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...

We report here the identification of an angiopoietin-related growth factor (AGF). To examine the biological function of AGF in vivo, we created transgenic mice expressing AGF in epidermal keratinocytes (K14-AGF). K14-AGF mice exhibited swollen and reddish ears, nose and eyelids. Histological analyses of K14-AGF mice revealed significantly thickened epidermis and a marked increase in proliferating epidermal cells as well as vascular cells in the skin compared with nontransgenic controls. In addition, we found rapid wound closure in the healing process and an unusual closure of holes punched in the ears of K14-AGF mice. Furthermore, we observed that AGF is expressed in platelets and mast cells, and detected at wounded skin, whereas there was no expression of AGF detected in normal skin tissues, suggesting that AGF derived from these infiltrated cells affects epidermal proliferation and thereby plays a role in the wound healing process. These findings demonstrate that biological functions of AGF in epidermal keratinocytes could lead to novel therapeutic strategies for wound care and epidermal regenerative medicine. S kin tissues, especially epidermis, are a barrier against the environment, which becomes accessible in wounds and various infections. An important goal in wound management is to achieve rapid wound closure. Analysis of gene activation in skin tissues shows that transforming growth factor-␣ (TGF-␣) (1) produced by keratinocytes and keratinocyte growth factor (KGF) (2, 3) made by dermal fibroblasts are both powerful growth factors for epidermal keratinocytes, indicating an important role for the interaction between dermis-epidermis in skin development. Although these two growth factors play critical roles in wound healing, gene inactivation studies show that these factors are not essential for epidermal growth or regeneration and suggest that regulation of epidermal growth is more complex than has been previously appreciated (4, 5).Angiopoietin-1 (Ang-1) (6) is a ligand for the receptor tyrosine kinase TIE2 (7,8), which contributes to signaling in angiogenesis (9). Ang-1 is characterized structurally by two domains, a coiled-coil domain and a fibrinogen-like domain (10). Recently, members of the angiopoietins (Angs) family have been identified by a domain homology-based molecular cloning strategy. One of these proteins, angiopoietin-related protein 2 (ARP2), was also reported as an angiogenic factor (11). Several recent reports demonstrate that angiopoietin-related proteins (ARPs) show pleiotropic effects not only on vascular cells but on cells of other lineages. For example, it has been shown that ANGPTL3 (12, 13) and FIAF͞PGAR͞ARP4 (14) may play central roles in lipid͞adipocyte metabolism as well as in angiogenesis. Here we identify, by screening EST databases, a previously undescribed angiopoietin-related growth factor (AGF), which is abundantly expressed in hepatocytes. To determine whether AGF promotes in vivo angiogenesis as does Ang-1, we created transgenic (TG) mice overexpressing mouse AGF in epi...