Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.

Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1 ؉ ) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2. IntroductionSeveral endothelial cell growth factors have thus far been identified as essential for vascular development, based primarily on genetargeting approaches. Among these factors, members of the angiopoietin (Ang) family are ligands for the receptor tyrosine kinase Tie2. 1,2 The first member of the family, Ang-1, activates Tie2 receptors expressed on vascular endothelial cells and functions as a positive regulator of angiogenesis and of remodeling and stabilization of blood vessels. 3 In contrast, the second member of the Ang family, Ang-2, plays a role in the context of vessel regression as a negative regulator of angiogenesis by blocking Tie2 activation. 4 Loss of function assays in mice have revealed that Ang-1 is essential for embryonic vascular development, 3 whereas Ang-2 is dispensable for embryonic angiogenesis but required for normal postnatal vascular remodeling. 5 These findings indicate different roles for Ang-1 and Ang-2 in blood vessel formation.The recent discovery of lymphatic endothelial cell (LEC) markers and factors regulating the development of lymphatic vessels has shed new light on the molecular mechanisms underlying lymphangiogenesis. 6,7 More recent findings from mice with targeted mutations in Ang-2 indicate that Ang-2 loss results in profound defects in patterning and function of the lymphatic vasculature, indicating that Ang-2 is crucial for lymphatic vessel development. 5 Interestingly, defects in lymphatics seen in Ang-2 Ϫ/Ϫ mice are completely rescued by Ang-1, suggesting a possible role for Ang in lymphangiogenesis. Moreover, this finding suggests an important role for Ang signaling in the formation of the lymphatic vessel sy...