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      Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

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          Obesity is a worldwide epidemic that predisposes individuals to metabolic complications, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease, all of which are related to an imbalance between food intake and energy expenditure. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are urgently needed. A well-accepted paradigm is that crosstalk between organs/tissues contributes to diseases. Endothelial dysfunction characterizes metabolic disorders and the related vascular complications. Over the past two decades, overwhelming studies have focused on mechanisms that lead to endothelial dysfunction. New investigations, however, have begun to appreciate the opposite direction of the crosstalk: endothelial regulation of metabolism, although the underlying mechanisms remain to be elucidated. This review summarizes the evidence that supports the concept of endothelial regulation of obesity and the associated insulin resistance in fat, liver, and skeletal muscles, the classic targets of insulin. Outstanding questions and future research directions are highlighted. Identification of the mechanisms of vascular endothelial regulation of metabolism may offer strategies for prevention and treatment of obesity and the related metabolic complications.

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          Most cited references 88

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          Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.

          Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the second of a 2-part review on the phenotypic heterogeneity of blood vessel endothelial cells. The first part discusses the scope, the underlying mechanisms, and the diagnostic and therapeutic implications of phenotypic heterogeneity. Here, these principles are applied to an understanding of organ-specific phenotypes in representative vascular beds including arteries and veins, heart, lung, liver, and kidney. The goal is to underscore the importance of site-specific properties of the endothelium in mediating homeostasis and focal vascular pathology, while at the same time emphasizing the value of approaching the endothelium as an integrated system.
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            Selective versus total insulin resistance: a pathogenic paradox.

            Mice with type 2 diabetes manifest selective hepatic insulin resistance: insulin fails to suppress gluconeogenesis but continues to activate lipogenesis, producing the deadly combination of hyperglycemia and hypertriglyceridemia. In this issue of Cell Metabolism, Biddinger et al. (2008) show that mice with total hepatic insulin resistance exhibit hyperglycemia without hypertriglyceridemia-a state paradoxically less severe than selective insulin resistance.
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              MicroRNA-181b regulates NF-κB-mediated vascular inflammation.

              EC activation and dysfunction have been linked to a variety of vascular inflammatory disease states. The function of microRNAs (miRNAs) in vascular EC activation and inflammation remains poorly understood. Herein, we report that microRNA-181b (miR-181b) serves as a potent regulator of downstream NF-κB signaling in the vascular endothelium by targeting importin-α3, a protein that is required for nuclear translocation of NF-κB. Overexpression of miR-181b inhibited importin-α3 expression and an enriched set of NF-κB-responsive genes such as adhesion molecules VCAM-1 and E-selectin in ECs in vitro and in vivo. In addition, treatment of mice with proinflammatory stimuli reduced miR-181b expression. Rescue of miR-181b levels by systemic administration of miR-181b "mimics" reduced downstream NF-κB signaling and leukocyte influx in the vascular endothelium and decreased lung injury and mortality in endotoxemic mice. In contrast, miR-181b inhibition exacerbated endotoxin-induced NF-κB activity, leukocyte influx, and lung injury. Finally, we observed that critically ill patients with sepsis had reduced levels of miR-181b compared with control intensive care unit (ICU) subjects. Collectively, these findings demonstrate that miR-181b regulates NF-κB-mediated EC activation and vascular inflammation in response to proinflammatory stimuli and that rescue of miR-181b expression could provide a new target for antiinflammatory therapy and critical illness.

                Author and article information

                Front Cardiovasc Med
                Front Cardiovasc Med
                Front. Cardiovasc. Med.
                Frontiers in Cardiovascular Medicine
                Frontiers Media S.A.
                09 August 2017
                : 4
                1Department of Medicine, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center , Oklahoma City, OK, United States
                Author notes

                Edited by: Hong Chen, Boston Children’s Hospital, United States

                Reviewed by: Jun Yu, Temple University, United States; Sathish Srinivasan, Oklahoma Medical Research Foundation, United States

                *Correspondence: Jian Xu, jian-xu@

                Specialty section: This article was submitted to Atherosclerosis and Vascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine

                Copyright © 2017 Li, Qian and Xu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 127, Pages: 9, Words: 7475
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01HL-130845, 5P20GM104934
                Funded by: American Heart Association 10.13039/100000968
                Award ID: 14BGIA20030027
                Funded by: American Diabetes Association 10.13039/100000041
                Award ID: 1-12-JF-58
                Funded by: Oklahoma Center for the Advancement of Science and Technology 10.13039/100008569
                Award ID: HR11-200, HR14-062, HR17-046
                Cardiovascular Medicine


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