Osamu Nakayama

Increased oxidative stress in obesity and its impact on metabolic syndrome

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.

FR258900, a novel glycogen phosphorylase inhibitor isolated from Fungus No. 138354. II. Anti-hyperglycemic effects in diabetic animal models.

A novel glycogen phosphorylase inhibitor FR258900 was isolated from the cultured broth of a fungal strain No. 138354. We examined the hypoglycemic effects of FR258900 in diabetic animal models. FR258900 treatment significantly reduced the plasma glucose concentrations during oral glucose tolerance tests in diabetic mice models, including db/db mice and STZ-induced diabetic mice. Furthermore, FR258900 treatment resulted in rapid decrease in the plasma glucose levels in db/db mice. These improvements in glucose disposal were accompanied by increased liver glycogen contents, suggesting that the glucose lowering effects of FR258900 were attributed to suppressed hepatic glycogen breakdown and increased hepatic glycogen synthesis. Taken together, our results suggest that glycogen phosphorylase is a potentially useful target in new therapies against diabetes.

FR258900, a novel glycogen phosphorylase inhibitor isolated from Fungus No. 138354. I. Taxonomy, fermentation, isolation and biological activities.

FR258900 is a novel glycogen synthesis activator produced by Fungus No. 138354. This compound was isolated from the culture broth by solvent extraction and reverse-phase column chromatography. FR258900 stimulated glycogen synthesis and glycogen synthase activity in primary rat hepatocytes. FR258900 exhibited a potent inhibitory effect on the activity of liver glycogen phosphorylase, suggesting that this compound may activate hepatic glycogen synthesis via glycogen phosphorylase inhibition. Thus, this glycogen phosphorylase inhibitor may be useful in the treatment of postprandial hyperglycemia in type 2 diabetes.