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      The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice

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          Abstract

          Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)–dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)–deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (−41%; thoracic aorta), subcutaneous fat mass (−44%), and cholesterol levels (−35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.—Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J.-O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

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          Most cited references53

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          Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement.

          The objective of the study was to evaluate the current state of clinical assays for total and free testosterone. The five participants were appointed by the Council of The Endocrine Society and charged with attaining the objective using published data and expert opinion. Data were gleaned from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), the College of American Pathologists, and the clinical and laboratory experiences of the participants. The statement was an effort of the committee and was reviewed in detail by each member. The Council of The Endocrine Society reviewed a late draft and made specific recommendations. Laboratory proficiency testing should be based on the ability to measure accurately and precisely samples containing known concentrations of testosterone, not only on agreement with others using the same method. When such standardization is in place, normative values for total and free testosterone should be established for both genders and children, taking into account the many variables that influence serum testosterone concentration.
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            Sex differences in lipid and lipoprotein metabolism: it's not just about sex hormones.

            It is commonly thought that sex hormones are important regulators of plasma lipid kinetics and are responsible for sexual dimorphism in the plasma lipid profile. Here we discuss the findings from studies evaluating lipid and lipoprotein kinetics in men and women in the context of what we know about the effects of exogenous sex hormone administration, and we conclude that it is more complicated than that. It has become clear that normal physiological alterations in the hormonal milieu (i.e. due to menopause or throughout the menstrual cycle) do not significantly affect plasma lipid homeostasis. Furthermore, parenterally administered estrogens have either no effect or only very small beneficial effects, whereas orally administered estrogens raise plasma triglyceride concentrations--a phenomenon that is not consistent with the observed sex differences and likely results from the hepatic "first-pass effect." The effects of progestogens and androgens mimic only in part the differences in plasma lipids between men and women. Thus, the underlying physiological modulators of plasma lipid metabolism responsible for the differences between men and women remain to be elucidated.
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              ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.

              Initial description of apolipoprotein (apo) E-deficient transgenic mice demonstrated the development of severe hypercholesterolemia due to probable delayed clearance of large atherogenic particles from the circulation. Examination of these mice demonstrated foam cell accumulation in the aortic root and pulmonary arteries by 10 weeks of age. In the present study, the animals were fed either chow or a high-fat, Western-type diet and examined at ages ranging from 6 to 40 weeks. Gross examination by dissection microscopy revealed a predilection for development of lesions in the aortic root, at the lesser curvature of the aortic arch, the principal branches of the aorta, and in the pulmonary and carotid arteries. Monocyte attachment to endothelial cells was observed by light and electron microscopic examination at 6 weeks, the earliest time point examined. Foam cell lesions developed as early as 8 weeks, and after 15 weeks advanced lesions (fibrous plaques) were observed. The latter consisted of a fibrous cap containing smooth muscle cells surrounded by connective tissue matrix that covered a necrotic core with numerous foamy macrophages. Mice fed the Western-type diet generally had more advanced lesions than those fed a chow diet. The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. This model should provide numerous opportunities to study the pathogenesis and therapy of atherosclerosis in a small, genetically defined animal.
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                Author and article information

                Journal
                FASEB J
                FASEB J
                fasebj
                fasebj
                FASEB
                The FASEB Journal
                Federation of American Societies for Experimental Biology (Bethesda, MD, USA )
                0892-6638
                1530-6860
                April 2015
                30 December 2014
                30 December 2014
                : 29
                : 4
                : 1540-1550
                Affiliations
                Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Physiology, Institute of Neuroscience and Physiology, and Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Nordic School of Public Health, Gothenburg, Sweden; and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                Author notes
                [1 ]Correspondence: Wallenberg Laboratory for Cardiovascular and Metabolic Research, Bruna Stråket 16, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: asa.tivesten@ 123456medic.gu.se
                Article
                FJ_259234
                10.1096/fj.14-259234
                4470404
                25550469
                6d463c99-8f47-42b9-9150-99086fd1a586
                © The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) ( http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 June 2014
                : 09 December 2014
                Page count
                Pages: 11
                Categories
                Research Communication
                Custom metadata
                v1

                Molecular biology
                genetically altered mice,metabolism,sex hormones
                Molecular biology
                genetically altered mice, metabolism, sex hormones

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