title: Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet.
abstract: Skeletal muscle microvascular dysfunction contributes to disease severity in type 2 diabetes. Recent studies indicate a role for Forkhead box O (FoxO) transcription factors in modulating endothelial cell phenotype. We hypothesized that a high-fat (HF) diet generates a dysfunctional vascular niche through an increased expression of endothelial FoxO. FoxO1 protein increased (+130%) in the skeletal muscle capillaries from HF compared to normal chow-fed mice. FoxO1 protein was significantly elevated in cultured endothelial cells exposed to the saturated fatty acid palmitate or the proinflammatory cytokine TNF-α. In HF-fed mice, endothelium-directed depletion of FoxO1/3/4 (FoxO(Δ)) improved insulin sensitivity (+110%) compared to that of the controls (FoxO(L/L)). The number of skeletal muscle capillaries increased significantly in the HF-FoxO(Δ) mice. Transcript profiling of skeletal muscle identified significant increases in genes associated with angiogenesis and lipid metabolism in HF-FoxO(Δ) vs. HF-FoxO(L/L) mice. HF-FoxO(Δ) muscle also was characterized by a decrease in inflammation-related genes and an enriched M2 macrophage signature. We conclude that endothelial FoxO proteins promote insulin resistance in HF diet, which may in part result from FoxO proteins establishing an antiangiogenic and proinflammatory microenvironment within skeletal muscle. These findings provide mechanistic insight into the development of microvascular dysfunction in the progression of type 2 diabetes.-Nwadozi, E., Roudier, E., Rullman, E., Tharmalingam, S., Liu, H.-Y., Gustafsson, T., Haas, T. L. Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet.
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nwadozi
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada;
authors.forename: Emilie
authors.initials: E
authors.lastname: Roudier
authors.affiliation: Department of Laboratory Medicine, Clinical Physiology, Karolinska Institutet, Stockholm, Sweden; and Department of Cardiology and.
authors.forename: Eric
authors.initials: E
authors.lastname: Rullman
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada;
authors.forename: Sujeenthar
authors.initials: S
authors.lastname: Tharmalingam
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada;
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Clinical Physiology, Karolinska Institutet, Stockholm, Sweden; and Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gustafsson
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada; thaas@yorku.ca.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Haas
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D042783:Endothelial Cells / Q000187:drug effects; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009765:Obesity
chemical_list: D004041:Dietary Fats; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse
keywords: capillary; diabetes; gene expression; microcirculation; obesity