| 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. |
- Li, T. T., et al.
(författare)
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Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82:6, s. 799-808
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTo identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA). MethodsIgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining. ResultsPeptide GPI(293-307) was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI(293-307) epitopes, and high affinity anti-GPI(293-307) IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI(293-307) IgG antibodies induced arthritis in mice. Moreover, anti-GPI(293-307) IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI(293-307)-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI(293-307) antibodies. ConclusionsWe have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.
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| 3. |
- 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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| 4. |
- Westas, Mats, 1972-
(författare)
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Internet-based cognitive behavioural therapy for depression : Effects and experiences among patients with cardiovascular disease
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Depressive symptoms are common in patients with cardiovascular disease (CVD). CVD has a negative impact on patients’ prognosis and health-related quality of life (HRQoL). Guidelines for the treatment of CVD recommend treatment of depressive symptoms. However, the detection rate of depressive symptoms in CVD care is low and patients are therefore at risk of not receiving treatment. The reason for the low detection rate in CVD patients has not been fully explored, but may be related to healthcare professionals or the patients themselves. CVD patients’ experience of how depressive symptoms are discussed or managed by healthcare providers has not currently been fully explored. Today, cognitive behavioural therapy (CBT) is the recommended treatment for mild to moderate depressive symptoms and has been found to be effective in CVD patients. One problem with CBT is the low access to the treatment, which is mainly due to a lack of psychotherapists. A solution could be to use the internet to provide CBT (iCBT), since this has been shown to be effective in the treatment of depressive symptoms in non- CVD populations and is as effective as regular CBT. At the time when this thesis was planned there was a lack of iCBT studies on patients with CVD and depressive symptoms, and more research regarding iCBT in CVD has been called for in the literature. AimThe overall aim of this thesis was to generate knowledge which can lead to improvements in the care of patients with CVD and depressive symptoms. This is done by exploring how depressive symptoms are managed in the healthcare setting from the patient’s perspective, and by evaluating the effects and experiences of an iCBT programme for depressive symptoms in patients with CVD. Design and methodsThis thesis represents two quantitative and two qualitative studies that were performed on the same cohort of participants (n=144) recruited to a randomised controlled trial (RCT) aiming to evaluate a nine-week iCBT programme (n=72) adapted for patients with CVD and depressive symptoms. In the RCT, the comparator was a nine-week online discussion forum (n=72). These participants were recruited via an invitation letter sent to patients diagnosed with CVD (i.e. coronary heart disease, atrial fibrillation/atrial flutter or heart failure) who had contacted four hospitals in southeast Sweden during the past year. Study I had a qualitative study design with an inductive semantic approach. The sample (n=20) was recruited from those who had performed iCBT and had completed at least one module of the treatment programme. The interviews were conducted by telephone using a semi-structured interview guide. Study II was designed as an RCT, and compared the effect of a nine-week iCBT programme adapted for CVD (n=72) with nine weeks of ODF (n=72) on depressive symptoms in CVD patients. Data regarding depressive symptoms and HRQoL was collected at baseline and at nine weeks post-intervention. Study III used the same cohort as study I, and had a qualitative study design with an inductive latent approach. Study IV used a quantitative longitudinal and explorative design. Data regarding depressive symptoms was collected at baseline, at nine weeks post-intervention and at six- and twelve-month follow-ups. ResultsThe mean age of the participants in studies II and IV was 63 years, and 61% (n=89) were men. Atrial fibrillation/flutter was found in 56% (n=81), 44% (n=63) had coronary heart disease and 26% (n=38) had heart failure. The mean age of the participants in studies I and III (n=20) was 62 years, and 55% (n=11) were men. The patients experienced how depressive symptoms were addressed and managed in clinical cardiac care encounters under three main themes: “Not being seen as a whole person”; “Denying depressive symptoms”; and “I was provided with help”. The RCT study showed that iCBT after nine weeks was more effective than ODF in terms of decreasing depressive symptoms and improving HRQoL. At six- and twelve-month follow-ups, the improvements in depressive symptoms in the iCBT group were sustained. At the twelve-month follow-up, it was those who had more depressive symptoms at baseline who also experienced more improvements in depressive symptoms through iCBT, whereas those with heart failure were less likely to improve. The experience of participating in the iCBT programme was perceived as: taking control of the disease; not just a walk in the park; and feeling a personal engagement with the iCBT programme. ConclusionsCVD patients experienced that healthcare professionals focused on somatic symptoms and did not address their depressive symptoms. On the other hand, CVD patients did not always understand that they had depressive symptoms – or denied having depressive symptoms – when meeting healthcare professionals. Those who had received treatment had taken the initiative to address this by themselves or through support from family or friends. A nine-week iCBT programme adapted for CVD and guided by nurses with clinical experience of CVD and psychiatry and a brief education in iCBT seems to be useful for decreasing depressive symptoms and improving HRQoL. The effect of iCBT seems to be more beneficial in CVD patients with higher levels depressive symptoms, whereas the effect of iCBT on heart failure patients is less certain. The iCBT programme adapted to CVD seems to provide knowledge, and was experienced by patients as helpful for taking control of their disease. A CVD-adapted iCBT programme including feedback from nurses with clinical experience of CVD and psychiatry was helpful for engaging with and motivating carrying out the iCBT programme. Participating in the iCBT programme can be demanding and emotionally challenging, but is sometimes necessary to achieve improvements in depressive symptoms.
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| 5. |
- Wilhelmson, Anna S K, et al.
(författare)
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Deficiency of mature B cells does not alter the atherogenic response to castration in male mice
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone deficiency in men is associated with increased atherosclerosis burden and increased cardiovascular risk. In male mice, testosterone deficiency induced by castration increases atherosclerosis as well as mature B cell numbers in spleen. As B cells are potentially pro-atherogenic, we hypothesized that there may be a link between these effects. To address whether mature B cell deficiency alter the atherogenic response to castration, we studied B cell-deficient mu MT and genotype control male mice on an atherosclerosis-prone Apoe(-/-) background that were castrated or sham-operated pre-pubertally and fed a high-fat diet between 8 and 16 weeks of age to accelerate atherosclerosis development. Genotype did not affect the effects of castration on body weight or weights of fat depots and there were no differences in serum cholesterol levels across the four groups. Atherosclerosis assessed by quantification of lesion area in serial sections of the aortic root was significantly increased by castration and by the mu MT mutation, with no significant interaction between genotype and surgery. In conclusion, castration evokes a similar atherogenic response in B cell-deficient mu MT and control mice. These data suggest that atherogenesis following castration is unrelated to the effects of androgens on mature B cell numbers.
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