Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.

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An antitumor polysaccharide SPR-901 was found in a fermented broth of a kind of lactic acid bacteria isolated from rice bran. SPR-901 is a high molecular alpha-glucan and its linkages are almost linear alpha-1,6 glucosidic ones with a small amount (ca. 5%) of branches at C-3 positions. It is a highly purified alpha-glucan and it contains no protein and no inorganic salts. SPR-901 showed significant antitumor activities against murine allogeneic and syngeneic tumors by both intraperitoneal and oral administration, and enhanced carbon clearance ability in mice, while it showed no direct cytotoxicities in vitro. The mechanism of antitumor activities of SPR-901 is supposed to be a host-mediated one, and this substance is classified as one of the biological response modifiers. These properties of SPR-901 were identical to those of RON, which was obtained from rice bran, therefore we concluded that these two polysaccharides were the same substance.