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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats^1,2

³ Faculty of Nutrition and Department of Animal Science, Texas A&M University, College Station, TX 77843; ⁴ Cardiovascular Research Institute and Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College Station, TX 77843; ⁵ USDA-Agricultural Research Service, South Central Agricultural Research Laboratories, Lane, OK 74555; ⁶ Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824; and ⁷ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843

^* To whom correspondence should be addressed. E-mail: g-wu{at}tamu.edu.

	ABSTRACT

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Watermelon is rich in L-citrulline, an effective precursor of L-arginine. This study was conducted to determine whether dietary supplementation with watermelon pomace juice could ameliorate the metabolic syndrome in the Zucker diabetic fatty (ZDF) rat, an animal model of noninsulin-dependent diabetes mellitus. Nine-week-old ZDF rats were assigned randomly to receive drinking water containing 0% (control) or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). At the end of the 4-wk supplementation period, blood samples, aortic rings, and hearts were obtained for biochemical and physiological analyses. Feed or energy intakes did not differ among the 5 groups of rats. However, dietary supplementation with watermelon pomace juice or L-arginine increased serum concentrations of arginine; reduced fat accretion; lowered serum concentrations of glucose, free fatty acids, homocysteine, and dimethylarginines; enhanced GTP cyclohydrolase-I activity and tetrahydrobiopterin concentrations in the heart; and improved acetylcholine-induced vascular relaxation. Compared with the control, dietary supplementation with lycopene or citrus pectin did not affect any measured parameter. These results provide the first evidence to our knowledge for a beneficial effect of watermelon pomace juice as a functional food for increasing arginine availability, reducing serum concentrations of cardiovascular risk factors, improving glycemic control, and ameliorating vascular dysfunction in obese animals with type-II diabetes.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Growing evidence shows that physiological levels of NO play an important role in regulating the oxidation of energy substrates, insulin sensitivity, and hemodynamics in animals and humans (6). In addition, NO is a key mediator of the immune response (7) and neurological function (8). NO is synthesized from L-arginine by tetrahydrobiopterin (BH4)-dependent NO synthase (9), underscoring a crucial role for this amino acid in maintaining health and treating a wide array of chronic diseases. In support of this notion, recent findings indicate that dietary supplementation with L-arginine reduced plasma levels of glucose in chemically induced diabetic rats (10–12) and the Zucker diabetic fatty (ZDF) rat (a genetically obese animal model of NIDDM) (13), decreased excess fat mass in ZDF rats (13) and diabetic patients (14), and improved vascular reactivity in diabetic rats (2), obese hamsters (15), and hypercholesterolemic humans (16).

Because arginine has a strong alkaline property in physiological solutions, its HCl salt or a mixture with acidic organic substances is generally used for administration into animals (17) or humans (18) to prevent an acid-base imbalance. However, high oral doses of arginine (> 9 g/d) is associated with nausea, gastrointestinal discomfort, and diarrhea in some subjects (19,20). Also, oral administration of arginine is currently not recommended for patients with myocardial infarction because of a possible increase in mortality (21), likely due to an abrupt increase in NO production. A solution to this potentially severe problem associated with dietary arginine supplementation may be the alternative use of L-citrulline, a neutral amino acid and an effective precursor for L-arginine synthesis (22). L-Citrulline is unusually rich in watermelon (23) and we recently found that chronic consumption of this functional food was effective in increasing plasma concentrations of arginine in healthy humans (24). However, there is a paucity of literature regarding a role for watermelon consumption in improving health in obese or diabetic subjects.

We hypothesized that dietary supplementation with watermelon pomace juice might be beneficial for enhancing arginine availability and ameliorating the metabolic syndrome in NIDDM. This hypothesis was tested in the present study using the ZDF rat as an animal model.

	Materials and Methods

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    Chemicals. Hexokinase, glucose-6-phosphate dehydrogenase, and nitrate reductase were purchased from Roche. HPLC-grade water and methanol were procured from Fisher Scientific. Unless indicated, all other chemicals were obtained from Sigma.

    Preparation of watermelon pomace juice and its amino acid concentrations. We purchased seedless watermelons from a local source in East Lansing, Michigan. Pomace was prepared from the watermelons using a rack and cloth hydraulic press. Immediately before use, the pomace was squeezed using a juice maker. The resulting juice was filtered through a fine screen (03–250/50 NITEX, SefarFiltration) to obtain fluid, which was then added to drinking water for rats. Concentrations of carbohydrates, protein, and fat in the watermelon pomace juice were 24, 0.87, and 0.45 g/L, respectively, as determined using the proximate analysis (25). Concentrations of free amino acids in the watermelon pomace juice (mg/L), analyzed using HPLC methods (13), were as follows: citrulline, 2014; arginine, 1150; aspartate, 66; glutamate, 17; asparagine, 45; serine, 60; glutamine, 172; histidine, 88; glycine, 18; threonine, 34; alanine, 32; tyrosine, 37; tryptophan, 48; methionine, 39; valine, 78; phenylalanine, 89; isoleucine, 87; leucine, 79; ornithine, 18; lysine, 75; cysteine, 62; and proline, 74. Citrulline plus arginine accounted for 71% of total free amino acids (4.5 g/L) in the watermelon pomace juice.

    Experimental design and animals. Male ZDF rats (8 wk old) were obtained from Charles River and had free access to drinking water and a Purina 5008 diet (13) throughout the study. This nonpurified diet contained 23.5% crude protein, 6.0% fat, 34.9% starch, 2.6% sucrose, 0.5% glucose plus fructose, 6.8% minerals, 3.8% fiber, and 17,364 kJ gross energy/kg. Alanine content in the diet was 1.39%, arginine was 1.44%, and lysine was 1.40%. Rats were housed in a temperature- and humidity-controlled facility on a 12-h-light:12-h-dark cycle.

At 9 wk of age, rats were assigned randomly to receive drinking water (distilled and deionized water) containing 0.0% or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). L-Arginine was used as a positive control. The dose of watermelon pomace juice was chosen to provide 0.2% L-citrulline plus L-arginine (this study). Because almost all dietary L-citrulline is converted into arginine in animals (9), the dose of watermelon pomace juice was chosen to provide L-arginine similar to L-arginine intake from drinking water by arginine-supplemented ZDF rats. The doses of lycopene and citrus pectin were selected to mimic those in 63% watermelon pomace juice (26). The drinking water was changed daily at 0900. We measured body weights and food intakes of rats daily. At the end of the 4-wk dietary supplementation, rats were killed to obtain tissues. On the day before rats were killed, tail venous blood samples (0.2 mL) were obtained at 1200 (6 h after feeding) from unanesthetized rats, as described by Wu (27). In the morning of the next day, 6 h after feeding, rats were killed with an effective dose of CO₂ and cardiac blood samples, aorta, and other tissues were obtained. Blood samples were centrifuged at 10,000 x g for 1 min to obtain serum, aorta was placed in PBS on wet ice, and other tissues were frozen in liquid nitrogen. This study was approved by Texas A&M University Animal Care and Use Committee.

    Biochemical analysis. Serum samples from the tail vein were analyzed for amino acids, glucose, nitrite and nitrate (NO_x), oxidation products of NO, and lipids using established methods (13,17,28). Cardiac serum samples were used for the determination of methylarginines (inhibitors of NO synthase), homocysteine, insulin, and growth hormone, as we previously described (12,13). Methylarginines and homocysteine are independent risk factors for cardiovascular disease (18).

    Determination of NO synthase activity, GTP cyclohydrolase-I activity, and BH4 concentrations in the heart. The enzymatic activities of NO synthase (both constitutive and inducible) and GTP cyclohydrolase-I in the heart (as a vascular tissue) were determined using radiochemical and HPLC methods, respectively, as described by Meininger and Wu (28). Concentrations of BH4 were measured by HPLC after oxidation of samples under acidic and alkaline conditions (28).

    Measurement of endothelium-dependent relaxation in aorta. The endothelium-dependent relaxation of thoracic aortic rings was determined in the presence of 10^–9 to 10^–5 mol/L acetylcholine and 0 or 0.1 mmol/L N^G-monomethyl-L-arginine (an inhibitor of NO synthase), as described by Heaps et al. (29). In all rings, NO-mediated relaxation was verified at the end of the experiment using 100 µmol/L sodium nitroprusside, a spontaneous NO donor (30).

    Calculation and statistical analysis. Results are expressed as means ± SEM. Combustion energy values of arginine (21.45 kJ/g), protein (22.6 kJ/g), carbohydrate (17.2 kJ/g), and fat (39.3 kJ/g) were used to calculate energy intake from the drinking water (12). Data on body and tissue weights, nutrient intakes, metabolite concentrations, and enzyme activities were analyzed by 1-way ANOVA. Data on aortic vessel relaxation were analyzed using 2-way ANOVA for repeated measurements. Differences among the means of treatment groups were determined by the Student-Newman-Keuls test. All statistical analyses were performed using SAS software (SAS Institute). P 0.05 was considered significant.

	Results

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    Intake of water, food, and energy. Food, water, and gross energy intakes over the 4-wk period of the study did not differ among ZDF rats supplemented with 0 or 0.2% L-arginine, 63% watermelon pomace, 0.01% lycopene, and 0.05% citrus pectin (Table 1). Arginine intake from the diet was 1.17 ± 0.08, 1.19 ± 0.07, 1.13 ± 0.09, 1.16 ± 0.06, and 1.15 ± 0.07 g·kg body weight^–1·d^–1, respectively, for rats supplemented with 0.0%, 0.2% L-arginine, 63% watermelon pomace juice, 0.01% lycopene, and 0.05% citrus pectin. L-Arginine intake from drinking water by arginine-supplemented rats was 0.616 ± 0.04 g·kg body weight^–1·d^–1. For rats supplemented with watermelon pomace juice, the intake of L-citrulline plus L-arginine from drinking water was 0.632 ± 0.06 g·kg body weight^–1·d^–1. Total energy intakes from the diet plus drinking water were 1416 ± 97, 1453 ± 84, 1478 ± 115, 1401 ± 78, and 1391 ± 89 kJ·kg body weight^–1·d^–1, respectively, for rats supplemented with 0.0%, 0.2% L-arginine, 63% watermelon pomace juice, 0.01% lycopene, and 0.05% citrus pectin.

View larger version (13K): [in this window] [in a new window]   FIGURE 1  Effect of dietary supplementation with 0.0% (control), 63% watermelon pomace juice, 0.2% L-arginine, 0.01% lycopene, and 0.05% citrus pectin on acetylcholine-induced relaxation of aortic rings from ZDF rats. Aortic vessel reactivity was measured in the presence of increasing concentrations of acetylcholine. The assay medium contained no NG-monomethyl-L-arginine. Data are mean ± SEM, n = 5. At each concentration of acetylcholine, means without a common letter differ, P < 0.05.

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Endothelial dysfunction is a major risk factor that contributes to high rates of morbidity and mortality in NIDDM (5). Aortic rings from all groups of ZDF rats exhibited similar relaxation (93%) in response to sodium nitroprusside (a spontaneous donor of NO), suggesting that NO signaling pathways are intact in vascular smooth cells. Interestingly, when NO synthesis was blocked by N^G-monomethylarginine, vessel reactivity was minimal (< 8% relaxation) and did not differ among all the groups of ZDF rats. This result demonstrates that acetylcholine-induced relaxation in aortic rings was primarily mediated by NO and that NO-independent vessel reactivity was likely not affected by dietary supplementation with L-arginine or watermelon pomace juice. In contrast, compelling evidence shows that endothelium-dependent relaxation is impaired in obese ZDF rats compared with lean Zucker rats (32,33). Thus, increasing NO availability would be beneficial for improving hemodynamics and, therefore, preventing and treating cardiovascular disease in ZDF rats and perhaps humans.

We reported that the endothelial synthesis of NO is impaired in the Bio-Breeding rat (a spontaneous model of type I diabetes) and the ZDF rat due to a deficiency of GTP cyclohydrolase-I (30,34), the first and rate-controlling enzyme for the de novo synthesis of BH4 (an essential cofactor for NO synthase). Increasing the availability of BH4 through either the transfer of the GTP cyclohydrolase-I gene or addition of sepiapterin (an effective precursor of BH4) restored NO synthesis in endothelial cells (12,30). The GTP cyclohydrolase-I gene therapy also normalized aortic vessel reactivity in both Bio-Breeding and ZDF rats (30). Notably, results from this study indicate that endothelium-dependent relaxation was markedly improved in ZDF rats that received chronic supplementation with either watermelon pomace juice or L-arginine (Fig. 1), in association with reduced serum concentrations of risk factors for vascular dysfunction (including glucose, free fatty acids, methylarginines, and homocysteine) (Tables 2–5). In contrast, dietary supplementation with lycopene and pectin, 2 other substances that are present in watermelon pomace juice (26), had no effect on all the measured parameters in ZDF rats. These results suggest that the beneficial effect of watermelon pomace juice as a functional food on vascular function results from its provision of citrulline and arginine.

In endothelial cells, L-arginine itself is not limiting for NO synthase, because intracellular concentrations of arginine (0.5–1.5 mmol/L) are well above the K_m value for the nitrogenous substrate (3 µmol/L) (22). L-Arginine did not affect expression of NO synthase-3 protein in endothelial cells (35). However, physiological concentrations of L-arginine stimulates GTP cyclohydrolase-I expression in these cells (35), therefore increasing the synthesis and availability of BH4 that is required for maximal NO generation and vessel relaxation (30). Consistent with this observation, we found that dietary supplementation with L-arginine or watermelon pomace juice did not affect the amount of NO synthase protein (as indicated by no change in its enzymatic activity measured under optimal conditions) in the heart of ZDF rats (Table 6). However, the arginine treatment enhanced GTP cyclohydrolase-I activity and BH4 concentrations in this vascular tissue (Table 6).

Another novel and interesting result from this study is that dietary supplementation with either watermelon pomace juice or L-arginine increased the mass of brown adipose tissue and reduced the mass of subcutaneous and retroperitoneal fat pads in ZDF rats (Table 2). Brown adipose tissue is rich in mitochondria, where fatty acid and glucose oxidation results in the production of heat rather than ATP because of the presence of uncoupling protein-1 (6). Increased brown adipose tissue brought about by the treatment with watermelon pomace juice or L-arginine is expected to augment the oxidation of fatty acids and glucose in this tissue, thereby reducing their plasma concentrations and use for fat synthesis in white adipose tissue. Our finding is consistent with the recent discovery that NO stimulates mitochondrial biogenesis in various tissues, including brown adipose tissue (8). Additionally, L-arginine enhanced gene expression of peroxisome proliferator-activated receptor coactivator-1 (13), a master regulator of oxidative phosphorylation and mitochondrial biogenesis in diverse cell types (8), therefore reducing the mass of white adipose tissue in ZDF rats (Table 2).

Chronic consumption of watermelon is a safe and effective alternative to oral administration of L-arginine in raising its plasma levels in healthy subjects (24) and may represent a novel and useful strategy for the management of obesity and diabetes. Provision of citrulline from watermelon also offers a unique advantage over the enteral supply of L-arginine for the following reasons. First, 40% of dietary L-arginine is catabolized by the intestinal tissues of adult humans and other mammals in the first pass (36). In contrast, citrulline undergoes limited degradation in enterocytes of postweaning animals due to a low activity of argininosuccinate synthase in the cells (37). Thus, on the same equal molar basis, the entry of dietary citrulline into the portal circulation is much greater than that of dietary arginine in adults. Second, there is little uptake of circulating citrulline by liver and, therefore, nearly all the citrulline absorbed from the small intestine bypasses the liver and enters the systemic circulation (38). Third, in mammals, the synthesis of arginine from citrulline is the only pathway for its utilization by extrahepatic tissues, including predominantly kidneys as well as other tissue and cell types (e.g. heart, brain, macrophages, and endothelial cells) (9). Indeed, the vascular effects of dietary supplementation with 63% watermelon pomace juice were equivalent to those brought about by supplementation with 0.2% L-arginine in ZDF rats (Fig. 1). Thus, watermelon may be a functional food for ameliorating the metabolic syndrome of NIDDM. Future studies are warranted to determine the effect of watermelon consumption on human subjects with obesity and diabetes.

In conclusion, results of this study demonstrate for the first time to our knowledge a beneficial effect of oral administration of watermelon pomace juice on increasing the mass of brown adipose tissue, reducing excess white fat mass and serum concentrations of risk factors for cardiovascular disease, and enhancing NO-dependent vessel reactivity in ZDF rats. Consumption of this functional food may represent a potentially novel and useful strategy for the dietary management of the metabolic syndrome in NIDDM and obesity.

	ACKNOWLEDGMENTS

 
The authors thank Scott Jobgen, Dr. Wenjuan Jobgen, and Dr. Peng Li for technical assistance, Dr. Janet Parker for helpful discussion, and Ms. Frances Mutscher for office support.

	FOOTNOTES

 
¹ Supported by the U.S. National Watermelon Promotion Board and American Heart Association-TX grant 0755024Y.

² G. Wu, J. K. Collins, P. Perkins-Veazie, M. Siddiq, K. Dolan, K. A. Kelly, C. L. Heaps, and C. J. Meininger, no conflicts of interest.

⁸ Abbreviations used: BH4, tetrahydrobiopterin; NIDDM, noninsulin-dependent diabetes mellitus; NO, nitric oxide; NO_x, oxidation products of nitric oxide; ZDF, Zucker diabetic fatty.

Manuscript received 23 July 2007. Initial review completed 4 September 2007. Revision accepted 2 October 2007.

	LITERATURE CITED

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