Takayuki Tsukui

The allenic carotenoid fucoxanthin, a novel marine nutraceutical from brown seaweeds.

Obesity and type 2 diabetes are pathologies with rapidly growing prevalence throughout the world. A few molecular targets offer the most hope for anti-obesity and anti-diabetic therapeutics. One of the keys to success will be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity and anti-diabetic effects of fucoxanthin, a characteristic carotenoid found in brown seaweeds, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of carotenoids for the expression of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups.

Fucoxanthin regulates adipocytokine mRNA expression in white adipose tissue of diabetic/obese KK-Ay mice.

Fucoxanthin, a marine carotenoid found in edible brown seaweeds, attenuates white adipose tissue (WAT) weight gain and hyperglycemia in diabetic/obese KK-A(y) mice, although it does not affect these parameters in lean C57BL/6J mice. In perigonadal and mesenteric WATs of KK-A(y) mice fed fucoxanthin, mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), which are considered to induce insulin resistance, were markedly reduced compared to control mice. In contrast to KK-A(y) mice, fucoxanthin did not alter MCP-1 and TNF-α mRNA expression levels in the WAT of lean C57BL/6J mice. Interleukin-6 (IL-6) and plasminogen activator inhibitor-1 mRNA expression levels in WAT were also decreased by fucoxanthin in KK-A(y) mice. In differentiating 3T3-F442A adipocytes, fucoxanthinol, which is a fucoxanthin metabolite found in WAT, attenuated TNF-α-induced MCP-1 and IL-6 mRNA overexpression and protein secretion into the culture medium. In addition, fucoxanthinol decreased TNF-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression in RAW264.7 macrophage-like cells stimulated by palmitic acid. These findings indicate that fucoxanthin regulates mRNA expression of inflammatory adipocytokines involved in insulin resistance, iNOS, and COX-2 in WAT and has specific effects on diabetic/obese KK-A(y) mice, but not on lean C57BL/6J mice.

Enhancement of hepatic docosahexaenoic acid and arachidonic acid contents in C57BL/6J mice by dietary fucoxanthin

The n-3 highly unsaturated fatty acids (HUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are known to possess beneficial health properties such as reduction of serum triacylglycerol and cholesterol [1], anti-inflammatory [2], and anticancer effects [3]. In addition, DHA has been reported to be essential for brain function [4] and development, especially in babies and infants [5]. Major source of DHA is fish oil obtained from fishes such as salmon, tuna, and bonito. Dietary intake of fish results in absorption and increases the amount of DHA in body. On the other hand, DHA and EPA are also synthesized from the precursor a-linolenic acid (ALA), while arachidonic acid (AA), an n-6 HUFA, is synthesized from linoleic acid (LA). In these biosynthetic pathways of HUFAs, D6-desaturase, which catalyzes the desaturation of LA, ALA, and 24:5n-3, has been reported to be the ratelimiting enzyme [6]. Fucoxanthin is a major marine carotenoid found in edible seaweeds such as Undaria pinnatifida and Sargassum fulvellum. In a previous study, we reported an increase in the amount of DHA in the livers of 4-week-old, obese/ diabetic KK-A mice due to dietary feeding of fucoxanthin [7]. Because the liver plays an important role in lipid metabolism, an increase in hepatic DHA by fucoxanthin is expected to show beneficial health effects. However, KK-A mouse strain used in our previous study was a genetically modified model for obesity/diabetes syndrome due to its A/? genotype and young, 4-week age. In this study, we therefore examined the effect of fucoxanthin on the level of HUFAs in the liver using normal adult mice, namely C57BL/6J mice (male, 19 weeks old prior to fucoxanthin feeding). Lipids were extracted from commercially available dry wakame (U. pinnatifida) with acetone. Fucoxanthin was purified from the extracted lipids by silica gel column chromatography according to the procedure previously reported [8]. The neutral lipids and chlorophylls were removed with acetone:n-hexane (3:7, v/v), followed by elution of fucoxanthin with acetone:n-hexane (1:1, v/v). Silica gel column chromatography was repeated. Purity of fucoxanthin was 93% by high-performance liquid chromatography (HPLC). C57BL/6J mice (male, 9 weeks old) were purchased from CLEA Japan, Inc. (Tokyo, Japan). The mice were housed at 23 ± 1 C and 50% relative humidity under a 12h light/dark cycle, and had free access to food and drinking water. All procedures for the use and care of animals for this research were approved by the Ethical Committee of Experimental Animal Care at Hokkaido University. Mice were fed with AIN-93G diet containing 7% soybean oil for 10 weeks, and then divided into groups of six each and fed control or experimental diets for the next 5 weeks. Fucoxanthin was added to the basal diet AIN-93G at the rate of 0.025% and 0.05%. Fatty acid composition of lipids contained in 0.025% and 0.05% fucoxanthin diets were the same as that of the control diet with 7% soybean oil. After 5 weeks on the experimental or control diet, animals were T. Tsukui N. Baba M. Hosokawa (&) K. Miyashita Faculty of Fisheries Sciences, Hokkaido University, Hakodate, Hokkaido 041-8611, Japan e-mail: hoso@fish.hokudai.ac.jp