The physiological role of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vascular endothelial cells ~ Investigation by using vascular endothelial cell-specific PDK1 knockour mice *
The phosophoinositide-dependent protein kinese 1 (PDK1) signaling pathway is involved in a broad range of cellular processes governed by growth factors. This study investigated the physiological role of PDK1 in vascular endothelial cells by generating tissuespecific knockout mice that lacked PDK1 in their vascular endothelial cells (VEPDK1KO). The VEPDK1KO mice at 24 weeks of age fed the standard diet manifested enhanced glucose tolerance and whole-body insulin sensitivity due to the suppression of hepatic glucose production. Circulating adiponectin levels were higher and the activities of hepatic gluconeogenic enzymes were lower in the VEPDK1KO mice than in the control mice. When the VEPDK1KO and the control mice were fed a high-fat diet, adiponectin mRNA abundance was readily higher and MCP1, leptin and TNFα mRNA levels were lower in white adipose tissue of the VEPDK1KO compared with the control mice at 12 weeks of age. As a result, hepatic AMPactivated protein kinase (AMPK) was significantly activated, subsequently enhancing wholebody insulin sensitivity in the VEPDK1KO mice. High-fat-diet-induced obesity and adipocyte hypertrophy were attenuated in the VEPDK1KO mice, due to the suppression of angiogenesis in the white adipose tissue, in association with a reduction in the visceral fat area. These results suggest that angiogenesis and adipogenesis are closely related and that PDK1 signaling in endothelial cells plays an important role in maintaining proper glucose homeostasis, primarily through regulation of adipocyte development. (Accepted on October 22, 2010)
