Anti-obesity and anti-diabetic effects of allenic carotenoid, fucoxanthin KAZUO MIYASHITA*, HAYATO MAEDA, TOMOKO OKADA, MASAYUKI ABE, MASASHI HOSOKAWA Kazuo Miyashita *Corresponding author Hokkaido University, Faculty of Fisheries Sciences 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan

KEYWORDS: Fucoxanthin, anti-obesity, anti-diabetes, UCP1, insulin resistance, GLUT4.

ABSTRACT: Fucoxanthin, a characteristic carotenoid found in brown seaweeds, shows anti-obesity and anti-diabetic effects on the basis of specific molecular mechanism. Fucoxanthin induces uncoupling protein 1 expression in white adipose tissue (WAT) mitochondria leading to oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose level through the down-regulation of adipokines such as TNFα, MCP-1, IL-6, and PAI-1 in WAT and up-regulation of glucose transporter 4 (GLUT4) in skeletal muscle. The anti-obesity effect of fucoxanthin is likely linked to its structural characteristic - an allene bond and an additional hydroxyl substituent on the side group of the fucoxanthin metabolites, fucoxanthinol and amarouciaxanthin A.

INTRODUCTION FUCOXANTHIN AND ITS METABOLISM

Carotenoids are the largest group of lipid-soluble natural Fucoxanthin is a major carotenoid present in chloroplasts of pigments, being responsible for red, orange, and yellow brown seaweeds. It is the most abundant of all carotenoids colours in many fruits and vegetables. The best known accounting for >10 percent of estimated total natural biological function of carotenoids is their established role as production of carotenoids (24). Fucoxanthin has a unique provitamin A. Dietary carotenoids are also known to reduce structure including an unusual allenic bond and

Functional food the risk of cardiovascular diseases, age related macular 5,6-monoepoxide in its molecule (Figure 1). Of approximately degeneration and cancers (1-8). The antioxidant properties 700 naturally occurring carotenoids, about 40 carotenoids of carotenoids have been suggested as being the main contain the allenic bond. The principal allenic carotenoids mechanism by which they afford their beneficial health are fucoxanthin in brown seaweeds and neoxanthin in effects (7, 9-15). There is little doubt that, under the right higher plants (25) (Figure 1). conditions, antioxidant activity of

vol 21 n 6 carotenoids can protect cells, tissues and - other structures such as lipoproteins against oxidative damage. However, it would be difficult to explain all the physiological effects of carotenoids only by their antioxidant activity. Other mechanisms of action that are independent of the antioxidant activity are likely to be more important. November/December 2010

- Carotenoids are capable of altering patterns of gene and protein expressions Figure 1. Structure of allenic carotenoids. and cell function with a specific and important nutritional and bio-functional impact on the Fucoxanthinol and amarouciaxanthin A are known as major body (6). This modulation effect of carotenoids will depend fucoxanthin metabolites (Figure 1) (26). Dietary fucoxanthin is industry hi-tech on their chemical structures which differ depending on the hydrolysed to fucoxanthinol in the gastrointestinal tract by

OOD length of the polyene, the nature of the end group and the digestive enzymes such as lipase and cholesterol esterase (27), various substituents they contain. Many studies reported on and then converted to amarouciaxanthin A in the liver (26) (Figure gro F

A the cancer preventative activities of carotenoids, showing 1). Fucoxanthinol was detectable at 0.8 pmol/ml in human that a considerable part of the anticancer effects of plasma after a daily intake of cooked edible brown seaweed, carotenoids will be independent of their antioxidant Undaria pinnatifida (Wakame), (6 g dry weight) including 6.1mg activity. They are summarized in several reviews (16-19). On (9.26 mmol) of fucoxanthin for 1 week (28). Fucoxanthinol and the other hand, little information is available on the amarouciaxanthin A have been detected in plasma and tissues relationship between other action of carotenoids and their of mouse with different accumulation ratio (26, 27, 29-31). Dietary modulation effects on related gene and protein fucoxanthin preferentially accumulates as amarouciaxanthin A in expressions. Therefore, recent study on the anti-obesity and the adipose tissue and as fucoxanthinol in the other tissues (30). anti-diabetic effects of an edible brown seaweed When a duodenal infusion of 1 ml of test oil emulsion with 2 mg of carotenoid, fucoxanthin, is highly remarkable, as its fucoxanthin was administered in the lymph duct and the portal absorption and molecular mechanism have been made cannulated rats, intact fucoxanthin was not detected in either clear (20-23). lymph fluid or portal blood at any time point (23). However, In this review, we describe these biological activities of fucoxanthinol was detected in the lymph, but not in portal blood, fucoxanthin, with special reference to its regulations on showing a conversion of fucoxanthin to fucoxanthinol during the relative gene and protein expressions. lymphatic absorption from intestine.

24 Overall, dietary fucoxanthin is absorbed from small intestine after very similar in structure to fucoxanthinol and amarouciaxanthin A conversion to fucoxanthinol and fucoxanthinol enters into a (Figure 1). Thus, it was hypothesized that the specific structure systemic circulation system through lymph. Some of the that both carotenoids contain is somewhat responsible for the fucoxanthinols are reduced to amarouciaxanthin A mainly in suppressive effect on the adipocyte differentiation. The liver. Although fucoxanthin metabolites are found in plasma and relationship between the biological activity of an allenic in tissues, the level and the accumulation ratios of fucoxanthinol carotenoid and its chemical structure is very interesting. More and amarouciaxanthin are different from each part. research is expected to make clear the active site of allenic Fucoxanthin metabolites accumulate in abdominal adipose carotenoids. tissue at the higher ratio than plasma and other tissues, suggesting that the adipose tissue will be a main target of fucoxanthin metabolites. ANTI-OBESITY AND ANTI-DIABETIC EFFECTS OF FUCOXANTHIN

The anti-obesity effect of fucoxanthin was confirmed by in vivo NOVEL BIOLOGICAL ACTIVITY OF FUCOXANTHIN AND OTHER study (20, 21, 39). By feeding with 0.2 percent fucoxanthin to the ALLENIC CAROTENOIDS obese-diabetes model mice, KK-Ay mice, body weight gain was significantly reduced compared with that of the control, Fucoxanthin has been reported to be very effective in inducing although there was no difference in the amount of food intake. apoptosis in human leukemia cells (32, 33) and colon cancer This reduction was consistent with the decrease in the weight of cells (34, 35). The strong inhibitory effect of fucoxanthin on the uterine, mesentery, perirenal and retroperitoneal white adipose growth of cancer cells has been also confirmed using human tissue (WAT) normalized for body weight in the mice fed 0.2 prostrate cancer cells (36). In their study, the effect of 15 kinds percent fucoxanthin and was significantly lower than in the of carotenoids (phytoene, phytofluene, lycopene, b-carotene, control group. Further, brown adipose tissue (BAT) weight Functional food b-cryptoxanthin, a-carotene, canthaxanthin, astaxanthin, normalized body weight, which is related to energy expenditure, capsanthin, luetin, zeaxanthin, violoxanthin, neoxanthin and increased in the mice fed 0.1 percent, 0.2 percent fucoxanthin fucoxanthin) present in food stuffs was evaluated on the compared with the control group. growth of the human prostrate cell cancer lines (PC-3, DU 145 KK-Ay mice in this study not only developed obesity but also and LNCap). Among the carotenoids evaluated, they hyperleptinemia and hyperinsulinemia along with insulin reported two allenic carotenoids, fucoxanthin and neoxanthin, resistance. Therefore, glucose levels of mice fed the control diet to cause a remarkable reduction in the growth of prostrate reached levels higher than 400 mg/dl. On the other hand, mice cancer cells. fed the 0.1 percent and 0.2 percent purified fucoxanthin diets DNA fragmentation revealed that these two carotenoids had significantly lower blood glucose concentrations of around apparently reduced the cell viability by inducing apoptosis (36). 220 mg/dl and 170 mg/dl, respectively (21). Furthermore, plasma Although other acyclic carotenoids such as phytofluene, insulin levels decreased in a dose-dependent manner after b-carotene and lycopene also significantly reduced cell viability, purified fucoxanthin intake (21). the effect was lower than those of neoxanthin and fucoxanthin. The anti-obesity and anti-diabetic effects of fucoxanthin were Further, other carotenoids did not affect the growth of the also found in high fat (HF) diet-induced obesity in mice (40). prostate cancer cells. The higher activity of fucoxanthin and Fucoxanthin intake significantly suppressed body weight and neoxanthin will be due to their characteristic chemical structure WAT weight gain induced by the HF diet. Dietary administration including allenic bond and other polar groups. of the HF diet resulted in hyper-glycemia, hyperinsulinemia and The strong activity of allenic carotenoids have been also found hyperleptinemia in the mouse model. These perturbations were in the inhibition of lipid accumulation in adipose cell. When completely normalized in the fucoxanthin-fed group. In addition, various carotenoids were screened for potential suppression plasma leptin content was significantly lower in fucoxanthin effects on adipocyte differentiation (37, 38), only fucoxanthin, feeding group compared to the control group. Leptin neoxanthin, and two fucoxanthin metabolites (fucoxanthinol suppresses appetite and controls body weight (41). However, and amarouciaxanthin A) (Figure 1) showed an encouraging obese individuals have leptin resistance due to high leptin levels suppressive effect on the differentiation of 3T3-L1 adipose cells, in the blood. Hence, plasma leptin levels can be used as an while other carotenoids did not show such an effect. The index of body fat accumulation. Low leptin levels above four allenic carotenoids significantly detected in the groups fed a fucoxanthin inhibited intercellular lipid accumulation during confirmed the anti-obesity effect adipocyte differentiation of 3T3-L1 cells and of fucoxanthin with HF diet- significantly decreased glycerol-3- induced obese phosphate, an indicator of adipocyte conditions. differentiation, as compared with the control cells (38). Studies of the uptake and metabolism of fucoxanthin in 3T3-L1 cells indicated that fucoxanthin added into the culture medium was incorporated in cells and further converted to fucoxanthinol by deacetylation within 24 h (37). Fucoxanthinol, but not fucoxanthin levels increased in a time-dependent manner. In addition, the carotenoid accumulation in 3T3-L1 cells was greater following treatment with fucoxanthinol than after treatment with fucoxanthin. As described above, orally administrated fucoxanthin is converted to fucoxanthinol and amarouciaxanthin A (26), showing that the active form of fucoxanthin in biological system is fucoxanthinol and/or amarouciaxanthin A. Interestingly, neoxanthin is

25 ANTI-OBESITY EFFECT OF FUCOXANTHIN THROUGH UCP1 steady-state levels of several WAT and BAT derives mRNAs (56). UPREGULATION IN WHITE ADIPOSE TISSUE (WAT) (Figure 2) This result suggests the possibility of UCP1 expression in WAT, which would be an increasingly attractive target for the UCP is the inner-membrane mitochondrial protein that has development of anti-obesity therapies. As the key molecular the ability to dissipate energy through uncoupling of components become defined, screening for food constituent oxidative phosphorylation to produce heat instead of ATP. that increase energy dissipation is becoming a more attainable A great deal of interest has focused on adaptive goal. From this viewpoint, it is noteworthy that fucoxanthin thermogenesis by UCP families (UCP1, 2 and 3) in several tissues induces both protein and mRNA expressions of UCP1 in WAT and organs as a physiological defense against obesity, (20, 21). This finding will give a clue for new dietary anti-obesity hyperlipidemia, and diabetes (42, 43). UCP are found in brown therapy. An enormous amount of data has been collected on adipose tissue (BAT) (UCP1, UCP2 and UCP3), white adipose thermogenesis in BAT through UCP1 expression. However, there tissue (WAT) (UCP2), skeletal muscle (UCP2 and UCP3), and had been little information on UCP1 expression in WAT induced brain (UCP4 and UCP5) (43, 44). UCP2 and UCP3 are members by a dietary component until our report (20, 21) had appeared. of the mitochondorial anion carrier superfamily with high Furthermore, we have found that fucoxathin promoted mRNA homology to UCP1, a well characterized uncoupling protein expressions of b3-adrenergic receptor (Adrb3) in WAT (40). playing a key role in facultative thermogenesis in rodents. Adrb3 is considered to be responsible for lipolysis and adaptive Interest in UCPs increased with the discovery of proteins similar thermogenesis through UCP1 expression. The degree of obesity to UCP1, including UCP2 and UCP3. These proteins are is correlated with the extent of loss of Adrb3 gene expression in expressed in tissues besides BAT and, thus, are candidates to WAT. Our result indicated the promotion effect of fucoxanthin influence energy efficiency and expenditure (43, 45). Since metabolites on sympathetic nerve stimulation and metabolic rate, metabolic efficiency, and obesity are up-regulation of fat oxidation in WAT (56). integrated properties of the whole animal, researchers have Only recently, the effect of fucoxanthin on the weight produced mice lacking UCP2 (46) and UCP3 (47, 48). However, management of obese premenopausal women has been despite of UCP2 or UCP3, no consistent phenotypic abnormality determined in 16-week, double-blind, randomized, and was observed in the knockout mice. They were not obese and placebo-controlled trial (57). Fucoxanthin (2.4 mg) intake per had normal thermogenesis. These results suggest that UCP2 and day resulted in statistically significant reduction of body weight, UCP3 are not a major determinant of metabolic rate in normal waist circumference, body and liver fat content, and serum condition but, rather, have other functions (43, 46, 49, 50). Apart triacylglycerol contents with a significant increase in resting from UCP2 and UCP3, it is certain that UCP1 can potentially energy expenditure. This result suggests the involvement of reduce excess abdominal fat (51). mitochondrial uncoupling UCP1 in the antiobesity effect of Adaptive thermogenesis in BAT is mainly mediated by UCP1, fucoxanthin, which leads to an increased resting energy

Functional food an inner mitochondrial membrane protein which can expenditure by uncoupling a step during cellular metabolism in catalyse the reentry of protons into the mitochondrial matrix, human (58). so bypassing ATP synthase, uncoupling oxidative phospholyration, and releasing chemical energy as heat. UCP1 is exclusively expressed in BAT, where the gene REGULATORY EFFECT OF FUCOXANTHIN ON ADIPOKINE expression is increased by cold, adrenergic stimulation, SECRETIONS (Figure 2)

vol 21 n 6 b -agonists, retinoids and thyroid hormone (52). Thermogenic

- 3 activity of BAT is dependent on UCP1 expression level WAT plays an important role as an energy storage organ, as controlled by the sympathetic nervous system via well as an endocrine organ producing adipocytokines such as noradrenaline (51, 53-55). As a consequence of noradrenaline MCP-1, TNF-a, IL-6, and adiponectin (59, 60). In obesity, binding to the adipocyte plasma membrane, protein kinase dysregulation of the adipocytokine production in WAT is (PKA) is expressed, and then, cyclic AMP response element induced, which promotes glucose intolerance, dyslipidemia, binding protein (CREB) and hormone-sensitive lipase (HSL) are and high blood pressure (61, 62). In the WAT of obesity mice expressed. HSL stimulates lipolysis and free fatty acids such as KK-Ay mice, ob/ob mice and diet-induced obesity liberated serve as substrate in BAT thermognesis (55). mice, MCP-1 and TNF-a mRNAs increase compared to normal November/December 2010

- Thus, UCP1 expression in 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. In contrast to rodents, humans industry hi-tech have only minute amounts of BAT, and thereby the contribution of BAT to the OOD regulation of energy balance may be less in gro F

A humans. Even though BAT is scanty in adult humans, it will be true that BAT serves as a good model for the study of energy expenditure regulation; moreover, due to the high thermogenic capacity of BAT (500W/ kg), even very small quantities such as those found in adult humans may influence heat production. Considered as breakthrough discoveries for an ideal therapy of obesity, regulation of UCP expression in tissues other than BAT by food constituent would be important. UCP1, usually expressed only in BAT, has been also found in WAT of mice overexpressing Foxc2, a Figure 2. Molecular mechanism for anti-obesity and anti-diabetic effect of fucoxanthin. winged helix gene, with a change in

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GLUT4 (76, 77) is aand muscle, insulin-resistant in utilization glucose reduced in levels mRNA and protein GLUT4 in reduction significant (78, cases diet fat high in reported been has muscle skeletal or over-expressed with animals transgenic addition, In 79). have provided significant insights into theknocked out GLUT4 homeostasis (80).role of GLUT4 in glucose a fucoxanthin-containing diet promotedThe administration of glucose uptake to muscle by regulatingthe recovery of blood (40). In this study (40), mice were fed aGLUT4 mRNA expression fat (NF) diets for 10 weeks. And then, NFhigh fat (HF) or normal continued to receive the NF diet orgroup or half of HF group weeks, respectively, while another HF diet- HF diet for another 5 HF diet containing fucoxanthin for afed group was administered total 15 weeks feeding, GLUT4 mRNA levelsfurther 5 weeks. After were markedly lower in the HF groupin skeletal muscle tissue mRNA levels in thecompared to the NF group. 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TNF-a and IL-6 levelsuptake and leads to and induce insulin resistance (67, 68).are increased in obesity of MCP-1, TNF-a, and IL-6 mRNA inTherefore, downregulation the underlies that be a mechanism would KK-Ay of WAT the by fucoxanthin. improvement of hyperglycemia Another remarkablefucoxanthin effect of on adipokine decrease in PAI-1 mRNA expression insecretion was significant (64). PAI-1 mRNA level is overexpressedthe WAT of KK-Ay mice has PAI-1 in increase Recently, (69). tissue adipose obese in been reported to link to not only thrombosis fibrosis, and, but insulin resistance (70). Therefore, the also to obesity, and mRNA expression in obese WAT woulddownregulation of PAI-1 of fucoxanthinalso be a mechanism of the suppressive effects on obesity and hyperglycemia. Dietary fucoxanthin is hydrolyzed to fucoxanthinol in the metabolized to gastrointestinal tract and partly Their metabolites amarouciaxanthin A in the liver (26). as the liver and accumulate in the internal organs such on fucoxanthin of effect Regulatory (30). tissue adipose confirmed using adipokine secretions from WAT has been metabolite, cultivated cells after addition of fucoxanthin fucoxanthinol. Fucoxanthinol reduced MCP-1 and IL-6 mRNA cells stimulatedexpression in differentiating 3T3-F442A adipose byproduced cytokine inflammatory an is which TNF-a, with This study shows thatboth macrophages and adipocytes (64). culturethe into cells 3T3-F442A from IL-6 and MCP-1 of secretion fucoxanthinol by attenuated significantly also was medium treatment. These findings indicate that fucoxanthinol directly adipocytokine pro-inflammatory of production the suppress such as MCP-1 and IL-6, whose increase is related to insulin resistance and type-2 diabetes. iNOS and COX-2 In addition, fucoxanthinol reduced TNF-a, of TNF-a in RAW264.7mRNA expressions and protein production (64). acid palmitic with treated cells macrophage-like mediators.major as acids fatty saturated release Adipocytes activate acid as palmitic acids such fatty Saturated macrophages infiltrated into WAT and enhance TNF-a production to induce insulin resistance (71). iNOS is an enzyme that produces NO, which is a free radical molecule related to iNOSof Overexpression (72). inflammation of pathogenesis the and mice obese of WAT the in observed been has mRNA adipocytes (73, 74). Treatment of diabetic db/db mice with an insulin iNOS inhibitor reversed hyperglycemia and improved sensitivity, showing that the downregulation of iNOS mRNA in macrophages is the molecular target for the prevention of type-2 diabetes (73). COX-2 is an inducible enzyme that reducesCOX-2 of inhibition Pharmacologic PGE2. produces IL-6 in WAT (75). fucoxanthinolthat show (64) cells cultivated using results The prevents inflammation and insulin resistance by inhibiting NO and PGE2 production through the downregulation of iNOS and COX-2 mRNA expression as well as adipocytokine production in WAT. We observed that fucoxanthinol and amarouciaxanthin A were accumulated at 0.85 mg/mg protein and 2.67 mg/mg protein in the perigonadal WAT of KK-Ay mice fed 0.1 percent detectednot were metabolites fucoxanthin while fucoxanthin, in control mice (64). Further studies are needed to determine the mechanism for the regulatory effects of amarouciaxanthin insulin obesity, to related mediators inflammatory on A resistance, and type-2 diabetes. 4 transporter glucose on fucoxanthin of effect Regulatory