Flaxseed Secoisolariciresinol Diglucoside and Visceral Obesity

C H A P T E R

29 Flaxseed Secoisolariciresinol Diglucoside and Visceral Obesity A Closer Look at its Chemical Properties, Absorption, Metabolism, Bioavailability, and Effects on Visceral Fat, Lipid Profile, Systemic Inflammation, and Hypertension Jae B. Park Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, United States Department of Agriculture, Agricultural Research Service, Beltsville, MD, USA

INTRODUCTION Linum usitatissimum (flax), which belongs to the Linaceae family, is an important flowering crop that is cultivated worldwide. Although the genus Linum consists of more than 100 species, L. usitatissimum (flax) has long been considered as a valuable agricultural crop plant due to the production of oil, fiber, lignan, and other products [1–3]. Traditionally, flax products and compounds have also been prescribed for treating several human chronic diseases such as diabetes, high cholesterol, cardiovascular diseases, and related conditions [4–7]. Although flaxseed contains various bioactive compounds, it contains a relatively high amount of lignans such as secoisolariciresinol diglucoside (SDG), which has been reported to have numerous biological activities and health benefits [8–13]. Obesity is a serious, rampant health problem closely associated with multiple contributing factors such as unhealthy or unbalanced diets, a sedentary lifestyle, and genetic factors [14–16]. Obesity causes many physiological changes in humans; visceral obesity, manifested by increased adiposity around the waist, is a hallmark physical change [17–19]. In fact, visceral obesity is strongly associated with the development and progression of several chronic diseases such as diabetes, cardiovascular diseases, hypertension, and kidney diseases [20–26]. In the marketplace, many flaxseed-related products are currently available. SDG lignan-enriched flaxseed powder was recently introduced as a dietary ingredient in the marketplace, but

Nutrition in the Prevention and Treatment of Abdominal Obesity http://dx.doi.org/10.1016/B978-0-12-407869-7.00029-5

the potential effects of the powder on obesity and hypertension have not been examined in detail. Therefore, in this chapter, the potential effects of SDG lignan-enriched flaxseed powder on obesity are reviewed via closely examining the chemical properties, absorption, metabolism, and bioavailability of SDG, as well as its effects on body weight, visceral fat, lipid profiles, systemic inflammation, and blood pressure. Particularly, the potential effects of SDG lignan powder on systemic inflammation induced by adipokines are thoroughly reviewed because increased adiposity is closely associated with systemic inflammation manifested by increased production of cytokines [C-C motif chemokine 2/monocyte chemoattractant protein 1 (MCP-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α)], as well as decreased production of anti-inflammatory and antidiabetic adiponectin [27–33]. The overall aim of this review is to provide scientific information to enable a better understanding of the potential effects of SDG on obesity and its related conditions.

FLAXSEED CHEMICALS The nutritional composition of flaxseed is about 30% carbohydrate, 18% protein, and 39% fat [34–35]. Most of the carbohydrate in flaxseed is in the form of fiber and more than 45% of the oil comprises omega-3 fatty acids [34]. Other compounds include coumaric acid ferulic acid glucoside, glucoside, herbacetin diglucoside,

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© 2014 Elsevier Inc. All rights reserved.

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29.  POTENTIAL EFFECTS OF SDG ON VISCERAL OBESITY

TABLE 29.2  Amounts of Lignans in Plant Sourcesa

TABLE 29.1  Composition of Flaxseed Products Flaxseed

Flaxseed Oil

Defatted Flaxseed

SDG Powdera

Carbohydrate

30%

–

48%

–

Fiber

27%

–

45%

–

Protein

18%

–

30%

–

Fat

39%

100%

< 3%

–

Lignan

0.3%

–

0.4%

< 35%

Source: Data were taken from Refs [34,35]. a Indicates SDG-enriched powder used in [66]. –, amounts are negligible or unknown.

lariciresinol, matairesinol, pinoresinol, and secoisolariciresinol (Table 29.1) [35]. Currently, many flaxseed products such as whole flaxseeds, milled flaxseeds, flaxseed oil, (defatted) flaxseed cakes, and lignan-enriched flaxseed powder are available on the market. Among them, SDG lignan-enriched flaxseed powder is a relatively new flaxseed product. As shown in Table 29.1, SDG-enriched powder contains approximately 35% SDG complex, with 15.1% coumaric acid glucoside, 8.1% ferulic acid glucoside, and 15.6% hydroxymethylglutaric acid [35]. Since any potential effects of SDG should be understood within the context of its chemical properties, absorption, and metabolism, these topics are reviewed first.

CHEMICAL PROPERTIES, ABSORPTION, AND METABOLISM OF SECOISOLARICIRESINOL DIGLUCOSIDE Lignans belong to a class of diphenolic compounds that occur widely in nature, which are often classified into several major subgroups: dibenzocyclooctadienetype, dibenzylbutane-type, dibenzylbutyrolactone-type, naphthalene-type, neo-type tetrahydrofuran-type, and tetralin-type lignans. In plants; lignans are synthesized from phenylpropanoic acids (caffeic, cinnamic, coumaric, and ferulic acids) via oxidative coupling and other processes [36]. As shown in Table 29.2, lignans are found in a variety of food sources [37–39]. Among the lignans, SDG (empirical formula, C32H46O16; molecular weight, 686.7) is a dibenzylbutanetype lignan and a major lignan component in flaxseed products [38–39]. The total proportion of lignans in flaxseeds is about 0.335%, and most are in the form of secoisolariciresinol (SECO; 0.32%) [1]. In flaxseeds, SECO (empirical formula, C20H26O6; molecular weight, 362.4) is synthesized via a radical-initiated dimerization process that converts coniferyl alcohols to pinoresinol

Sources

SECO

MATA

LARI

PINO

Flax

323.6

5.202

3.670

2.460

Sesame

0.014

0.734

5.389

25.88

Wheat

0.035

0.003

0.062

0.037

Barley

0.030

0.003

0.085

0.072

Rye

0.038

0.027

0.324

0.381

Oat

0.019

0.071

0.018

0.019

Rice

0.003

0.002

0.028

0.007

Broccoli

0.038

–

0.970

0.310

Garlic

0.050

–

0.280

0.200

French bean

0.028

–

0220

0.022

Carrot

0.092

–

0.060

0.018

Pumpkin

0.971

0.003

3.913

0.235

Asparagus

0.183

0.002

0.047

0.049

Eggplant

0.005

–

0.068

0.028

Strawberry

2.305

0.005

0.970

0.817

Lingonberry

1.402

0.005

0.308

2.625

Mango

0.265

0.011

0.561

0.080

Kiwi

0.116

–

0.010

0.008

Avocado

0.081

0.011

0.076

0.494

Grape

0.032

–

0.037

0.028

Orange

0.011

–

0.019

0.009

Pineapple

0.007

0.010

0.067

0.004

Lemon

0.004

–

0.025

0.185

Tomato

0.001

–

0.011

0.005

Seeds/Grains

Vegetables

Fruits

Source: Data were taken from Refs [1,38]. a In mg/100 g –, amounts are negligible or unknown. LARI, lariciresinol; MATA, matairesinol; PINO, pinoresinol; SECO, secoisolariciresinol.

(PINO), which is then converted into a dibenzylbutanetype SECO (Fig. 29.1) [36]. SECO is then glycosylated into SDG by the addition of UDP-glucose (Fig. 29.1) [40]. After SDG intake, the lignan is believed to be deglycosylated in the small intestine by glucosidase, either in the brush border of the gut mucosa or in gut bacteria, back into SECO. SECO is then converted by the gut microflora into mammalian lignans such as enterodiol

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FIGURE 29.1  Chemical structures. END, enterodiol; ENL, enterolactone; SDG, secoisolariciresinol diglucoside; SECO, secoisolariciresinol.

(END; empirical formula, C18H22O4; molecular weight, 302.3) and enterolactone (ENL; empirical formula, C18H18O4; molecular weight, 298.3) probably via multiple processes including demethylation, dehydroxylation, and dehydrogenation (Fig. 29.1) [41,42]. ENL and END generated in the intestine are then absorbed into the bloodstream and reach the liver, where they may be conjugated with glucuronic acid or sulfate [43]. In fact, most of ENL and END appear as conjugates in various body fluids in humans and animals [44,45], and the main END and ENL metabolites found in plasma and urine are glucuronide conjugates [45–47]. In addition it is possible for oxidative metabolism of ENL and END to occur in liver microsomes, whereby additional hydroxylation is added to the para and ortho positions of the original hydroxy position in the phenolic moiety [43]. From the antioxidant perspective, these hydroxylation processes may be important because ENL and END then contain a catechol-like structure that can be reversibly oxidized to an O-quinone structure upon oxidation. In fact, a catechol-like structure is usually found in well-known antioxidant compounds, and is believed to be involved in scavenging the radical oxygen species (ROS) generated in cells. Another property of enterolignans (ELs; including ENL and END) is that they are relatively stable in biological fluids. Therefore, they are commonly used as biomarkers, as described below [48].

BIOAVAILABILITY OF SECOISOLARICIRESINOL DIGLUCOSIDE Bioavailability is the term used to describe the physiological availability of a compound in a given amount; it depends mainly on the amount initially administered, as well as absorption, metabolism, tissue distribution, and excretion. Studies often use several different doses and different administration routes to determine the bioavailability of a compound. To evaluate the potential effects of SDG on human health, it is critical to determine its bioavailability. As mentioned above, due to its relative stability in biological fluids, EL is commonly used as a biomarker for determining SDG bioavailability [49]. Several reported bioavailability studies are worth examining. First, SDG bioavailability was investigated in healthy human subjects who consumed 30 g milled flaxseeds (equivalent to 90 mg SDG lignan) daily for 4 weeks. This study reported that the total EL concentration was about 513 nM, and average END and ENL concentrations were 209 nM and 304 nM, respectively [49,50]. Another human study investigated the possible effects of different types of flaxseed products (whole flaxseed, crushed flaxseed, and ground flaxseed) on SDG lignan bioavailability. In this study, the total EL concentration of ELs was approximately 270 nM, and average concentrations of END and ENL were 103 nM and 167 nM, respective, following the consumption of about 20 g ground flaxseed

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(equivalent to 60 mg lignan) [51]. The latter study also reported that plasma EL concentrations following the consumption of crushed flaxseed and whole flaxseed were lower than those observed in the ground flaxseed group. Data showed that the relative bioavailability of ELs from whole flaxseed was about 28% that of ground flaxseed, whereas the relative bioavailability of ELs from crushed flaxseeds was about 43% [51]. Although a number of studies have clearly shown that the intake of lignan-rich foods leads to increased plasma EL levels in most subjects, there are growing concerns that the bioavailability of ELs may be significantly influenced by food matrix, gut microbial action, and other factors, thereby being subject to large interpersonal, foodstuffderived, and other variations. For examples, a continuous increase serum EL concentration was observed over a 4-month intervention with flaxseed (33, 52, and 70 nM at baseline and after 2 and 4 months, respectively) [52]. In another study, a dose-response urinary excretion of SDG metabolites was reported (with no plateau) after the daily consumption of 5, 15, and 25 g flaxseed products for 7 days [53]. These data indicate that the amount of ELs produced by intestinal bacteria may increase linearly, but that blood levels of ELs may largely depend on an individual-specific threshold, caused by adaption to metabolic and excretory mechanisms. This indicates that future intervention studies in human subjects should comprehensively assess the effects of several different lignan concentrations on the digestive system, blood, and urine. As noted, variations and individual limitations in EL concentrations are expected; this point should be considered when interpreting potential in vivo biological activities.

EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON OBESITY AND LEVELS OF REACTIVE OXYGEN SPECIES So far, we have looked at the chemical properties, absorption, metabolism, and bioavailability of SDG. Now, it is time to turn our attention to the potential effects of SDG on obesity because (1) obesity is a serious global health problem affecting many people and (2) flaxseed products have often been used to treat obesityrelated conditions [14–18]. In fact, obesity is a result of multiple contributing factors such as unhealthy or unbalanced diets, eating habits, lifestyle, and genetic factors [14,15]. Particularly, modern sedentary lifestyles, lack of exercise, and/or unhealthy diets that often contain high levels of daily calories have been blamed for the increase in obesity worldwide [16–18]. Although obesity is associated with many physiological changes, visceral obesity is a noticeable physical change that is strongly associated with “bad” lipid profiles and low-level systemic

inflammation, which are the main causes of the development and progression of several chronic diseases including diabetes, cardiovascular diseases, hypertension, and kidney disease [16–19]. Although the cellular and molecular events related to obesity are still being elucidated, a high-calorie diet coupled with the lack of physical activity is believed to be a leading cause of the increased body weight associated with significant visceral fat accumulation, high triglyceride and cholesterol levels, and systemic inflammation (Fig. 29.2) [20–23]. Currently, there are only a limited number of studies relating the effects of SDG on body weight, particularly in humans. Therefore, more studies should be performed in the future to determine the potential effects and mechanisms of SDG in obesity. Nonetheless, there are some reports that flaxseed compounds including SDG possess a broad spectrum of biological properties, thus paving the way to endorsing their positive effects on risk factors associated with several obesity-related chronic diseases such as diabetes, cardiovascular diseases, and hypertension [4,6,7,14–17,54,55]. In fact, some epidemiological studies also suggest that flaxseeds containing SDG may protect against obesity-related diseases [17–19]. As mentioned previously, SDG and its mammalian metabolites (SECO, END, and ENL) have good antioxidant properties [56]. Oxidative stress is a major concern in obesity because increased levels are seen in obese subjects; these are considered to be a major cause of diabetes, cardiovascular disease, hypertension, kidney disease, and neuronal disorders [57,58]. Oxidative stress is mainly caused by ROS, produced as normal or abnormal by-products from several sources such as mitochondria, xanthine oxidase, and NADPH oxidase [59,60]. Along with insufficient antioxidant defense systems and/or some types of disease conditions, elevated ROS can cause grave damage to cellular components such as carbohydrates, lipids, proteins, and DNA, thus leading to homeostatic changes, cellular transformation, and/or apoptosis [61,62]. SDG is reported to restore antioxidant capacity in diabetic rats and to deliver positive effects on obesity in mice fed a high-fat diet [63,64]. The latter study showed that both oral administration of (−)-SECO and subcutaneous injection of SECO significantly suppressed the gain of body weight in mice [64]. Also, the subcutaneous injection of (−)-SECO, (−)-END, or (−)-ENL was reported to upregulate the expression of several genes such as those encoding acyl-CoA oxidase (ACO), carnitine O-palmitoyltransferase 1 (CPT-1; encoded by Cpt1b), and peroxisome proliferator-activated receptor alpha (PPAR-α), suggesting that (−)-SECO may be able to reduce body weight gain in mice fed a high-fat diet, possibly by inducing changes the expression of genes related to fatty acid synthesis and beta-oxidation [64,65]. Similarly, our study showed that 0.02% SDG-enriched flaxseed power (SEFP) was effective in reducing body

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Effects of Secoisolariciresinol Diglucoside on Adipose Tissues

weight in rats [66]. In this study, after feeding a control, a high-fat diet, or a high-fat diet containing SEFP (equivalent to 200  mg/day in body weight of 60  kg) for 12  weeks, the body weight of rats fed the high-fat diet containing SEFP was comparable to those on the control diet and significantly lower than that of rats fed the highfat diet, although the initial body weights and feed intakes of rats in the three groups were similar. In other words, body weight gain per day was significantly lower in rats fed both the control and the high-fat diet supplemented with SEFP compared to those fed the high-fat diet alone. These data indicates that SDG supplementation may have positive effects on body weight reduction in rats fed a high-fat diet. Although these data are limited, a human study also reported that the daily consumption of a flaxseed lignan complex (600 mg SDG) for 3  months leads to a reduction of abdominal fat

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accumulation along with other benefits in older type 2 diabetics [67]. However, the potential effects of SDG on body weight reduction are still limited, so more studies should be performed in the future.

EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON ADIPOSE TISSUES If SDG is truly able to suppress body weight gain, then this may result mainly from a reduction in adipose tissue, because adipose tissues are major sites of fat storage that contribute to nonmuscular body weight gain (Fig. 29.2). In an in vitro study, (−)-SECO was reported to reduce lipid accumulation in adipocytic 3T3-L1 cells [68]. In this study, mRNA expression of adipogenesisrelated genes and DNA-binding activity of PPAR-γ to

FIGURE 29.2  Diagram of lignan, cholesterol, and lipid absorption, cholesterol metabolism, and systemic inflammation. BA, bile acids; CETP, cholesteryl ester transfer protein; CM, chylomicrons; CMR, chylomicron remnants; END, enterodiol; ENL, enterolactone; FFA, free fatty acids; FC, free cholesterol; HDL, high-density lipoprotein; HL, hepatic lipase; Imm, inner mitochondrial membrane; LCAT, lecithin cholesterol acyl transferase; LPL, lipoprotein lipase; LRP, lipoprotein receptor-related proteins; Ox-LDL, oxidized low-density lipoprotein; SDG, secoisolariciresinol diglucoside; SECO, secoisolariciresinol. (See color plate at the back of the book.)

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29.  POTENTIAL EFFECTS OF SDG ON VISCERAL OBESITY

PPAR response elements were investigated in differentiated 3T3-L1 adipocytes treated with several doses of END. END induced the mRNA expression of several adipogenesis-related genes, such as those encoding adiponectin, leptin, solute carrier family 2, facilitated glucose transporter member 4 (GLUT4), and PPAR-γ, and also increased the DNA-binding activity of PPAR-γ to the PPAR response sequence [68]. These in vitro data are supported to some extent by an in vivo study showing that (−)-SECO has positive effects on obesity in C57BL/6 male mice fed a high-fat diet, even though this study did not specifically investigate effects on adipose tissue [64]. As mentioned previously, subcutaneous injection of (−)-SECO increases the expression of genes related to fat metabolism, suggesting that this lignan may suppress fat accumulation in adipocytes via altering the gene expression of various enzymes related to fatty acid synthesis and beta-oxidation. In another study, body weight, visceral fat weight, liver fat content, and other parameters were investigated in mice fed a low-fat diet (5%), a high-fat diet (30%), or high-fat diet containing 0.5% and 1.0% SDG for 4 weeks. In this study, SDG significantly reduced high-fat diet-induced visceral and liver fat accumulation [68]. Likewise, our study showed that a high-fat diet was clearly a major factor in obesity in rats; the high-fat diet increased the average rat body weight by 10% more than the control diet and the highfat diet containing SEFP. Therefore, in this study, the fat sources contributing to body weight gain were investigated by measuring the weights of the major organs (liver, heart, and kidney) and adiposes tissues (epididymal, subdiaphragmatic, and visceral) [66]. Although no significant change in the weight of hearts was found in any of the three groups, the average liver weight of rats fed the high-fat diet and high-fat diet containing SEFP were slightly but not significantly higher than those of rats fed a control diet [66]. However, the average kidney weight of rats fed the high-fat diet were significantly (20%) higher than those of rates fed the control diet [66]. In the same study, three different types of adipose fats were also measured and compared as potential fatcontributing sources of body weight gain. Although the average weights of epididymal and subdiaphragmatic fats were not significantly different in rats fed any of the three diets, the average visceral fat weight of rats fed a high-fat diet was more than 40% higher than that of rats fed a control diet [66]. However, the increased weight was reduced by more than 40% in rats fed the high-fat diet containing SEFP. Similarly, the average weight of combined adipose fats (epididymal, subdiaphragmatic, and visceral) from rats fed a high-fat diet was 27% higher than in rats fed a control diet, but the average weight was reduced by more than 50% in rats fed the high-fat diet containing SEFP. These data indicate that rats fed both a high-fat diet and a high-fat diet containing SEFP

gained weight particularly in visceral fat, but that SDG lignan supplementation significantly lowered the average visceral fat weight. Since rat visceral fat is considered to be equivalent to abdominal fat in humans, these data suggest that SDG supplementation may alleviate central obesity-related conditions in humans. However, there is still limited information about changes in fat accumulation in human adipose tissues and organs, although SDG has been reported to have some positive effects on central obesity.

EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON PLASMA LIPIDS AND CHOLESTEROLS Hyperlipidemia and hypercholesterolemia are often associated with the onset of obesity, leading to the initiation and progression of several chronic diseases such as atherosclerosis and cardiovascular disease (Fig. 29.2) [69]. In humans, dyslipidemia is manifested by high total cholesterol (TC; > 240 mg/dL), low high-density lipoprotein cholesterol (HDLc; < 40 mg/dL), high low-density lipoprotein cholesterol (LDLc; > 160 mg/dL), and high triglyceride (> 200 mg/dL) levels, all of which are significant contributors to plaque formation in blood vessels [69]. In the obese, diminished antioxidants and rising ROS increase the chance of LDL oxidation, thus promoting the increased production of the proinflammatory cytokines IL-6, TNF-α, and others (Fig. 29.2), which are associated with the progressions of atherosclerosis, cardiovascular disease, hypertension, and kidney disease [58]. In animal studies, dietary flaxseed supplementation was associated with significant reductions in plasma TC levels and TC:HDLc ratio and increased plasma HDLc, compared to animals without the supplementation [70,71]. The first report also pointed out that flaxseed significantly reduced hepatic cholesterol and triglyceride levels in chemically induced diabetic hamsters [70], and the second report suggested that flaxseed supplementation has positive effects on hypertriglyceridemia and hypercholesterolemia in SHR rats, although the effects were not solely derived from SDG [71]. In a rabbit model, similar results were obtained: rabbits fed CDC-flaxseed (i.e. type II flaxseed) with a very low omega-linolenic acid content for 4-8 weeks showed lower plasma TC and LDLc concentrations [54]. Similarly, SDG supplementation was reported to reduce hyperlipemia, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia in mice fed a high-fat diet [68]. In this study, SDG also suppressed the expression of info Srebf1 mRNA (encoding sterol response element-binding protein 1c (SREBP-1c)] in the liver and increased the expression of Cpt1b mRNA in the skeletal muscle [68]. Our study showed similar results: plasma triglycerides and LDL concentrations

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EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON ADIPONECTIN, TNF-α, IL-6, AND SYSTEMIC INFLAMMATION

in rats fed a high-fat diet containing SEFP were lower than in those fed a high-fat diet and similar to in those on a control diet [66]. In addition SDG supplementation restored plasma HDL concentration in rats fed a high-fat diet containing SEFP, indicating that supplementation may improve serum LDL and HDL levels and increase the HDL:TC ratio [66]. These data suggest that SDG supplementation may improve the plasma lipid profile in animals, compared to those fed on a high-fat diet alone. Dyslipidemia is also profoundly associated with obesity in humans [69]. In a human study, diets supplemented with partially defatted flaxseed were reported to lower TC and LDLc, possibly due to the fiber and other components present in defatted flaxseed [72]. However, this study hinted that the hypocholesterolemic effect may be attributed to flaxseed components other than omegalinolenic acid (such as SDG) because partially defatted flaxseed is low in this fatty acid. This hypothesis is actually supported by another human study reporting that SDG (600 mg/day for 8 days) decreases cholesterol, LDL, and TC levels in humans with hypercholesterolemia and hypertriglyceridemia [73]. However, human studies often provided contradictory or outcomes showing no effect. For example, SDG (20 mg/day for 12 weeks) was reported to have no effect on lipid parameters, and only a small drop in the LDL:HDL ratio [10]. Another human study reported that although flaxseed may be able to reduce circulating TC and LDLc concentrations, these changes were often dependent on the type of intervention, gender, and initial lipid profiles of the subjects participating in the study [74]. Therefore, more studies are required to determine the dose-dependent efficiency of SDG on lipid profiles in men and women in order to determine its potential benefits in obesity.

EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON ADIPONECTIN, TNF-α, IL-6, AND SYSTEMIC INFLAMMATION As discussed above, obesity is often associated with dyslipidemia and hypercholesterolemia. Excessive fats and cholesterols in the obese often accumulate in adipocytes and other cells (Fig. 29.2). Besides their fat-storage capacity, adipose tissues can produce a wide range of hormones and cytokines such as adiponectin, leptin, IL-6, and TNF-α as a result of adipocyte hypertrophy, and these molecules greatly affect the metabolism and function of many organs and tissues including muscle, liver, vasculature, kidney, and brain [28,30]. Leptin is considered to be a key signaling molecule in communicating longterm nutritional and fat mass status to the brain (hypothalamus), and its production is remarkably increased in large adipocytes [27,75,76]. Like leptin, adiponectin is

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an adipocyte-derived hormone with antidiabetic, antiatherogenic, and anti-inflammatory functions. However, plasma adiponectin decreases with obesity and insulin resistance. In an in vitro study, (−)-SECO was reported to reduce lipid accumulation and induce adiponectin production in 3T3-L1 adipocytes [65]. In another study, lignan was also reported to increase the expression of adiponectin mRNA in white adipose tissue [10]. Similarly, in our animal study, average plasma adiponectin levels in the control group were higher than those in the high-fat group, and the average plasma adiponectin levels in rats fed a high-fat diet containing SEFP were slightly higher than those in rats fed a high-fat diet, indicating that the supplementation can increase adiponectin levels to those found in the control group [66]. In the same study, the levels of inflammatory cytokines such as IL-6 and TNF-α were also investigated. TNF-α is a cytokine that is critically involved in normal host resistance to infection and to the growth of malignant tumors; it is produced by activated macrophages and other cell types such as T and B cells, natural killer cells, endothelial cells, and muscle cells [77–79]. In fact, macrophages are more prevalent in the adipose tissue of obese subjects than in lean subjects, and macrophage quantity correlates well with the severity of insulin resistance and obesity [77]. However, in our study, no significant difference in plasma TNF-α level was observed among all three groups. IL-6 is another inflammatory cytokine related to obesity that is involved in the acute-phase reactions, inflammation, hematopoiesis, and cancer [27,80,81]. Like TNF-α, IL-6 levels are often higher in obese subjects than in lean subjects [27]. However, no significant change in IL-6 levels was observed among all three groups. These observations are actually consistent with other studies, indicating that changes in the levels of these two molecules (IL-6 and TNF-α) are not often followed by a moderate body weight gain [82–84]. Therefore, it is likely that the level of obesity plays a critical role in changing the expression of inflammatory cytokines. In a human study, C-reactive protein (CRP), IL-6, thiobarbituric acid reactive substance (TBARS), and TNF-α levels and homeostatic model assessment of insulin resistance (HOMA-IR) were measured before and after a daily intake of 40 g ground flaxseed (equivalent to 120 mg SDG) for 3 months. This study showed that flaxseed supplementation decreased TBARS and HOMA-IR, although the flaxseed supplement in this study included more components than SDG alone. In another human study, flaxseed lignan complex (about 600 mg SDG/ day) for 3 months was reported to reduce central obesity, dyslipidemia, and inflammation, although the levels of adiponectin, leptin, IL-6, and TNF-α were not specifically investigated [67]. In addition the daily consumption of a low-fat muffin enriched with a lignan complex for 6 weeks may reduce CRP concentrations compared to a low-fat muffin without supplementation, although no data about

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IL-6 and TNF-α were reported [85]. Taken together, the evidence shows that SDG supplementation is likely to attenuate systemic inflammation via lowering inflammatory cytokine levels. However, further comprehensive studies should be conducted in order to fully determine its effects on systemic inflammation in humans.

EFFECTS OF SECOISOLARICIRESINOL DIGLUCOSIDE ON OBESITY-RELATED HYPERTENSION As discussed, obesity and hypertension (high blood pressure) are strongly correlated, indicating that a small amount of weight loss may significantly lower blood pressure, despite the cause of hypertension in obesity being complex and multifactorial [86,87]. Hypertension is a serious widespread health condition. Left untreated, hypertension leads to severe damage to many organs, eventually causing organ failure in the heart, lung, kidneys, and brain [88]. Therefore, weight reduction is strongly recommended to improve hypertension and related conditions in humans. In fact, weight loss is highly recommended in the obese, and commonly results in improved lipid profile, insulin sensitivity, as well as heart, lung, and kidney function [89,90]. In our animal study, significant body weight reduction and a moderate reduction in systolic blood pressure were observed in rats fed a high-fat diet containing SEFP compared to rats fed a high-fat diet alone, even though the average blood pressure of rats fed a high-fat diet containing SEFP remained higher than that of the control group [66]. However, we did not observe any significant change in diastolic blood pressure among all three groups. These data indicate that SDG supplementation may lower systolic blood pressure in the rats fed a high-fat diet containing SEFP compared to rats fed a high-fat diet alone. Although no specific mechanism is known to be involved in this effect, improved endothelial dysfunction by SDG antioxidant activity was suggested as a possible mechanism. This is echoed by a previous study showing that a high-flaxseed diet improves endothelial vascular relaxation through a pressure-independent mechanism in spontaneously hypertensive rats [91]. Regarding the potential effects of SDG on hypertension, few reports are currently available. However, one human study reported that daily consumption of flaxseed lignan complex (about 600 mg SDG) for 3 months reduced blood pressure along with improvements in other areas such as central obesity, hyperglycemia, dyslipidemia, and LDL oxidation [67]. Another human study suggested that flaxseed omega-3 polyunsaturated fatty acid may prevent hypertension induced by its deficiency, although this was not directly linked to SDG [92]. Another report indicates effects of flaxseed peptide mixture on hypertension [93]:

a flaxseed peptide mixture prepared from flaxseed protein hydrolysates was reported to have antihypertensive properties by inhibiting angiotensin-converting enzyme (ACE) [93]. With respect to nitric oxide (NO) production, a report indicates that cationic protein hydrolysate fractions may reduce activity of calmodulin-dependent endothelial NO synthase (eNOS) in vitro [94]. Again, all these data provide only limited information about the potential effects of SDG on hypertension, and more studies are required in the future.

CONCLUSION In this chapter, we have taken a close look at the potential health benefits of SDG on obesity, body weight, visceral fat, lipid profile, systemic inflammation, and hypertension. As mentioned, the overall effects of SDG on obesity should be interpreted and understood as part of a comprehensive milieu because (1) obesity is closely clustered with other chronic diseases such as diabetes, cardiovascular disease, and kidney disease and (2) most flaxseed products available on the market may contain other components in addition to SDG such as fiber and omega-3 fatty acid (e.g. α-linolenic acid). Therefore, potential effects of flaxseed products should be evaluated and validated in a broad setting, including potential effects of active ingredients and pre-existing disease conditions. Nonetheless, this review provides valuable information about the potential health benefits of SDG on body weight, visceral fat, lipid profile, systemic inflammation, and blood pressure obtained from both in vitro and in vivo models.

Acknowledgments The mention of trade names or commercial products in this chapter is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. The USDA is an equal opportunity provider and employer.

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