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      Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice

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          Abstract

          The aim of the present study was to compare different diets used to induce obesity in a head-to-head manner with a focus on insulin resistance and vascular dysfunction. Male C57BL/6J mice were put on standard chow diet (SCD), normal-fat diet (NFD), cafeteria diet (CAF) or high-fat diet (HFD) for 12 weeks starting at the age of 6 weeks. Both CAF and HFD led to obesity (weight gain of 179% and 194%, respectively), glucose intolerance and insulin resistance to a comparable extent. In aortas containing perivascular adipose tissue (PVAT), acetylcholine-induced vasodilation was best in the NFD group and worst in the CAF group. Reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 was observed in both CAF and HFD groups. Plasma coagulation activity was highest in the HFD group and lowest in the SCD group. Even the NFD group had significantly higher coagulation activity than the SCD group. In conclusions, CAF and HFD are both reliable mouse diets in inducing visceral obesity, glucose intolerance and insulin resistance. CAF is more effective than HFD in causing PVAT dysfunction and vascular dysfunction, whereas hypercoagulability was mostly evident in the HFD group. Coagulation activity was higher in NFD than NCD group.

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          A mouse model of diet-induced obesity and insulin resistance.

          Obesity is reaching pandemic proportions in Western society. It has resulted in increasing health care burden and decreasing life expectancy. Obesity is a complex, chronic disease, involving decades of pathophysiological changes and adaptation. Therefore, it is difficult ascertain the exact mechanisms for this long-term process in humans. To circumvent some of these issues, several surrogate models are available, including murine genetic loss-of-function mutations, transgenic gain-of-function mutations, polygenic models, and different environmental exposure models. The mouse model of diet-induced obesity has become one of the most important tools for understanding the interplay of high-fat Western diets and the development of obesity. The diet-induced obesity model closely mimics the increasingly availability of the high-fat/high-density foods in modern society over the past two decades, which are main contributors to the obesity trend in human. This model has lead to many discoveries of the important signalings in obesity, such as Akt and mTOR. The chapter describes protocols for diet induced-obesity model in mice and protocols for measuring insulin resistance and sensitivity.
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            Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia.

            Type 2 diabetes is associated with altered immune and hemostatic responses. We investigated the selective effects of hyperglycemia and hyperinsulinemia on innate immune, coagulation, and fibrinolytic responses during systemic inflammation. Twenty-four healthy humans were studied for 8 hours during clamp experiments in which either plasma glucose, insulin, both, or none was increased, depending on randomization. Target plasma concentrations were 5 versus 12 mM for glucose, and 100 versus 400 pmol/L for insulin. After 3 hours, 4 ng/kg Escherichia coli endotoxin was injected intravenously to induce a systemic inflammatory and procoagulant response. Endotoxin administration induced cytokine release, activation of neutrophils, endothelium and coagulation, and inhibition of fibrinolysis. Hyperglycemia reduced neutrophil degranulation (plasma elastase levels, P < .001) and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < .001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activator-inhibitor-1 levels (P < .001). Endothelial cell activation markers and cytokine concentrations did not differ between clamps. We conclude that in humans with systemic inflammation induced by intravenous endotoxin administration hyperglycemia impairs neutrophil degranulation and potentiates coagulation, whereas hyperinsulinemia inhibits fibrinolysis. These data suggest that type 2 diabetes patients may be especially vulnerable to prothrombotic events during inflammatory states.
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              Mechanisms of thrombosis in obesity.

              Obesity has become a worldwide epidemic that is driving increased morbidity and mortality from thrombotic disorders such as myocardial infarction, stroke, and venous thromboembolism. Effective prevention and treatment of thrombosis in obese patients is limited by an incomplete understanding of the underlying prothrombotic mechanisms and by uncertainties about risks, benefits, and dosing of anticoagulant drugs in this patient population. This review summarizes our current understanding of established and emerging mechanisms contributing to the obesity-induced prothrombotic state. The mechanistic impact of chronic inflammation and impaired fibrinolysis in mediating obesity-associated thrombosis is highlighted. Recent data demonstrating the aberrant expression of adipokines and microRNAs, which appear to function as key modulators of proinflammatory and prothrombotic pathways in obesity, are also reviewed. Finally, some challenges and new approaches to the prevention and management of thrombotic disorders in obese and overweight patients are discussed. Obesity-driven chronic inflammation and impaired fibrinolysis appear to be major effector mechanisms of thrombosis in obesity. The proinflammatory and hypofibrinolytic effects of obesity may be exacerbated by dysregulated expression and secretion of adipokines and microRNAs, which further increase the risk of thrombosis and suggest new potential targets for therapy.
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                Author and article information

                Contributors
                huigeli@uni-mainz.de
                xianing@uni-mainz.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 December 2019
                20 December 2019
                2019
                : 9
                : 19556
                Affiliations
                GRID grid.410607.4, Department of Pharmacology, , Johannes Gutenberg University Medical Center, ; Mainz, Germany
                Author information
                http://orcid.org/0000-0003-3458-7391
                Article
                55987
                10.1038/s41598-019-55987-x
                6925252
                31862918
                a05bc251-fe54-4b76-a9d5-932462b145d1
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 June 2019
                : 22 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: LI-1042/3-1
                Award ID: LI-1042/5-1
                Award ID: XI 139/-21
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                cardiovascular biology,cardiovascular diseases
                Uncategorized
                cardiovascular biology, cardiovascular diseases

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