans. Plant Foods Hum. Nutr. 2013, 68 (1), 18−23. (30) Esteghamati, A.; Noshad, S.; Khalilzadeh, O.; Khalili, M.; Zandieh, A.; Nakhjavani, M. Insulin resistance is independently associated with liver aminotransferases in diabetic patients without ultrasound signs of nonalcoholic fatty liver disease. Metab. Syndr. Relat. Disord. 2011, 9 (2), 111−117. (31) Zhang, B. B.; Zhou, G.; Li, C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 2009, 9 (5), 407−416. (32) Hardie, D. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. 2008, 32 (S4), S7. (33) Kang, S.-I.; Shin, H.-S.; Kim, H.-M.; Hong, Y.-S.; Yoon, S.-A.; Kang, S.-W.; Kim, J.-H.; Ko, H.-C.; Kim, S.-J. Anti-obesity properties of a Sasa quelpaertensis extract in high-fat diet-induced obese mice. Biosci., Biotechnol., Biochem. 2012, 76 (4), 755−761. (34) Harada, N.; Oda, Z.; Hara, Y.; Fujinami, K.; Okawa, M.; Ohbuchi, K.; Yonemoto, M.; Ikeda, Y.; Ohwaki, K.; Aragane, K. Hepatic de novo lipogenesis is present in liver-specific ACC1deficient mice. Mol. Cell. Biol. 2007, 27 (5), 1881−1888. (35) Tung, Y.-C.; Li, S.; Huang, Q.; Hung, W.-L.; Ho, C.-T.; Wei, G.-J.; Pan, M.-H. 5-Demethylnobiletin and 5-Acetoxy-6, 7, 8, 3′, 4′pentamethoxyflavone suppress lipid accumulation by activating the LKB1-AMPK pathway in 3T3-L1 preadipocytes and high fat diet-fed C57BL/6 mice. J. Agric. Food Chem. 2016, 64 (16), 3196−3205. (36) Yen, C. L. E.; Stone, S. J.; Koliwad, S.; Harris, C.; Farese, R. V. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008, 49 (11), 2283−2301. (37) Villanueva, C. J.; Monetti, M.; Shih, M.; Zhou, P.; Watkins, S. M.; Bhanot, S.; Farese, R. V., Jr A specific role for Dgat1 in hepatic 9994
DOI: 10.1021/acs.jafc.8b03312 J. Agric. Food Chem. 2018, 66, 9989−9994
