Angiopoietin-Like Proteins

besity and related metabolic diseases (known as the metabolic syndrome (MetS)) are associated with increased risk of cardiovascular disease (CVD). Thus, it is necessary to both understand the underlying molecular basis and develop effective preventive and therapeutic approaches. We and others have independently identified 7 angiopoietin-like proteins (Angptls), namely, Angptl1/angiopoietin-related protein 1 (ARP1)/angioarrestin,1,2 Angptl2/ARP2,3 Angptl3,4,5 Angptl4/ARP4/PPARγ angiopoietin-related (PGAR)/fasting-induced adipose factor (FIAF)/hepatic fibrinogen/angiopoietin-related protein (HFARP),6–9 Angptl5,10,11 Angptl6/angiopoietin-like growth factor (AGF),12 and Angptl7.13 These Angptls are structurally similar to angiopoietins, which are characterized by a coiled-coil domain at the N-terminus and a fibrinogen-like domain at the C-terminus. In addition, at the N-terminus Angptls exhibit a highly hydrophobic region reminiscent of a signal sequence for protein secretion. Cells transfected with Angptl expression vectors secrete Angptl protein into culture supernatants,1,8,14 and Angptls 2, 3, 4, and 6 have all been detected in the systemic circulation, suggesting that some Angptls function in an endocrine manner in vivo.1,9,15–19 Whereas angiopoietins act via the Tie2 receptor tyrosine kinase, the signaling of which regulates vascular stabilization and remodeling, Angptls do not bind to either Tie2 or the related Tie1 receptor, suggesting that these orphan ligands function differently from angiopoietins. Although several studies show that Angptls potently regulate angiogenesis,11,20 as do angiopoietins, some Angptls also possess pleiotropic activities other than angiogenesis, such as inhibition of lipoprotein lipase and endothelial lipase,19,20 augmentation of energy expenditure,19,21 and induction of inflammation.22 Lifestyle changes in developed and developing countries, such as inactivity and overnutrition, have lead to the recent increase in the incidence of obesity, which is creating an exploding medical and social problem.23,24 Because hypercholesterolemia, a major risk factor of CVD, can now be well controlled by statins (HMG-CoA reductase inhibitors25), obesity is receiving much attention as an underlying cause of MetS in an effort to prevent CVD, still the leading cause of death in these countries.26–28 MetS is a cluster of risk factors known to increase the risk of CVD29 and its major manifestation is systemic insulin resistance.26,27 The concept of chronic low-grade activation of proinflammatory pathways in adipose tissue directly promoting systemic insulin resistance has recently emerged. Adipocytes and macrophages could be the source of several proinflammatory cytokines that activate inflammatory pathways in resident and infiltrating cells within adipose tissue in an autocrine/paracrine fashion. We recently reported that adipocyte-derived Angptl2 is involved in mechanisms underlying inflammation of adipose tissue in obesity.22 One promising strategy to combat MetS and the resulting CVD is to prevent or treat the “obesity” that occurs at the beginning of this pathogenesis. Persistent weight gain develop-