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- Hansson, Björn, et al.
(författare)
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A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ
- 2020
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 533:1, s. 64-69
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function. Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob mice. Overexpression of MRTF-A, but not MRTF-B, markedly suppressed PPARγ expression. Further, MRTF-A expression resulted in decreased IRS-1 level, shifted phosphorylation of Akt (pS473/pT308), IRS-1 (pS302) and AS160 (pT642), and lowered insulin-stimulated glucose uptake. Hypertrophic adipocytes from Ob/Ob mice displayed an increased proportion of polymerized actin, and increased nuclear translocation of MRTF-A compared with control (Ob/+). Similar with human adipocytes overexpressing MRTF-A, adipocytes isolated from Ob/Ob mice had reduced expression of IRS-1 and PPARγ, as well as impaired insulin response. Together, these data demonstrate that MRTF-A negatively influences insulin sensitivity and the expression of key targets in fully mature human adipocytes. This suggests that MRTF-A is poised to exert a transcriptional response in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance.
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| 2. |
- Hansson, Björn, et al.
(författare)
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Adipose cell size changes are associated with a drastic actin remodeling
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes. In the present study, we demonstrate that changes in adipocyte size correlate with a drastic remodeling of the actin cytoskeleton. Expansion of primary adipocytes following 2 weeks of high-fat diet (HFD)-feeding in C57BL6/J mice was associated with a drastic increase in filamentous (F)-actin as assessed by fluorescence microscopy, increased Rho-kinase activity, and changed expression of actin-regulating proteins, favoring actin polymerization. At the same time, increased cell size was associated with impaired insulin response, while the interaction between the cytoskeletal scaffolding protein IQGAP1 and insulin receptor substrate (IRS)-1 remained intact. Reversed feeding from HFD to chow restored cell size, insulin response, expression of actin-regulatory proteins and decreased the amount of F-actin filaments. Together, we report a drastic cytoskeletal remodeling during adipocyte expansion, a process which could contribute to deteriorating adipocyte function.
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| 3. |
- Hansson, Björn, et al.
(författare)
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Intact glucose uptake despite deteriorating signaling in adipocytes with high-fat feeding
- 2018
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 60:3, s. 199-211
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Tidskriftsartikel (refereegranskat)abstract
- To capture immediate cellular changes during diet-induced expansion of adipocyte cell volume and number, we characterized mature adipocytes during a short-term high-fat diet (HFD) intervention. Male C57BL6/J mice were fed chow diet, and then switched to HFD for 2, 4, 6 or 14 days. Systemic glucose clearance was assessed by glucose tolerance test. Adipose tissue was dissected for RNA-seq and cell size distribution analysis using coulter counting. Insulin response in isolated adipocytes was monitored by glucose uptake assay and Western blotting, and confocal microscopy was used to assess autophagic activity. Switching to HFD was accompanied by an immediate adipocyte size expansion and onset of systemic insulin resistance already after two days, followed by recruitment of new adipocytes. Despite an initially increased non-stimulated and preserved insulin-stimulated glucose uptake, we observed a decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and protein kinase B (PKB). After 14 days of HFD, both the insulin-stimulated phosphorylation of Akt substrate of 160 kDa (AS160) and glucose uptake was blunted. RNA-seq analysis of adipose tissue revealed transient changes in gene expression at day four, including highly significant upregulation of Trp53inp, previously demonstrated to be involved in autophagy. We confirmed increased autophagy, measured as an increased density of LC3-positive puncta and decreased p62 expression after 14 days of HFD. In conclusion, HFD rapidly induced systemic insulin resistance, whereas insulin-stimulated glucose uptake remained intact throughout 6 days of HFD feeding. We also identified autophagy as an early cellular process that potentially influences adipocyte function upon switching to HFD.
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| 4. |
- Morén, Björn, et al.
(författare)
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EHD2 regulates adipocyte function and is enriched at cell surface-associated lipid droplets in primary human adipocytes
- 2019
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Ingår i: Molecular Biology of the Cell. - : AMER SOC CELL BIOLOGY. - 1059-1524 .- 1939-4586. ; 30:10, s. 1147-1159
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Tidskriftsartikel (refereegranskat)abstract
- Adipocytes play a central role in energy balance, and dysfunctional adipose tissue severely affects systemic energy homeostasis. The ATPase EH domain-containing 2 (EHD2) has previously been shown to regulate caveolae, plasma membrane-specific domains that are involved in lipid uptake and signal transduction. Here, we investigated the role of EHD2 in adipocyte function. We demonstrate that EHD2 protein expression is highly up-regulated at the onset of triglyceride accumulation during adipocyte differentiation. Small interfering RNA-mediated EHD2 silencing affected the differentiation process and impaired insulin sensitivity, lipid storage capacity, and lipolysis. Fluorescence imaging revealed localization of EHD2 to caveolae, close to cell surface-associated lipid droplets in primary human adipocytes. These lipid droplets stained positive for glycerol transporter aquaporin 7 and phosphorylated perilipin-1 following adrenergic stimulation. Further, EHD2 overexpression in human adipocytes increased the lipolytic signaling and suppressed the activity of transcription factor PPAR.. Overall, these data suggest that EHD2 plays a key role for adipocyte function.
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| 5. |
- Morén, Björn, 1987-, et al.
(författare)
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Technical note: evaluation of a spatial optimization model for prostate high dose‐rate brachytherapy in a clinical treatment planning system
- 2023
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Ingår i: Medical physics (Lancaster). - : WILEY. - 0094-2405 .- 2473-4209. ; 50:2, s. 688-693
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSpatial properties of a dose distribution, such as volumes of contiguous hot spots, are of clinical importance in treatment planning for high dose-rate brachytherapy (HDR BT). We have in an earlier study developed an optimization model that reduces the prevalence of contiguous hot spots by modifying a tentative treatment plan. PurposeThe aim of this study is to incorporate the correction of hot spots in a standard inverse planning workflow and to validate the integrated model in a clinical treatment planning system. The spatial function is included in the objective function for the inverse planning, as opposed to in the previous study where it was applied as a separate post-processing step. Our aim is to demonstrate that fine-adjustments of dose distributions, which are often performed manually in todays clinical practice, can be automated. MethodsA spatial optimization function was introduced in the treatment planning system RayStation (RaySearch Laboratories AB, Stockholm, Sweden) via a research interface. A series of 10 consecutive prostate patients treated with HDR BT was retrospectively replanned with and without the spatial function. ResultsOptimization with the spatial function decreased the volume of the largest contiguous hot spot by on average 31%, compared to if the function was not included. The volume receiving at least 200% of the prescription dose decreased by on average 11%. Target coverage, measured as the fractions of the clinical target volume (CTV) and the planning target volume (PTV) receiving at least the prescription dose, was virtually unchanged (less than a percent change for both metrics). Organs-at-risk received comparable or slightly decreased doses if the spatial function was included in the optimization model. ConclusionsOptimization of spatial properties such as the volume of contiguous hot spots can be integrated in a standard inverse planning workflow for brachytherapy, and need not be conducted as a separate post-processing step.
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| 6. |
- Akerblom, H., et al.
(författare)
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Association of Gastric Bypass Surgery With Risk of Developing Diabetic Retinopathy Among Patients With Obesity and Type 2 Diabetes in Sweden: An Observational Study
- 2021
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Ingår i: Jama Ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 139:2, s. 200-205
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Knowledge of the incidence and progression of diabetic retinopathy (DR) after gastric bypass surgery (GBP) in patients with obesity and diabetes could guide the management of these patients. OBJECTIVE To investigate the incidence of diabetic ocular complications in patients with type 2 diabetes after GBP compared with the incidence of diabetic ocular complications in a matched cohort of patients with obesity and diabetes who have not undergone GBP. DESIGN, SETTING, AND PARTICIPANTS Data from 2 nationwide registers in Sweden, the Scandinavian Obesity Surgery Registry and the National Diabetes Register, were used for this cohort study. A total of 5321 patients with diabetes from the Scandinavian Obesity Surgery Registry who had undergone GBP from January 1, 2007, to December 31, 2013, were matched with 5321 patients with diabetes from the National Diabetes Register who had not undergone GBP, based on sex, age, body mass index (BMI), and calendar time (2007-2013). Follow-up data were obtained until December 31, 2015. Statistical analysis was performed from October 5, 2018, to September 30, 2019. EXPOSURE Gastric bypass surgery. MAIN OUTCOMES AND MEASURES Incidence of new DR and other diabetic ocular complications. RESULTS The study population consisted of 5321 patients who had undergone GBP (3223 women [60.6%]; mean [SD] age, 49.0 [9.5] years) and 5321 matched controls (3395 women [63.8%]; mean [SD] age, 47.1 [11.5] years). Mean (SD) follow-up was 4.5 (1.6) years. The mean (SD) BMI and hemoglobin A1c concentration at baseline were 42.0 (5.7) and 7.6%(1.5%), respectively, in the GBP group and 40.9 (7.3) and 7.5%(1.5%), respectively, in the control group. The mean (SD) duration of diabetes was 6.8 (6.3) years in the GBP group and 6.4 (6.4) years in the control group. The risk for new DR was reduced in the patients who underwent GBP (hazard ratio, 0.62 [95% CI, 0.49-0.78]; P <.001). The dominant risk factors for development of DR at baseline were diabetes duration, hemoglobin A1c concentration, use of insulin, glomerular filtration rate, and BMI. CONCLUSIONS AND RELEVANCE This nationwide matched cohort study suggests that there is a reduced risk of developing new DR associated with GBP, and no evidence of an increased risk of developing DR that threatened sight or required treatment. (c) 2021 American Medical Association. All rights reserved.
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| 10. |
- Avery, Rachael S., et al.
(författare)
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A 725-year integrated offshore terrestrial varve chronology for southeastern Sweden suggests rapid ice retreat ~ 15 ka BP
- 2021
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Ingår i: Boreas. - : Wiley. - 0300-9483 .- 1502-3885. ; 50:2, s. 477-496
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Tidskriftsartikel (refereegranskat)abstract
- The Swedish Varve Chronology is an unparalleled tool for linking the deglacial history of Sweden with associated palaeo-environmental change at an annual time scale, and it forms part of Sweden's cultural heritage. A full deglacial chronology connected to the present day does not yet exist; a notable gap is in southeasternmost Sweden, where few varved records are successfully connected to reconstruct ice-margin retreat. Deglaciation in southern Sweden covers both the climate transition to the Bølling warm period (similar to 14.7 ka BP) and the ice-margin transition from a subaqueous to terrestrial terminus. To facilitate investigations into the links between ice-margin dynamics and abrupt climate change, we revisited the varve chronologies of southern Sweden. We digitized unpublished records, reanalysed existing varve thickness records, and obtained and analysed new varve series both on land and offshore. This combined approach has enabled us to refine and extend the existing south coast chronology east and 78 km northwards. Our new Skåne-Småland chronology records 725 years of deglaciation, in addition to a younger floating chronology in parts. This chronology suggests that the glacial-lake terminating Fennoscandian Ice Sheet in southern Sweden initially retreated northwards at similar to 110-160 m a(-1) slowing to 60-70 m a(-1) near the palaeo-shoreline. Between today's mainland and the (now) island of Öland the retreat rates increase three- to fivefold. Ice-margin retreat was initially oriented towards the north (as along the south coast), but later pivoted towards the northwest, signifying a landward retreat of terrestrial 'Swedish' ice that became divorced from the Baltic Sea ice-sheet catchment. Our new 725-year-long varve thickness series reveals repeated multidecadal scale episodes of increased sedimentation. These likely signify phases of enhanced ice-sheet melting that repeat and persist throughout the deglaciation of Skåne-Småland.
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