Angiopoietin-like protein 4 (angptl4) is mainly secreted from adipose tissue and inhibits lipoprotein lipase activity. The expression and plasma levels of angptl4 are increased by fasting. To clarify its regulation in diabetes and metabolic syndrome, we investigated the effect of insulin on angptl4 mRNA expression in 3T3-L1 adipocytes by using quantitative real-time PCR. Insulin suppressed angptl4 mRNA expression in time- and dose-dependent manners, and the inhibitory effect was attenuated by a RNA synthesis inhibitor actinomycin D and a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Adenoviral-mediated overexpression of forkhead transcription factor Foxo1 increased angptl4 mRNA expression, and insulin significantly suppressed its effect. In addition, insulin failed to decrease angptl4 mRNA expression in an insulin-resistant state induced by TNF-alpha in 3T3-L1 adipocytes. These results suggest that insulin downregulates angptl4 mRNA expression via P13K/Foxo1 pathway in 3T3-L1 adipocytes, and that the reduction of angptl4 mRNA by insulin is attenuated in insulin resistance. (c) 2006 Elsevier Inc. All rights reserved.