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...
Angiopoietin-like protein (Angptl) 1 and Angptl2, which are considered orphan ligands, are highly homologous, particularly in the fibrinogen-like domain containing the putative receptor binding site. This similarity suggests potentially cooperative functions between the two proteins. In this report, the function of Angptl1 and Angptl2 is analyzed by using morpholino antisense technology in zebrafish. Knockdown of both Angptl1 and Angptl2 produced severe vascular defects due to increased apoptosis of endothelial cells at the sprouting stage. In vitro studies showed that Angptl1 and Angptl2 have antiapoptotic activities through the phosphatidylinositol 3-kinase͞Akt pathway, and coinjection of constitutively active Akt͞protein kinase B mRNA rescued impaired vascular development seen in double knockdown embryos. These results provide a physiological demonstration of the cooperative interaction of Angptl1 and Angptl2 in endothelial cells through phosphatidylinositol 3-kinase͞Akt mediated antiapoptotic activities.angiogenesis ͉ morpholino ͉ phosphatidylinositol 3-kinase ͉ Akt ͉ apoptosis
We report here the identification of angiopoietin-related growth factor (AGF) as a positive mediator for angiogenesis. To investigate the biologic function of AGF in angiogenesis, we analyzed the vasculature in the dermis of transgenic mice expressing AGF in mouse epidermal keratinocytes (K14-AGF). K14-AGF transgenic mice were grossly red, especially in the ears and snout, suggesting that hypervascularization had occurred in their skin. Histologic examination of ear skin from K14-AGF transgenic mice revealed increased numbers of microvessels in the dermis, whereas the expression of several angiogenic factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factors (VEGFs), and angiopoietin-1 (Ang-1), was decreased. We showed that AGF is a secreted protein and does not bind to tyrosine kinase with immunoglobulin and EGF-homology domain (Tie1) or Tie2 receptors. An in vitro chamber assay revealed that AGF directly promotes chemotactic activity of vascular endothelial cells. Both mouse corneal and matrigel plug assays showed that AGF induces neovascularization in vivo.Furthermore, we found that plasma leakage occurred after direct injection of AGF into the mouse dermis, suggesting that AGF directly induces a permeability change in the local vasculature. On the basis of these observations, we propose that AGF is a novel angiogenic factor and that handling of its biologic functions could lead to novel therapeutic strategies for control of angiogenesis. IntroductionNormal tissue function requires an adequate supply of oxygen and nutrition through blood vessels. Therefore, maintenance of vascular system is critical for survival of tissues. In the case of repair or remodeling of tissues after injury, angiogenesis, which is the formation of new blood vessels from pre-existing primary plexus, plays a crucial role in reconstructing the vascular system. [1][2][3][4] In addition, angiogenesis is involved in responding directly to tissue demands in pathologic conditions such as inflammation, rheumatoid arthritis, diabetic retinopathy, and tumor growth. 5 Recently, several growth factors regulating angiogenesis have been reported. Among them, vascular endothelial growth factors (VEGFs), angiopoietins (Angs), and ephrins, all of which are ligands for receptor tyrosine kinases, have been identified to play pivotal roles in angiogenesis in a coordinated manner. 6 Angiopoietin-1,-2,-3, and -4 (Ang-1, Ang-2, Ang-3, and Ang-4) 7,8 are ligands for the receptor tyrosine kinase TIE2, 9,10 which contributes to signaling in angiogenesis. 11 Recently, several Angs have been identified as angiopoietin-related proteins (ARPs), which are structurally similar to Angs. Angs and ARPs are characterized structurally by 2 domains, a coiled-coil domain and a fibrinogen-like domain. 6,[12][13][14][15][16][17][18] It is noteworthy that all reported ARPs do not bind to either the TIE1 or TIE2 receptor, suggesting that ARPs have biologic functions different from Angs. Indeed, several recent reports demonstrate that ARPs show...
It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (
C pneumoniae pneumonia demonstrates a wide spectrum of thin-section CT findings that are similar to those of S pneumoniae pneumonia and M pneumoniae pneumonia; airway dilatation and bronchovascular thickening were significantly more frequent in patients with C pneumoniae pneumonia.
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