| 1. |
- Lantero Rodriguez, Marta, et al.
(författare)
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Testosterone reduces metabolic brown fat activity in male mice
- 2021
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 251:1, s. 83-96
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice ( 4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.
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| 2. |
- Svedlund Eriksson, Elin, et al.
(författare)
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Castration of Male Mice Induces Metabolic Remodeling of the Heart
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output, and cardiac index during pharmacological stress with dobutamine in castrated vs sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids toward glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in messenger RNA and protein levels of beta-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency.
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| 3. |
- Svedlund Eriksson, Elin
(författare)
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Roles of Androgens in Cardiovascular Physiology and Pathophysiology
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACT Atherosclerosis is the major underlying cause of cardiovascular disease, such as myocardial infarction (MI) and stroke, and these conditions are the leading causes of death both in Sweden and globally. The immune system is involved in the pathogenesis of atherosclerosis as well as post-MI cardiac injury. Men develop cardiovascular disease approximately ten years earlier than women and the incidence of MI is higher in men throughout life. It has been suggested that the female sex hormones, estrogens, have cardioprotective properties while the roles of androgens, often described as male sex hormones, in cardiovascular physiology and pathophysiology are less understood. The underlying mechanisms and target cells for the cardiovascular effects of androgens are poorly described and to a large extent unknown. The aim of this thesis was to define roles and underlying mechanisms of androgens in cardiac physiology, atherosclerosis and MI and to identify target cells that mediate these actions in male mice. The main findings of this thesis were that: atherosclerosis induced by testosterone deficiency in male mice is thymus- and T cell dependent and that the thymic epithelial cell is likely the target cell for the anti-atherogenic actions of testosterone. depletion of the androgen receptor (AR) in bone marrow stromal cells in male mice reduced post-MI neutrophil infiltration, mortality and adverse cardiac remodelling. Hence, we have identified the target cells for these androgenic effects. Further, we demonstrate that androgens promote neutrophil egress from the bone marrow by regulating leukocyte retention factors in bone cells. androgen deficiency in male mice induces metabolic remodelling and expression of the fetal gene program in the heart. concentrations of sex steroids in the heart do not merely reflect serum levels in male mice. We show that progesterone levels are much higher in the heart than in skeletal muscle and that the cardiac levels are reduced during the acute phase post MI. This thesis demonstrates important effects of androgens on both the cardiovascular and immune systems. Our results provide potential explanations to sex differences in cardiovascular disease and how androgens can exert beneficial effects in some conditions (atherosclerosis) while detrimental in others (post-MI myocardial injury). Our data may pave the way for the development of selective AR modulators for safer treatment of prostate cancer. Further, our data raise new questions, including whether the AR in bone cells may be explored as a treatment target in acute MI and if drugs that reduce androgen levels, which are used in large patient groups, may positively affect the outcome of an MI.
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| 4. |
- Wilhelmson, Anna S K, et al.
(författare)
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Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naive T cells in secondary lymphoid organs. Here we investigated the androgen target cell for effects on thymopoiesis and RTEs in spleen and lymph nodes. Male mice with a general androgen receptor knockout (G-ARKO), T cell-specific (T-ARKO), or epithelial cell-specific (E-ARKO) knockout were examined. G-ARKO mice showed increased thymus weight and increased numbers of thymic T cell progenitors. These effects were not T cell-intrinsic, since T-ARKO mice displayed unaltered thymus weight and thymopoiesis. In line with a role for thymic epithelial cells (TECs), E-ARKO mice showed increased thymus weight and numbers of thymic T cell progenitors. Further, E-ARKO mice had more CD4(+)and CD8(+)T cells in spleen and an increased frequency of RTEs among T cells in spleen and lymph nodes. Depletion of the androgen receptor in epithelial cells was also associated with a small shift in the relative number of cortical (reduced) and medullary (increased) TECs and increased CCL25 staining in the thymic medulla, similar to previous observations in castrated mice. In conclusion, we demonstrate that the thymic epithelium is a target compartment for androgen-mediated regulation of thymopoiesis and consequently the generation of RTEs.
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| 5. |
- Wilhelmson, Anna S K, et al.
(författare)
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Increased Intimal Hyperplasia After Vascular Injury in Male Androgen Receptor-Deficient Mice
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:10, s. 3915-3923
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Tidskriftsartikel (refereegranskat)abstract
- Intimal hyperplasia is a vascular pathological process involved in the pathogenesis of atherosclerosis. Data suggest that T, the most important sex steroid hormone in males, protects men from atherosclerotic cardiovascular disease. T mainly acts via the androgen receptor (AR), and in this study we evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular smooth muscle cells with a physiological T concentration inhibited both migration and proliferation of the cells. Analyzing the expression of central regulators of cell proliferation and migration, we found that mRNA and protein levels of p27 were lower in uninjured arteries from ARKO mice and that T replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells.
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| 6. |
- Wilhelmson, Anna S K, et al.
(författare)
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Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells.
- 2018
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 38:7, s. 1519-1527
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Tidskriftsartikel (refereegranskat)abstract
- Androgen deprivation therapy has been associated with increased cardiovascular risk in men. Experimental studies support that testosterone protects against atherosclerosis, but the target cell remains unclear. T cells are important modulators of atherosclerosis, and deficiency of testosterone or its receptor, the AR (androgen receptor), induces a prominent increase in thymus size. Here, we tested the hypothesis that atherosclerosis induced by testosterone deficiency in male mice is T-cell dependent. Further, given the important role of the thymic epithelium for T-cell homeostasis and development, we hypothesized that depletion of the AR in thymic epithelial cells will result in increased atherosclerosis.Prepubertal castration of male atherosclerosis-prone apoE-/- mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD (cluster of differentiation) 3 antibody abolished castration-induced atherogenesis, demonstrating a role of T cells. Male mice with depletion of the AR specifically in epithelial cells (E-ARKO [epithelial cell-specific AR knockout] mice) showed increased thymus weight, comparable with that of castrated mice. E-ARKO mice on an apoE-/- background displayed significantly increased atherosclerosis and increased infiltration of T cells in the vascular adventitia, supporting a T-cell-driven mechanism. Consistent with a role of the thymus, E-ARKO apoE-/- males subjected to prepubertal thymectomy showed no atherosclerosis phenotype.We show that atherogenesis induced by testosterone/AR deficiency is thymus- and T-cell dependent in male mice and that the thymic epithelial cell is a likely target cell for the antiatherogenic actions of testosterone. These insights may pave the way for new therapeutic strategies for safer endocrine treatment of prostate cancer.
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