Antiobesity Effect of Fucoxanthin from Edible Seaweeds and Its

Chapter 32

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Antiobesity Effect of Fucoxanthin from Edible Seaweeds and Its Multibiological Functions Hayato Maeda, Masashi Hosokawa, Tokutake Sashima, and Kazuo Miyashita Laboratory of Biofunctional Material Chemistry, Faculty of Fisheries Sciences, Hokkaido University, Hakodate, Japan

Fucoxanthin has a unique structure including an unusual allenic bond and 5,6-monoepoxide in its molecule. It induced a remarkable reduction in the growth of leukemia and prostate cancer cells. Furthermore, we have found that fucoxanthin showed anti-obesity effect with a new molecular mechanism. Uncoupling protein (UCP) is inner-membrane mitochondrial protein that has the ability to dissipate energy through uncoupling of oxidative phosphorylation which, instead of ATP, produces heat. A great deal of interest has focused on adaptive thermogenesis by UCP families (UCP1, 2 and 3) in several tissues and organs as a physiological defense against obesity, hyperlipidemia, and diabetes. In fact, UCP1 expression in brown adipose tissue (BAT) is known as a significant component of whole body energy expenditure, at least small rodents, and its dysfunction contributes to the development of obesity. However, adult humans have very little BAT, making it unlikely to be a major contributor to human weight regulation. In humans, most of fat is stored in white adipose tissue (WAT). Considered as breakthrough discoveries for an ideal therapy of obesity, regulation of UCP expression in white adipose tissue (WAT) by food constituent should be studied. Here, we show significant reduction of WAT in wistar rats and obese KK-Ay mice by feeding fucoxanthin (0.05 or 0.2 wt%/feed).

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© 2008 American Chemical Society In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

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Fucoxanthin, concentrated from edible seaweed, Undaria Pinnatifida (Japanese name is Wakame). The daily intake of fucoxanthin to KK-Ay mice also caused a significant reduction of body weight and a significant increase in BAT weight. Clear signals of U C P 1 protein and mRNA were detected by Western and Northern blot analyses in WAT in mice fed fucoxanthin, although there is little expression of U C P 1 in WAT in mice fed control diet. U C P 1 expression in WAT by fucoxanthin intake leads to oxidation of fatty acids and heat production in WAT mitochondria. The substrate oxidation can directly reduce WAT in animals.

Fucoxanthin has a unique structure including an allenic bond and a 5,6monoepoxide in the molecule (Figure 1).

Figure 1. Structure offucoxanthin andfucoxanthinol

It is the most abundant of all carotenoids accounting for >10% of estimated total natural production of carotenoids. In Southeast Asian countries, some seaweeds containing fucoxanthin are often used as a food source. Among them Undaria (Japanese name is Wakame) and Laminaria (Japanese name is Konbu) are most popular edible seaweeds in Japan. Fucoxanthin is easily converted fucoxanthinol in human intestinal cells and in mice (7), suggesting that the active form of fucoxanthin in biological system would be fucoxanthinol (Figure 1).

In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.


378 Studies involving quantification of fucoxanthin in different brown seaweeds, both wild and cultured, are limited. In a study involving quantitative and qualitative analysis of six different brown seaweeds, Haugan and Liaeen-Jensen (2) reported that fucoxanthin is the major contributing carotenoid to the total carotenoids in those seaweeds with the fiicoxanthin content varying between 43 to 83% of total carotenoids. Fucoxanthin when present in the thallus of seaweeds was found to be quite stable in the presence of organic ingredients apart from surviving the drying process and storage at ambient temperature; although, fucoxanthin in pure form is susceptible to oxidation (3). Further, fucoxanthin content in seaweeds exhibits seasonal variation (4,5) and also varies depending on the life cycle of the seaweeds (3) indicating the possible biological significance of this pigment in seaweeds. Cancer chemoprevention is one of the promising methods for cancer control. Among the chemopreventive agents, carotenoids, especially P-carotene, have been investigated extensively (6). Since Muto et al. (7) discovered that Pcarotene induces apoptosis in cervical dysplastic cells via down-regulation of an epidermal growth factor receptor, several carotenoids such as lycopene, Pcryptoxanthin, lutein, and canthaxanthin have been reported to induce apoptosis in certain cancer cells. Hosokawa et al. (8) found that HL-60 human promycelocytic leukemia cells underwent apoptosis by fucoxanthin. Its activity was higher than that of P-carotene. The strong inhibitory effect of fucoxanthin has also been confirmed using human prostate cancer cells (9,10). In their study, the effect of 15 kinds of carotenoids (phytoene, phytofluene, ^-carotene, lycopene, a-carotene, P-carotene, p-cryptoxanthin, canthaxanthin, astaxanthin, capsanthin, lutein, zeaxanthin, vioaxanthin, neoxanthin, and fucoxanthin) present in foodstuffs was evaluated on the growth of human prostate cancer cell lines (PC-3, DU 145 and LNCap). Among the carotenoids evaluated, fucoxanthin and neoxanthin, which has a structure similar to fucoxanthin, most remarkably reduced viability by inducing apoptosis as compared with other carotenoids. Furthermore, these two carotenoids have also been shown to suppress chemically induced carcinogenesis in experimental animals. On the other hand, fucoxanthin shows anti-obesity effect, anti-diabetic effect, and promotion effect of docosahexaenoic acid (DHA) synthesis in the liver. These activities are specific for fucoxanthin and have not been found in common carotenoids such as P-carotene and astaxanthin. Among the specific functionalities of fucoxanthin, the mechanisms for the anti-obesity effect have been well studied. Therefore, this chapter describes the anti-obesity effect of fucoxanthin.

Obesity and Anti-Obesity Natural Components Obesity is now recognized as a worldwide problem, with ominous implications for public health and health-related costs. It may be a second-most



379 important preventable cause of death, exceeded only by cigarette smoking. Obesity is defined as accumulation of body fat. Especially, the accumulation of fat around the internal organs is a major risk factor causing many kinds of diseases. Because when the fat cell differentiates and accumulates the excess fat into the cell, the cell secretes various bioactive components, adipo-cytokines. Some of these adipo-cytokines induce various health problems such as type-2 diabetes, hypertension, and dyslipidemia, co-morbidities that markedly increase the risk of cardiovascular disease. These problems have been regarded as metabolic syndrome. Therefore, safe and effective anti-obesity component has been keenly expected to find from food materials. Diacylglycerol (DG) with a 1,3-configuration (11,12) and medium-chain triacylglycerol (MCT) (13) have been used for the prevention of obesity. Several studies have demonstrated that conjugated linoleic acids (CLA) reduce body fat accumulation in growing animals but not all CLA isomers contributed to this effect equally (14-16). The reported mechanism of these lipids action includes characteristic digestion and absorption pathways, stimulation of lipolysis, reduction of lipid synthesis, and direct action on adipocytes (17,18). Caffeine is naturally consumed substance that is widely contained in beverages. It has thermogenic properties and increases the metabolic rate in humans (19-23). This effect can be explained by the stimulation of the secretion of catecholamine such as noradrenarine from the nerve endings. Noradrenaline stimulates (3 -adrenergic receptor (p -AR) and then induces promotion of energy expenditure through uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) (24-27) (Figure 2). Capsaicin, the major pungent principle of red pepper, also upregulates UCP1 in BAT by release of catecholamine (28-31). Green tea extract is reported to increase energy expenditure and fat oxidation in humans (32). The tea extract contains caffeine and catechin. Epigallocatechin gallate, a main tea catechin, promotes fat oxidation and decreases fat synthesis, but does not activate p -adrenergic receptor (33). Anti-obesity activity of green tea extract is attributed to both effects of UCP1 up-regulation by caffeine and of lipid metabolism control by catechin. 3

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Adaptive Thermogenesis through UCP1 Expression Although anti-obesity compounds render their activity by different molecular mechanisms; adaptive thermogenesis through UCP1 expression is most important. UCP1 is a member of UCP families (UCP1, UCP2 and UCP3) (34,35). UCPs are found in BAT (UCP1, UCP2 and UCP3), white adipose tissue (WAT) (UCP2), skeletal muscle (UCP2 and UCP3), and brain (UCP4 and UCP5) (35,36). UCP2 and UCP3 are expressed in BAT, muscle and other organs, thus, are candidates to influence energy efficiency and expenditure (35). Therefore, researchers have produced mice lacking UCP2 (36) and UCP3 (37,38). However, despite lack of UCP2 or UCP3, no consistent phenotypic



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Figure 2. Possible Mechanism for Up-regulation of UCP 1 in BAT

abnormality was observed in the knockout mice. They were not obese and had normal thermogenesis. These results suggest that UCP2 and UCP3 are not a major determinant of metabolic rate in normal condition, but rather, have other functions (35,36,39-44). Although more studies are required on the relationship between anti-obesity and the role of UCP2 and UCP3, it is certain that UCP1 can potentially reduce excess abdominal fat (45). UCP1 is a dimeric protein present in the inner mitochondrial membrane of BAT, and it dissipates the pH-gradient generated by oxidative phosphoryration, releasing chemical energy as heat. UCP1 is exclusively expressed in BAT, where the gene expression is increased by cold, adrenergic stimulation, p agonists, retinoids and thyroid hormone (46) (Figure 2). Thermogenic activity of BAT is dependent on UCP1 expression level controlled by the sympathetic nervous system via noradrenaline (45,47-49) As a consequence of noradrenaline binding to the adipocyte plasma membrane, protein kinase (PKA) is expressed, and then, cyclic AMP response element binding protein (CREB) and hormonesensitive lipase (HSL) are expressed. HSL stimulates lipolysis and free fatty acids liberated serve as substrate in BAT thermognesis (49). They also act as cytosolic second messengers which activated UCP1 as PPARy ligand. The same activity is expected in dietary polyunsaturated fatty acids including CLA, EPA 3



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Figure 3. Weight of WAT ofRats (A) and Mice (B) Fed Undaria Lipids and Control Diet Significant differentfromcontrol (P98% by HPLC) was given to diabetes model mouse at concentration 0.05-0.2 % (wt/diet), significant decrease in blood glucose was observed.

Reducing Effect of Fucoxanthin and Its Main Metabolite, Fucoxanthinol, on Adipocyte Differentiation Fucoxanthin is easily converted to fucoxanthinol in the human intestinal cells and in mice (55). Both fucoxanthin and fucoxanthinol inhibited intercellular lipid accumulation during adipocyte differentiation of 3T3-L1 cells (Figure 5). Fucoxanthin and fucoxanthinol also decreased glycerol-3-phosphate dehydrogenase activity, an indicator of adipocyte differentiation (54). The effects of fucoxanthinol were stronger than those of fucoxanthin. When 3T3-L1 cells treated with fucoxanthin and fucoxanthinol, PPARy, a regulater of adipogenic gene expression, was down-regulated by both carotenoids in a dosedependent manner (54) (Figure 6). These results suggest that fucoxanthin and fucoxanthinol inhibit the adipocyte differentiation of 3T3-L1 cells through down-regulation of PPARy and fucoxanthinol would be an active compound for the anti-obesity effect of fucoxanthin. PPARy plays an important role in the early stages of differentiation of 3T3L l cell, because it is a nuclear transcription factor that regulates adipogenic gene expression. Regulation of PPARy would be one of the expected mechanisms



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Figure 5. Effect ofFucoxanthin (A) and Fucoxanthinol (B) on Lipid Accumulation of3T3-Ll Cells During Adipocyte Differentiation. 3T3-L1 cells were treated with fucoxanthin or fucoxnthinol in differentiation medium for 120 hr. The intercellular lipid accumulation was determined by Oil Red-O staining. The values (n=3) are expressed as absorbance at 490 nm. Significant different from control (P < 0.01). (Adaptedfrom Ref 54). a



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Figure 6. Expression ofPPARyin 3T3-L1 Cells Treated with Fucoxanthin and Fucoxanthinol The PPARyprotein expression level was normalized to the βActin level and expressed as the value relative to preadipocyte PPA levels. (Adaptedfrom Ref. 54)

underlying the anti-obesity effect of dietary fucoxanthin. Catechin (55), sterols (56), tannic acid (57), phenolic lipids (58), and red yeast rice extracts (59) also inhibit 3T3-L1 differentiation. Retinoids inhibit the early stage of differentiation of 3T3-L1 cells (60). However, absorption rate of some of these compounds are very low and have not been fully investigated for their anti-obesity effects in vivo. Fucoxathin is absorbed into the animal body as fucoxanthinol and mainly accumulated in WAT and liver. On the other hand, when other carotenoids such as β-carotene and astaxanthin were given to animals, little accumulation was observed in WAT. The accumulation of fucoxanthin in WAT and regulation of fucoxanthin against PPARy in adipose cell will be a clue for the elucidation of the anti-obesity mechanism of this interesting marine carotenoid, fucoxanthin.

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Antiobesity Effect of Fucoxanthin from Edible Seaweeds and Its

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