Nwadozi E, Roudier E, Rullman E, Tharmalingam S, Liu HY, Gustafsson T, Haas TL. Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet. FASEB J. 2016 Sep;30(9):3039-52.
From the authors: "Impaired insulin responsiveness of skeletal muscle can have a profound influence on the development of Type-2 diabetes. The critical role that the microcirculation plays in regulating the delivery of insulin to skeletal muscle cells is often overlooked, despite several studies demonstrating a positive relationship between capillary number and insulin responsiveness. This is of particular importance in the context of obesity as several lines of evidence suggest that obesity is associated with a lack of capillary growth (angiogenesis) within skeletal muscle, despite an up-regulation of molecular factors that promote angiogenesis. The purpose of this study was to investigate whether an increase in repressive signals underlies the lack of angiogenesis in obese individuals, and whether this would in turn exacerbate the insulin resistant state. Specifically, our focus was on a family of proteins (FoxO1, FoxO3a and FoxO4) collectively referred to as “FoxO’s”, which our lab has shown to be potent repressors of the capillary network in muscle. We hypothesized that obesity would increase the expression of FoxO proteins within endothelial (capillary) cells, and exert repressive signals on the capillary network. Subsequent to a 16-week high fat diet to induce obesity, mice expressed greater levels of FoxO1 in isolated capillaries, which was positively related to their insulin resistance status. Using genetically modified mice (with ~80% reduction of FoxO’s in endothelial cells) subjected to the same diet, we observed enhanced vascular dependent skeletal muscle insulin sensitivity, together with an increase in capillary number, reduced inflammation and enhanced capacity of the muscle to metabolize lipids. Overall this study furthers our understanding of the mechanism by which capillaries are regulated in obesity and demonstrates that remodeling of the capillary network may serve as a critical node during the development of metabolic disturbances (i.e. insulin resistance). Such knowledge may prove useful for future diagnostic and targeted therapeutic approaches to enhance insulin responsiveness in obese individuals."