title: Ablation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vascular endothelial cells enhances insulin sensitivity by reducing visceral fat and suppressing angiogenesis.
abstract: The phosphatidylinositol 3-kinase signaling pathway in vascular endothelial cells is important for systemic angiogenesis and glucose metabolism. In this study, we addressed the precise role of the 3-phosphoinositide-dependent protein kinase 1 (PDK1)-regulated signaling network in endothelial cells in vivo, using vascular endothelial PDK1 knockout (VEPDK1KO) mice. Surprisingly, VEPDK1KO mice manifested enhanced glucose tolerance and whole-body insulin sensitivity due to suppression of their hepatic glucose production with no change in either peripheral glucose disposal or even impaired vascular endothelial function at 6 months of age. When mice were fed a standard diet at 6 months of age and a high-fat diet at 3 months of age, hypertrophy of epididymal adipose tissues was inhibited, adiponectin mRNA was significantly increased, and mRNA of MCP1, leptin, and TNFα was decreased in the white adipose tissue of VEPDK1KO mice in comparison with controls. Consequently, both the circulating adiponectin levels and the activity of hepatic AMP-activated protein kinase were significantly increased, subsequently enhancing whole-body insulin sensitivity and energy expenditure with increased hepatic fatty acid oxidation in VEPDK1KO mice. These results provide the first in vivo evidence that lowered angiogenesis through the deletion of PDK1 signaling not only interferes with the growth of adipose tissue but also induces increased energy expenditure due to amelioration of the adipocytokine profile. This demonstrates an unexpected role of PDK1 signaling in endothelial cells on the maintenance of proper glucose homeostasis through the regulation of adipocyte development.
authors: Division of Diabetes, Endocrinology, and Metabolism, Kawasaki Medical School, Okayama 701-0192, Japan.
authors: Kazuhito
authors: K
authors: Tawaramoto
authors: Ko
authors: K
authors: Kotani
authors: Mitsuru
authors: M
authors: Hashiramoto
authors: Yukiko
authors: Y
authors: Kanda
authors: Tomoki
authors: T
authors: Nagare
authors: Hiroshi
authors: H
authors: Sakaue
authors: Wataru
authors: W
authors: Ogawa
authors: Noriaki
authors: N
authors: Emoto
authors: Masashi
authors: M
authors: Yanagisawa
authors: Tetsuo
authors: T
authors: Noda
authors: Masato
authors: M
authors: Kasuga
authors: Kohei
authors: K
authors: Kaku
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D052242:Adiponectin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D020738:Leptin / Q000096:biosynthesis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D052242:Adiponectin; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020738:Leptin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D058539:Phosphatidylinositol 3-Kinase; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose