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Background: Disturbed white adipose tissue function is important for cardiometabolic risk and metabolic syndrome (MetS). Whether this involves adipose lipid turnover (lipolysis and synthesis of triglycerides) is unknown and was presently investigated in subcutaneous adipose tissue, the body's largest fat depot., Methods: In cross-sectional studies in 78 subjects, adipose lipid age, representing overall lipid turnover (mobilization and storage), and lipid storage capacity were assessed by the incorporation of atmospheric 14 C into adipose lipids. Adipose lipid age from an algorithm of adipocyte lipolysis and clinical parameters was also determined in 185 subjects. Adult Treatment Panel III (ATPIII) scoring defined MetS (scores 3-5) or healthy (score 0). ANOVA or ANCOVA and t test were used for statistical comparison. Because there was no method interaction to determine lipid age, the 2 groups were combined., Results: Lipid age increased by incremental ATPIII score (F=42; P <0.0001) and was 2-fold advanced in MetS (t=11.3; P <0.0001). The correlation with lipid age was independent of age, sex, body mass index, waist-to-hip ratio, sedentary lifestyle, absence of obesity, and adipose insulin resistance (F=10.7; P <0.0001). Lipid storage capacity was not related to the ATPIII score (F=1.0; P =0.44) or MetS (t=-0.9; P =0.35). Adipocyte lipolysis activation was decreased in MetS and inversely related to incremental ATPIII score, suggesting that decreased lipid mobilization is the major factor behind high lipid age in these conditions., Conclusions: Despite normal lipid assimilation capacity, abdominal subcutaneous adipose lipid turnover is decreased in MetS and high ATPIII score because of impaired ability to mobilize lipids involving low adipocyte lipolysis activation., Competing Interests: D.P. Andersson has received nonfinancial support from COVIS Pharma (study drug donation) as a principal investigator in another study. He is site principal investigator for Ionis 678354 at Ionis Pharmaceuticals, Inc. He has part-time employment at Werlabs AB. None of these studies or the employment of D.P. Andersson are related to the present work. The other authors report no conflicts.

Background: Longitudinal studies investigating hormone therapy in transgender individuals are rare and often limited to 1- to 2-year follow-up periods., Objectives and Methods: We examined changes in body composition, muscle volumes, and fat distribution as well as muscle strength, arterial stiffness, and cardiometabolic biomarkers in both transgender men (TM; n = 17, age 25 ± 5 years) and transgender women (TW; n = 16, age 28 ± 5 years) at baseline and after 1 and 5-6 years of hormone therapy in a longitudinal prospective cohort design. Whole-body and regional fat and muscle volumes were analyzed using magnetic resonance imaging, and blood samples were taken., Results: Skeletal muscle size increased in TM (21% after 6 years) and decreased in TW (7% after 5 years). Muscle strength increased 18% after 6 years in TM (p = 0.003) but was statistically unchanged in TW. Muscle fat infiltration changed (p < 0.05) almost completely toward the affirmed sex phenotype after 1 year of therapy in both TM and TW. The most notable changes in fat volume distribution were that TW increased total adiposity but decreased visceral fat volume, whereas TM showed increased visceral fat (70%) and liver fat but relatively stable total adipose tissue levels. Although arterial stiffness and blood pressure did not change, there was a significant increase in triglyceride and LDL cholesterol levels and a decrease in HDL levels in TM after 6 years., Conclusion: These unique longitudinal data underscore the importance of continued clinical monitoring of the long-term health effects of gender-affirming hormone therapy in both TW and, perhaps especially, TM., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Purpose: There is limited research on individuals undergoing self-initiated health examinations, and the Werlabs cohort will be a base for such research., Participants: All individuals aged 18 or older who had undertaken a self-initiated health examination at Werlabs AB with at least one recorded value of creatinine or cholesterol in Sweden (from 1 January 2015 through 31 December 2023) was included. Medical history and anthropometric measurements were self-reported through an online questionnaire. We describe cohort baseline characteristics, demographic variables and cardiometabolic risk factors., Findings to Date: The study population includes 149 556 individuals who provided at least one health screening. The median (IQR) age was 43 (33-54) years and 54% were women. The most common self-reported chronic disease was hypertension (4.5%), followed by cardiovascular disease (0.9%) and 12.6% reported values of obesity. The prevalence was 2.1% for diabetes, 1.2% for kidney disease (including an estimated glomerular filtration rate of <60 mL/min/1.73 m 2 ), 57.8% for a low-density lipoprotein cholesterol level of >3.0 mmol/L and 4.1% for anaemia (haemoglobin <120 g/L and <130 g/L for women and men, respectively). Interestingly, 1.5% of the individuals had a glucose measurement of >7.0 mmol/L, without reporting a previous diagnosis of diabetes. In an analysis restricted to 621 individuals with recorded blood pressure data between the age of 40 and 70 years and without existing cardiovascular disease, diabetes or kidney disease, 35,4% were classified as high or very high cardiovascular risk according to the 2021 ESC guidelines on cardiovascular disease prevention and with lipid levels that made them eligible for lipid-lowering therapy., Future Plans: The Werlabs cohort comprises a rather healthy and young population that can provide opportunities for future studies on individuals undergoing self-initiated health examinations and has the potential to impact treatment of cardiometabolic risk factors., Competing Interests: Competing interests: HCA, NBF, DPA and OH are employed by Werlabs AB. LK is a former employee of Werlabs. NBF and DPA are shareholders in Werlabs AB. AN and KB have contributed with medical and scientific advice to Werlabs AB, and non-reimbursed (AN and KB) in the later years. PU declares no conflict of interest and all other authors declare no further conflicts of interest., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Early in the COVID-19 pandemic, numerous clinical trials were initiated. Although concerns were raised regarding the quality of the trials, the eventual research output yielded from the trials remains unknown. The objective of this study was to include all clinical trials registered on ClinicalTrials.gov during the first 6 months of the pandemic and assess if and where their results had been reported, their completion and discontinuation rates, achieved enrolment and changes made to the primary outcome after trial registration., Methods: We included all interventional studies related to COVID-19 first registered on ClinicalTrials.gov between 1 January 2020 and 1 July 2020. We systematically searched for trial results, reported through 15 May 2023, in scientific publications, preprints and ClinicalTrials.gov. We assessed the achieved trial enrolment, trial discontinuation (reaching <90% of target enrolment), and whether the primary outcome had been changed as compared with the initial protocol registration., Results: The 775 clinical trials included in the analysis planned to enrol 238 933 (median (IQR) 120 (60, 304) patients; 355 (46%) of the trials had reported results, and 283 (36%) were published in a scientific journal. In the reported trials, the total enrolment was 95 332 (median (IQR) 105 (45, 222) patients. 186 (24%) trials were completed, and 169 (22%) trials were discontinued, with slow recruitment being the most stated reason for discontinuation (9% of all trials, although 30% of the discontinued trials did not report a reason). 117 (33%) of the reported trials had changed their primary outcome. In total, 157 (20%) trials were completed and published in a scientific journal, of which 105 enrolled ≥100 patients and 103 had not changed the primary outcome. 63 completed and published trials enrolled ≥100 patients and had not changed the primary outcome., Conclusions: Most clinical trials of COVID-19 registered at ClinicalTrials.gov during the first 6 months of the pandemic remained unreported or had been discontinued. Many of the trials whose results had been reported enrolled few patients and changed the primary outcome after trial registration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: While transgender individuals represent a significant group seeking medical care, the differential effect of sex on cardiometabolic risk metrics is incompletely understood. Therefore, the current study aimed to characterize the impact of sex hormones and chromosomes on a contemporary panel of cardiometabolic risk biomarkers and functional cardiovascular measurements., Methods: 17 transmen and 17 transwomen were studied at baseline (T0), 4 weeks (hormonal castration, T1), and 11 months following gender-affirming hormone treatment (T12). We analyzed carotid intima-media thickness (cIMT) and arterial stiffness, lipoproteins and other metabolites comprehensively by nuclear magnetic resonance spectroscopy and HDL-mediated cholesterol efflux capacity (CEC) from macrophages. T0 to T12 comparisons informed the impact of sex hormones, comparisons of genetic XX and XY individuals at T1 the impact of sex chromosomes., Results: Vascular function was comparable at T12 and T0; systolic blood pressure increased in transmen (p=0.002). Transmen developed a pro-atherogenic lipoprotein profile, estrogen treatment in transwomen tended to result in improvements. Several metabolites indicating increased diabetes risk including plasma glucose were changed in transmen (p=0.025), with opposite changes in transwomen (p=0.002). Interestingly, at T1 apparent diabetes risk was lower in XX compared with XY individuals (p=0.002). CEC decreased in transwomen (p<0.01), while remaining unchanged in transmen. However, in both groups the strong positive association of apoA-I with cholesterol efflux observed at T0 was lost at T12., Conclusions: The results are consistent with increased cardiometabolic risk in transmen, while transwomen show beneficial changes early during gender-affirming hormone therapy. Sex chromosomes have less intrinsic effects. XY individuals and transmen display an increased apparent diabetes risk. Further research of cardiometabolic risk is needed for transgender individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The organ-specific effects of gender-affirming sex hormone treatment (GAHT) in transgender women (TW) and transgender men (TM) are insufficiently explored. This study investigated the effects of GAHT on adipose tissue function., Methods: In a single-center interventional prospective study, 32 adults undergoing GAHT, 15 TW and 17 TM, were examined with anthropometry and abdominal subcutaneous adipose tissue biopsies obtained before initiation of treatment, 1 month after endogenous sex hormone inhibition and three and 11 months after initiated GAHT. Fat cell size, basal/stimulated lipolysis and cytokine secretion in adipose tissue were analyzed., Results: TW displayed an increase in complement component 3a and retinol-binding protein 4 (RBP4) secretion after sex hormone inhibition, which returned to baseline following estradiol treatment. No changes in lipolysis were seen in TW. TM showed downregulation of RBP4 after treatment, but no changes in basal lipolysis. In TM, the estrogen suppression led to higher noradrenaline stimulated (NA) lipolysis that was normalized following testosterone treatment. At 11 months, the ratio of NA/basal lipolysis was lower compared to baseline. There were no significant changes in fat cell size in either TW or TM., Conclusion: In TW, gonadal hormone suppression results in transient changes in cytokines and in TM there are some changes in NA-stimulated lipolysis following testosterone treatment. However, despite the known metabolic effects of sex hormones, the overall effects of GAHT on adipose tissue function are small and likely have limited clinical relevance, but larger studies with longer follow-up are needed to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT02518009, Retrospectively registered 7 August 2015., (© 2024. The Author(s).)

Background/objective: Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined., Subjects/methods: AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men., Results: Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m 2 or more) was present (p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women (p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women (p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes (p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 (IRS1) was lower in men than women (p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men (p < 0.0001)., Conclusions: In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1., (© 2024. The Author(s).)

Aims: Hypertriglyceridaemia (hTG) is associated with atherosclerotic cardiovascular disease, pancreatitis, and non-alcoholic fatty liver disease (NAFLD) in large population-based studies. The understanding of the impact of hereditary hTG and cardiometabolic disease status on the development of hTG and its associated cardiometabolic outcomes is more limited. We aimed to establish a multigenerational cohort to enable studies of the relationship between hTG, cardiometabolic disease and hereditary factors., Methods and Results: The population-based observational Stockholm hyperTRIglyceridaemia REGister (STRIREG) study includes 1 460 184 index individuals who have measured plasma triglycerides in the clinical routine in Region Stockholm, Sweden, between 1 January 2000 and 31 December 2021. The laboratory measurements also included basic haematology, blood lipid panel, liver function tests, and HbA1c. Using the Swedish Multi-Generation register, 2 147 635 parents and siblings to the indexes were identified to form the complete study cohort. Laboratory data from participants were combined with data from several national registers that provided information on the cause of death, medical diagnoses, dispensed medicines, and socioeconomic factors including country of birth, education level, and marital status., Conclusion: The multi-generational longitudinal STRIREG cohort provides a unique opportunity to investigate different aspects of hTG as well as heredity for other metabolic diseases. Important outcome measures include mortality, cardiovascular mortality, major cardiovascular events, development of incident diabetes, and NAFLD. The STRIREG study will provide a deeper understanding of the impact of hereditary factors and associated cardiometabolic complications., Competing Interests: Conflict of interest: J.B. reports research grant funding from Amgen, Novartis, and Sanofi, outside the submitted work, and honoraria from Ionis Pharmaceuticals Inc., Amarin, Amgen, Bayer, Novartis, and Sanofi. K.L. reports research grant funding from Amgen outside the submitted work and honoraria from Amgen and Sanofi., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Insulin resistance in all major target tissues is present in metabolic syndrome (MetS). The resistance in adipocytes is not well described and was presently examined., Methods: In this observational study on isolated abdominal white subcutaneous adipocytes from 419 adults, concentration-response effects of insulin on lipolysis inhibition (glycerol release) and lipogenesis stimulation (glucose conversion to total lipids) were determined. Insights into early and late insulin signaling events were obtained through the determination of insulin sensitivity (half maximum effective concentration) and responsiveness (maximum effect), respectively. In a subgroup of 132 subjects, we analyzed the subcutaneous adipose mRNA expression of genes in the canonical insulin signaling pathway using microarray. These results were validated using quantitative real-time polymerase chain reaction in 74 individuals., Results: While the insulin responsiveness was similar in subjects with or without Mets, the sensitivity to insulin-mediated inhibition of lipolysis and stimulation of lipogenesis was ∼tenfold lower in subjects with MetS (p < 0.0001). When age, sex, adipocyte volume, body mass index and body shape were considered, only the antilipolytic resistance was independently associated with MetS. The mRNA expression of several genes in the canonical insulin signaling pathway were altered in MetS (p < 0.0006 or better) where the mRNA levels of insulin receptor substrate 2 associated with the antilipolytic effect (Rho = 0.34; p = 0.0016)., Conclusion: The sensitivities of the antilipolytic and lipogenic effects of insulin are decreased in the MetS but only antilipolysis remains significant after multiple regression analysis. This resistance is localized at initial and receptor-near events in hormone signaling involving insulin receptor substrate 2., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication., Objectives: The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication., Methods: Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE)., Results: In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83)., Conclusions: The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted., Competing Interests: Funding Support and Author Disclosures Dr Trolle Lagerros was funded by the Stockholm County Council (clinical research appointment). Dr Andersson was funded by the Stockholm County Council (no. 954970, 963296, 962029), CIMED, and the Strategic Research Program at Karolinska Institutet (no. 961507). None of the funders were involved in the design, conduct of the study, data collection, data analysis, interpretation of data, or preparation, review, or approval of the manuscript. Dr Andersson has received nonfinancial support from COVIS Pharma (study drug donation) as principal investigator in another study; is site principal investigator for Ionis 678354 for Ionis Pharmaceuticals; and is employed at Werlabs; none of these studies or the outside employment are related to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adipose tissue insulin resistance is linked to altered plasma levels of triglycerides and HDL (high-density lipoprotein)-cholesterol. However, its degree of independence from liver resistance and different metabolic traits (lipolysis, lipogenesis) effected is not clear and was presently investigated., Methods: In 3290 adult subjects, plasma levels of triglycerides and HDL-cholesterol were cross-sectionally measured and related to interindividual variations in measures of insulin resistance in the liver (homeostasis mode assessment of insulin resistance index) or adipose tissue (Adipo-IR index). In subgroups, insulin-induced antilipolysis and lipogenesis in isolated subcutaneous fat cells (n=578) were determined alongside global adipose tissue gene expression (n=132)., Results: Using linear regression, homeostasis mode assessment of insulin resistance and Adipo-IR strongly correlated with the plasma lipids explaining 33% of the variations in triglycerides. Together with other variables (age, sex, body mass index, cardiometabolic disorders, nicotine use, ethnicity, and physical activity) in multiple regression, homeostasis mode assessment of insulin resistance, and Adipo-IR each remained an important regressor for triglycerides and HDL-cholesterol ( P <0.0001). In fat cells, half-maximum effective concentration but not maximum effect of insulin on antilipolysis and lipogenesis contributed independently to variations in triglycerides and HDL-cholesterol ( P =0.001 or lower). This was linked to expression of the insulin receptor, insulin receptor substrate-1, and AKT serine/threonine kinase 2 in adipose tissue., Conclusions: Markers of insulin resistance in the liver and adipose tissue each associate strongly, and independently of each other, to elevated triglycerides and decreased HDL levels. At the fat cell, early insulin receptor signaling and sensitivity, but not maximum insulin action contributes to the variations in circulating triglycerides and HDL-cholesterol., Competing Interests: Disclosures None.

Aim: Obesity is linked to cardiometabolic diseases, however non-obese individuals are also at risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). White adipose tissue (WAT) is known to play a role in both T2D and CVD, but the contribution of WAT inflammatory status especially in non-obese patients with cardiometabolic diseases is less understood. Therefore, we aimed to find associations between WAT inflammatory status and cardiometabolic diseases in non-obese individuals., Methods: In a population-based cohort containing non-obese healthy (n = 17), T2D (n = 16), CVD (n = 18), T2D + CVD (n = 19) individuals, seventeen different cytokines were measured in WAT and in circulation. In addition, 13-color flow cytometry profiling was employed to phenotype the immune cells. Human T cell line (Jurkat T cells) was stimulated by rCCL18, and conditioned media (CM) was added to the in vitro cultures of human adipocytes. Lipolysis was measured by glycerol release. Blocking antibodies against IFN-γ and TGF-β were used in vitro to prove a role for these cytokines in CCL18-T-cell-adipocyte lipolysis regulation axis., Results: In CVD, T2D and CVD + T2D groups, CCL18 and CD4 + T cells were upregulated significantly compared to healthy controls. WAT CCL18 secretion correlated with the amounts of WAT CD4 + T cells, which also highly expressed CCL18 receptors suggesting that WAT CD4 + T cells are responders to this chemokine. While direct addition of rCCL18 to mature adipocytes did not alter the adipocyte lipolysis, CM from CCL18-treated T cells increased glycerol release in in vitro cultures of adipocytes. IFN-γ and TGF-β secretion was significantly induced in CM obtained from T cells treated with CCL18. Blocking these cytokines in CM, prevented CM-induced upregulation of adipocyte lipolysis., Conclusion: We suggest that in T2D and CVD, increased production of CCL18 recruits and activates CD4 + T cells to secrete IFN-γ and TGF-β. This, in turn, promotes adipocyte lipolysis - a possible risk factor for cardiometabolic diseases., (© 2023. The Author(s).)

Sedentary people have insulin resistance in their skeletal muscle, but whether this also occurs in fat cells was unknown. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) were investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half-maximal effective concentration) were determined. In 69 women, hyperinsulinemia-induced circulating fatty acid levels were measured. In 128 women, adipose gene expression was analyzed. Responsiveness of insulin for antilipolysis (60% inhibition) and lipogenesis (twofold stimulation) were similar between sedentary and active subjects. Sensitivity for both measures decreased ˜10-fold in sedentary subjects (P < 0.01). However, upon multiple regression analysis, only the association between antilipolysis sensitivity and physical activity remained significant when adjusting for BMI, age, sex, waist-to-hip ratio, fat-cell size, and cardiometabolic disorders. Fatty acid levels decreased following hyperinsulinemia but remained higher in sedentary compared with active women (P = 0.01). mRNA expression of insulin receptor and its substrates 1 and 2 was decreased in sedentary subjects. In conclusion, while the maximum effect is preserved, sensitivity to insulin's antilipolytic effect in subcutaneous fat cells is selectively lower in sedentary subjects., (© 2023 by the American Diabetes Association.)

Objective: To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19., Design: Multicentre, randomised, controlled, open-label trial., Setting: 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021., Participants: Adults hospitalised with COVID-19 and receiving oxygen therapy., Intervention: Inhaled ciclesonide 320 µg two times a day for 14 days versus standard care., Main Outcome Measures: Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death., Results: Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49-67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3-9) days in the ciclesonide group and 4 (2-7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a <1 day absolute reduction in a post-hoc calculation). Three participants in each group died/received invasive mechanical ventilation (HR 0.90 (95% CI 0.15 to 5.32)). The trial was discontinued early due to slow enrolment., Conclusions: In patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully., Trial Registration Number: NCT04381364., Competing Interests: Competing interests: This study received non-financial support from COVIS Pharma (study drug donation). The authors have no conflict of interest to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome., Design/methods: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist)., Results: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m 2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007)., Conclusion: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background/objective: The development of overweight/obesity associates with alterations in white adipose tissue (WAT) cellularity (fat cell size/number) and lipid metabolism, in particular lipolysis. If these changes differ between early/juvenile (EOO < 18 years of age) or late onset overweight/obesity (LOO) is unknown and was presently examined., Subjects/methods: We included 439 subjects with validated information on body mass index (BMI) at 18 years of age. Using this information and current BMI, subjects were divided into never overweight/obese (BMI < 25 kg/m 2 ), EOO and LOO. Adipocyte size, number, morphology (size in relation to body fat) and lipolysis were determined in subcutaneous abdominal WAT. Body composition and WAT distribution was assessed by dual-X-ray absorptiometry., Results: Compared with never overweight/obese, EOO and LOO displayed larger WAT amounts in all examined depots, which in subcutaneous WAT was explained by a combination of increased size and number of fat cells in EOO and LOO. EOO had 40% larger subcutaneous fat mass than LOO (p < 0.0001). Visceral WAT mass, WAT morphology and lipolysis did not differ between EOO and LOO except for minor differences in men between the two obesity groups. On average, the increase in BMI per year was 57% higher in subjects with EOO compared to LOO (p < 0.0001)., Conclusion: Early onset overweight/obesity causes a more rapid and pronounced accumulation of subcutaneous WAT than adult onset. However, fat mass expansion measures including WAT cellularity, morphology and fat cell lipolysis do not differ in an important way suggesting that similar mechanisms of WAT growth operate in EOO and LOO., (© 2022. The Author(s).)

Background: There are few long-term mechanistic studies in adipose tissue that investigate the metabolic effects of bariatric surgery. Changes in lipogenesis may be involved in long-term weight development., Objectives: To investigate the long-term effect of bariatric surgery on lipogenesis in abdominal fat cells and whether surgical treatment could induce an epigenetic memory that would maintain improved lipogenesis in spite of body weight relapse., Setting: Karolinska University Hospital in Stockholm County, Sweden., Methods: A total of 22 women with obesity living in the Stockholm area were examined before, 2, 5, and 10 years after bariatric surgery. Abdominal adipose tissue biopsies were obtained. Fat cells were isolated and spontaneous and insulin stimulated glucose incorporation into lipids were assayed. CpG-methylation profiling was performed on adipocytes using the Infinium EPIC BeadChips., Results: Bariatric surgery was associated with improvement in adipocyte spontaneous and insulin stimulated lipogenesis, which was maintained despite some later weight regain (29 % of initial weight loss). There was also an increase in fat cell size between 2- and 10-year follow-up, albeit not to presurgery levels. There were 7729 differentially methylated CpG sites (DMS) at 2 years that showed no sign of return to baseline at either 5 or 10 years. Merging results with expression profiles identified 1259 genes with DMS which showed early response or continual change in expression in one direction after surgery. Upregulated genes with DMS were enriched in gene sets linked to cellular response to insulin stimulus (e.g., IRS1, IRS2, PDE3B, and AKT2) and regulation of lipid metabolic processes., Conclusion: Bariatric surgery leads to long-term improvement of lipogenesis and insulin responsiveness in subcutaneous adipocytes in women in spite of some partial body weight regain postoperatively. This may to some extent be explained by epigenetic modifications of fat cell function., (Copyright © 2022 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: We examined the longitudinal and cross-sectional relationship between automated MRI-analysis and single-slice axial CT imaging for determining muscle size and muscle fat infiltration (MFI) of the anterior thigh., Methods: Twenty-two patients completing sex-hormone treatment expected to result in muscle hypertrophy ( n = 12) and atrophy ( n = 10) underwent MRI scans using 2-point Dixon fat/water-separated sequences and CT scans using a system operating at 120 kV and a fixed flux of 100 mA. At baseline and 12 months after, automated volumetric MRI analysis of the anterior thigh was performed bilaterally, and fat-free muscle volume and MFI were computed. In addition, cross-sectional area (CSA) and radiological attenuation (RA) (as a marker of fat infiltration) were calculated from single slice axial CT-images using threshold-assisted planimetry. Linear regression models were used to convert units., Results: There was a strong correlation between MRI-derived fat-free muscle volume and CT-derived CSA ( R = 0.91), and between MRI-derived MFI and CT-derived RA ( R = -0.81). The 95% limits of agreement were ±0.32 L for muscle volume and ±1.3% units for %MFI. The longitudinal change in muscle size and MFI was comparable across imaging modalities., Conclusions: Both automated MRI and single-slice CT-imaging can be used to reliably quantify anterior thigh muscle size and MFI., Advances in Knowledge: This is the first study examining the intermodal agreement between automated MRI analysis and CT-image assessment of muscle size and MFI in the anterior thigh muscles. Our results support that both CT- and MRI-derived measures of muscle size and MFI can be used in clinical settings.

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m 2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state., (© 2021. The Author(s).)

Objective: To assess the association of cardiometabolic risk factors with hospitalisation or death due to COVID-19 in the general population., Design, Setting and Participants: Swedish population-based cohort including 29 955 participants., Exposures: Cardiometabolic risk factors assessed between 2014 and 2018., Main Outcome Measures: Hospitalisation or death due to COVID-19, as registered in nationwide registers from 31 January 2020 through 12 September 2020. Associations of cardiometabolic risk factors with the outcome were assessed using logistic regression adjusted for age, sex, birthplace and education., Results: Mean (SD) age was 61.2 (4.5) and 51.5% were women. 69 participants experienced hospitalisation or death due to COVID-19. Examples of statistically significant associations between baseline factors and subsequent hospitalisation or death due to COVID-19 included overweight (adjusted OR (aOR) vs normal weight 2.73 (95% CI 1.25 to 5.94)), obesity (aOR vs normal weight 4.09 (95% CI 1.82 to 9.18)), pre-diabetes (aOR vs normoglycaemia 2.56 (95% CI 1.44 to 4.55)), diabetes (aOR vs normoglycaemia 3.96 (95% CI 2.13 to 7.36)), sedentary time (aOR per hour/day increase 1.10 (95% CI 1.02 to 1.17)), grade 2 hypertension (aOR vs normotension 2.44 (95% CI 1.10 to 5.44)) and high density lipoprotein cholesterol (aOR per mmol/L increase 0.33 (95% CI 0.17 to 0.65)). Statistically significant associations were not observed for grade 1 hypertension (aOR vs normotension 1.03 (95% CI 0.55 to 1.96)), current smoking (aOR 0.56 (95% CI 0.24 to 1.30)), total cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.71 to 1.13)), low density lipoprotein cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.69 to 1.15)) and coronary artery calcium score (aOR per 10 units increase 1.00 (95% CI 0.99 to 1.01))., Conclusions: In a large population-based sample from the general population, several cardiometabolic risk factors were associated with hospitalisation or death due to COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, one-carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state, where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action., (© 2021 by the American Diabetes Association.)

Context: Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown., Objective: To investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies., Methods: The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up., Results: Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001)., Conclusions: Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI)., Objectives: This study sought to investigate the association between treatment with PDE5i or alprostadil and outcomes in men with stable coronary artery disease., Methods: All Swedish men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event were included, using the Swedish Patient Register and the Swedish Prescribed Drug Register. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i versus alprostadil., Results: This study included 16,548 men treated with PDE5i and 1,994 treated with alprostadil. The mean follow-up was 5.8 years, with 2,261 deaths (14%) in the PDE5i group and 521 (26%) in the alprostadil group. PDE5i compared with alprostadil treatment was associated with lower mortality (hazard ratio: 0.88; 95% confidence interval: 0.79 to 0.98) and with similar associations for MI, heart failure, cardiovascular mortality, and revascularization. When quintiles (q) of filled PDE5i prescriptions were compared using q1 as reference, patients in q3, q4, and q5 had lower all-cause mortality. Among alprostadil users, those in q5 had a lower all-cause mortality compared to q1., Conclusions: In men with stable coronary artery disease, treatment with PDE5i is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil treatment. Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design., Competing Interests: Funding Support and Author Disclosures Dr. Andersson was funded by a regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet. Dr. Holzmann holds research positions funded by the Swedish Heart-Lung Foundation (grant: 20170804) and Stockholm County Council (grant: 20170686). The sponsors had no role in the design or conduct of this study. Dr. Holzmann has received consultancy fees from Idorsia unrelated to this project. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is a major factor behind insulin resistance. The validity of simple biochemical surrogate measures to estimate insulin resistance at the fat cell level is unclear., Objective: To investigate if the surrogate measures HOMA-IR (glucose/insulin product) and Adipo-IR (fatty acids/insulin product) reflect insulin action on glucose/lipid metabolism in fat cells., Design: Insulin-induced lipogenesis and lipolysis inhibition (antilipolysis) in subcutaneous fat cells were investigated for sensitivity (reflecting receptor-near events) and responsiveness (i.e., maximum action reflecting distal post-receptor events) in 363 subjects. Results were compared with log 10 transformed values for HOMA-IR and Adipo-IR., Results: Individually, the four measures of in vitro insulin action on fat cells correlated significantly (p < 0.0001) but weakly with each other (adjusted r 2 0.05-0.23). HOMA-IR and Adipo-IR correlated strongly with each other (adjusted r 2  = 0.81). Using Spearman or simple linear regression all in vitro measures except antilipolytic responsiveness expressed per lipid weight, correlated significantly with Adipo-IR or HOMA-IR (p values <0.0001). Similar relationships remained after combined correction for age, body mass index and sex. Together, the four in vitro measures explained 50% of the variability in HOMA-IR and ADIPO-IR (p < 0.0001). Receiver-operating characteristic analysis showed good sensitivity and specificity for Adipo-IR and HOMA-IR to detect combined insulin resistance of antilipolysis and lipogenesis in fat cells (area under the curve = 0.8)., Conclusions: Insulin action at the receptor and post-receptor levels on lipolysis and lipogenesis in fat cells correlates significantly with Adipo-IR and HOMA-IR. Both surrogate measures give similar information about insulin resistance of glucose and lipid metabolism in fat cells.

Objective: Patients undergoing bariatric surgery present long-term metabolic improvements and reduced type 2 diabetes risk, despite long-term weight regain. We hypothesized that part of these protective effects could be linked to altered gene expression in white adipose tissue (WAT)., Methods: Transcriptomic profiling by gene microarray was performed in abdominal subcutaneous WAT from women before (n = 50) and two (n = 49) and five (n = 38) years after Roux-en-Y gastric bypass (RYGB) surgery as well as in 28 age-matched nonoperated women., Results: In the obese women, the average body weight decrease was 38 kg 2 years postsurgery followed by an 8 kg weight regain between 2 and 5 years. Most of the long-term changes in WAT gene expression occurred during the first 2 years. However, a subset of genes encoding proteins involved in inflammation displayed a continued decrease between baseline, 2 and 5 years, respectively; that is an expression pattern independent of body weight regain. Expression of 71 of these genes correlated with measurements of adipocyte morphology or serum adipokine levels., Conclusion: The continuous improvement in WAT inflammatory gene expression, despite body weight relapse, may contribute to the sustained effects on adipose morphology after bariatric surgery., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background/objective: Body mass index (BMI) is central when evaluating treatment effect after gastric bypass. The metabolic impact of BMI-independent differences in body fat percentage (BF%) after gastric bypass is not fully understood. We compared metabolic and adipose tissue characteristics in women with high versus low BF% independent of BMI after obesity remission following gastric bypass., Subjects/methods: A cohort of 215 women was included at baseline. A total of 166 women were re-examined 2 years after gastric bypass, whereof 130 had obesity remission (BMI < 30 kg/m 2 ). Anthropometric parameters, blood pressure, and lipids were measured. Total and regional body fat mass was determined by dual-energy X-ray absorptiometry. Insulin sensitivity was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and hyperinsulinemic euglycemic clamp (M value). Adipocyte size and number were determined., Results: Of the 130 women with obesity remission, 64 had BF% ≥ 35 and 65 < 35. Independent of BMI, high BF% were associated with higher HOMA-IR (P = 0.021), lower M value (P = 0.0046), higher triglycerides (P = 0.013), higher visceral/total and android/gynoid fat mass ratios (P = 0.0032 and 0.0003 respectively), and larger subcutaneous fat cell volume (P < 0.0001) 2 years after gastric bypass. No differences in anthropometric measures, glucose, blood pressure, or fat cell number were observed., Conclusions: Independent of BMI, patients with higher BF% displayed lower insulin sensitivity, higher triglyceride levels, central fat distribution, and larger subcutaneous adipocytes 2 years after gastric bypass. Thus, determination of BF% provides additional information of metabolic characteristics at follow-up of non-obese patients after gastric bypass.

Context: As many sports are divided in male/female categories, governing bodies have formed regulations on the eligibility for transgender individuals to compete in these categories. Yet, the magnitude of change in muscle mass and strength with gender-affirming treatment remains insufficiently explored., Objective: This study explored the effects of gender-affirming treatment on muscle function, size, and composition during 12 months of therapy., Design, Settings, Participants: In this single-center observational cohort study, untrained transgender women (TW, n = 11) and transgender men (TM, n = 12), approved to start gender-affirming medical interventions, underwent assessments at baseline, 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement, and 4 and 12 months after treatment initiation., Main Outcome Measures: Knee extensor and flexor strength were assessed at all examination time points, and muscle size and radiological density (using magnetic resonance imaging and computed tomography) at baseline and 12 months after treatment initiation., Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps cross-sectional area (CSA) (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained their strength levels., Conclusions: One year of gender-affirming treatment resulted in robust increases in muscle mass and strength in TM, but modest changes in TW. These findings add new knowledge on the magnitude of changes in muscle function, size, and composition with cross-hormone therapy, which could be relevant when evaluating the transgender eligibility rules for athletic competitions., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Transcriptome analysis of abdominal subcutaneous white adipose tissue (sWAT) has identified important obesity-associated disturbances. However, the relation between sWAT transcriptome and long-term future changes in body weight remains elusive., Objective: To investigate sWAT transcriptome signatures before and after long-term weight changes and assess their predictive value for body weight changes., Design: A total of 56 women were followed longitudinally and subdivided into weight-stable (WS, n = 25), weight-gaining (WG, n = 14) and weight-losing (WL, n = 17) groups between baseline and follow-up (13 ± 1 years). The fasting sWAT transcriptome was analyzed by gene microarray at baseline and follow-up. Key genes associated with weight changes were validated using quantitative real-time PCR., Results: In total 285 transcripts exhibited difference (FDR < 30%) in expression fold change over time between WL and WS women. WL women displayed decreased pro-inflammatory (NLRP3) but increased insulin-response gene (FASN and GLUT4) expression over time. In comparison, 461 transcripts displayed difference in expression fold change over time between WG and WS women (P < 0.05). Genes involved in autophagic processes (CDK5, SQSTM1 and FBXL2) were generally upregulated in WG women. At baseline, 307 and 302 transcripts were differentially expressed (FDR < 30%) in WL and WG women, respectively, when independently compared against WS women. Baseline expression of adipogenic and lipogenic genes (PPARG, IRS2 and HACD2) was lower, while pro-fibrotic (COL6A1) was higher, in WL than WS women; whereas protein processing genes were lower expressed in WG than in WS women., Conclusion: In adult women, long-term body weight change associates with altered sWAT transcriptome. Expression of genes associated with inflammation, insulin response, adipogenesis and lipogenesis are linked to weight loss. However, other pathways such as autophagy not only associate but also predict future weight gain suggesting that intrinsic factors in sWAT impact tissue expansion.

The worldwide obesity epidemic 1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates 2,3 . Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14 C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.

Objective: Many overweight/obese subjects appear metabolically healthy with normal in vivo insulin sensitivity. Still, they have increased long-term risk of developing type 2 diabetes. We hypothesized that adipose tissue dysfunction involving decreased insulin action in adipocytes is present in apparently healthy overweight/obese subjects., Design/methods: Subjects with normal metabolic health according to Adult Treatment Panel-III or Framingham risk score criteria were subdivided into 67 lean, 32 overweight and 37 obese according to body mass index. They were compared with 200 obese individuals with metabolic syndrome. Insulin sensitivity and maximum action on inhibition of lipolysis and stimulation of lipogenesis was determined in subcutaneous adipocytes. Gene expression was determined by micro-array and qPCR. DNA methylation was assessed by array, pyrosequencing and reporter assays., Results: Compared with lean, adipocytes in overweight/obese displayed marked reductions in insulin sensitivity in both antilipolysis and lipogenesis as well as an attenuated maximum lipogenic response. Among these, only antilipolysis sensitivity correlated with whole-body insulin sensitivity. These differences were already evident in the overweight state, were only slightly worse in the unhealthy obese state and were not related to fat cell size. Adipose tissue analyses linked this to reduced expression of the insulin signalling protein AKT2, which associated with increased methylation at regulatory sites in the AKT2 promoter., Conclusions: Apparently healthy subjects have severely disturbed adipocyte insulin signalling already in the overweight state which involves epigenetic dysregulation of AKT2. This may constitute an early defect in insulin action that appears even upon modest increases in fat mass., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background: The cardiometabolic risk profile improves following bariatric surgery. However, the degree of improvement in relation to weight-stable control subjects is unknown., Objectives: To study the differences in cardiometabolic risk profile between formerly obese patients following Roux-en-Y gastric bypass (RYGB) surgery and control subjects., Methods: Subjects undergoing RYGB and reaching a BMI <30 kg m -2 2 years postsurgery were matched with control subjects regarding age, sex and BMI. The following examinations were performed: insulin sensitivity measured by hyperinsulinaemic-euglycaemic clamp, insulin clearance, homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile, inflammatory marker levels, dual-energy X-ray absorptiometry and subcutaneous adipose tissue cellularity (fat cell size and number)., Results: Sixty-nine subjects undergoing RYGB were matched to a control subject. Insulin sensitivity measured by hyperinsulinaemic-euglycaemic clamp, blood pressure, inflammatory status and glucose, triglyceride and HDL cholesterol levels were comparable to values of control subjects. However, HOMA-IR (1.0 ± 0.5 vs. 1.3 ± 0.7, P = 0.005), insulin clearance (0.38 ± 0.08 vs. 0.34 ± 0.08 μL m -2  min -1 , P < 0.0001) and circulating levels of insulin (31 ± 15 vs. 37 ± 17 pmol L -1 , P = 0.008), total cholesterol (4.1 ± 0.7 vs. 4.8 ± 0.9 mmol L -1 , P < 0.0001) and LDL cholesterol (2.1 ± 0.6 vs. 2.9 ± 0.8 mmol L -1 , P < 0.0001) were improved beyond the levels in matched control subjects. Furthermore, formerly obese subjects had higher lean and lower fat mass as well as a more benign type of adipose cellularity (hyperplasia with many small fat cells) compared to control subjects., Conclusions: Subjects who underwent RYGB and reached a postobese state demonstrated a beneficial body composition, slightly increased insulin sensitivity as indirectly measured by HOMA-IR and higher insulin clearance, lower atherogenic lipid/lipoprotein levels and benign adipocyte morphology compared with control subjects who had never been obese. In line with previous results, our findings may in part explain why RYGB confers long-term protection against metabolic complications., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Adipocyte mobilization of fatty acids (lipolysis) is instrumental for energy expenditure. Lipolysis displays both spontaneous (basal) and hormone-stimulated activity. It is unknown if lipolysis is important for future body weight gain and associated disturbed glucose metabolism, and this was presently investigated in subcutaneous adipocytes from two female cohorts before and after ≥10-year follow-up. High basal and low stimulated lipolysis at baseline predicted future weight gain (odds ratios ≥4.6) as well as development of insulin resistance and impaired fasting glucose/type 2 diabetes (odds ratios ≥3.2). At baseline, weight gainers displayed lower adipose expression of several established lipolysis-regulating genes. Thus, inefficient lipolysis (high basal/low stimulated) involving altered gene expression is linked to future weight gain and impaired glucose metabolism and may constitute a treatment target. Finally, low stimulated lipolysis could be accurately estimated in vivo by simple clinical/biochemical measures and may be used to identify risk individuals for intensified preventive measures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) remains the most effective treatment of obesity and associated co-morbidities. Body fat distribution associates with metabolic function., Objective: To investigate if preoperative body fat mass and distribution measured by dual-energy x-ray absorptiometry (DXA) predict weight loss and metabolic outcome after RYGB, and to compare predictive value of DXA with simple anthropometric measures., Setting: Four Swedish hospitals within the Stockholm area., Methods: Two hundred fifteen women scheduled for RYGB were included. Evaluations before and 2 years after RYGB included determination of insulin sensitivity by the homeostatic model assessment of insulin resistance, blood pressure, plasma lipids, and anthropometric measures, such as waist-to-hip-ratio and fat percentage estimated by formula. Body fat mass and distribution were determined by DXA., Results: Follow-up rate was 77.2% (n = 166). All clinical, anthropometric, and DXA measures were improved/reduced postsurgery (all P<.0001). Android/gynoid fat mass ratio and waist-to-hip-ratio predicted improved homeostatic model assessment of insulin resistance (P = .0028 and .0014), independently of body mass index and age. Body fat percentage, measured by DXA or estimated by formula, predicted percent weight loss (P<.0001 and .0083). Body mass index predicted percent weight loss and percent excess body mass index lost (P = .0022 and<.0001). DXA and anthropometric measures performed equally as predictors, except for DXA measured fat percentage that was slightly better than formula estimated., Conclusion: DXA provided predictive values similar to those by basic anthropometric measures, suggesting a limited additional value of preoperative DXA to predict metabolic improvement and weight loss after RYGB in women., (Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Although the divergent male and female differentiation depends on key genes, many biological differences seen in men and women are driven by relative differences in estrogen and testosterone levels. Gender dysphoria denotes the distress that gender incongruence with the assigned sex at birth may cause. Gender-affirming treatment includes medical intervention such as inhibition of endogenous sex hormones and subsequent replacement with cross-sex hormones. The aim of this study is to investigate consequences of an altered sex hormone profile on different tissues and metabolic risk factors. By studying subjects undergoing gender-affirming medical intervention with sex hormones, we have the unique opportunity to distinguish between genetic and hormonal effects., Methods: The study is a single center observational cohort study conducted in Stockholm, Sweden. The subjects are examined at four time points; before initiation of treatment, after endogenous sex hormone inhibition, and three and eleven months following sex hormone treatment. Examinations include blood samples, skeletal muscle-, adipose- and skin tissue biopsies, arteriography, echocardiography, carotid Doppler examination, whole body MRI, CT of muscle and measurements of muscle strength., Results: The primary outcome measure is transcriptomic and epigenomic changes in skeletal muscle. Secondary outcome measures include transcriptomic and epigenomic changes associated with metabolism in adipose and skin, muscle strength, fat cell size and ability to release fatty acids from adipose tissue, cardiovascular function, and body composition., Conclusions: This study will provide novel information on the role of sex hormone treatment in skeletal muscle, adipose and skin, and its relation to cardiovascular and metabolic disease.

Background: Arterial stiffness, measured by pulse wave velocity (PWV), is linked to obesity, cardiovascular disease, and all-cause mortality. Short-term weight loss improves PWV, but the long-term effects are unknown. We investigated the effect of pronounced long-term weight loss on PWV and whether anthropometric/metabolic parameters and/or white adipose tissue (WAT) phenotype could predict this change in PWV., Methods: Eighty-two obese subjects were examined before and 2 years after Roux-en-Y gastric bypass. Analyses included anthropometrics, routine clinical chemistry, and hyperinsulinemic-euglycemic clamp. Arterial stiffness was measured as aortic PWV (aPWV) using the Arteriograph device. WAT mass and distribution were assessed by dual-X-ray absorptiometry. Baseline visceral and subcutaneous WAT samples were obtained to measure adipocyte cell size. Transcriptomic profiling of subcutaneous WAT was performed in a subset of subjects (n = 30)., Results: At the 2-year follow-up, there were significant decreases in body mass index (39.4 ± 3.5 kg/m2 vs. 26.6 ± 3.4 kg/m2; P < 0.0001) and aPWV (7.8 ± 1.5 m/s vs. 7.2 ± 1.4 m/s; P = 0.006). Multiple regression analyses showed that baseline subcutaneous adipocyte volume was associated with a reduction in aPWV (P = 0.014), after adjusting for confounders. Expression analyses of 52 genes implicated in arterial stiffness showed that only one, COL4A1, independently predicted improvements in aPWV after adjusting for confounders (P = 0.006)., Conclusions: Bariatric surgery leads to long-term reduction in aPWV. This improvement can be independently predicted by subcutaneous adipocyte volume and WAT COL4A1 expression, which suggests that subcutaneous WAT has a role in regulating aPWV., Clinical Trials Registration: Trial Number NCT01727245 (clinicaltrials.gov).

Background/objective: Differences in subcutaneous abdominal adipose tissue (SAT) fat cell size and number (cellularity) are linked to insulin resistance. Men are generally more insulin resistant than women but it is unknown whether there is a gender dimorphism in SAT cellularity. The objective was to determine SAT cellularity and its relationship to insulin sensitivity in men and women., Methods: In a cohort study performed at an outpatient academic clinic in Sweden, 798 women and 306 men were included. Estimated SAT mass (ESAT) was derived from measures of dual-energy X-ray absorptiometry and a formula. SAT biopsies were obtained to measure mean fat cell size; SAT adipocyte number was obtained by dividing ESAT with mean fat cell weight. Fat cell size was also compared with level of insulin sensitivity in vivo., Results: Over the entire range of body mass index (BMI) both fat cell size and number correlated positively with ESAT in either sex. On average, fat cell size was larger in men than in women, which was driven by significantly larger fat cells in non-obese men compared with non-obese women; no gender effect on fat cell size was seen in obese subjects. For all subjects fat cell number was larger in women than men, which was driven by a gender effect among non-obese individuals (P<0.0001). The relationship between fat cell size and insulin resistance was significant in both genders (P<0.0001) but steeper in men than in women (F=19, P<0.0001)., Conclusions: Although both fat cell size and number determine SAT mass, adipocyte number contributes more and size less in women than in men and this is most evident in non-obese subjects. Over the entire BMI range, fat cell size contributes stronger to insulin resistance in men.

Objective: Erectile dysfunction (ED) is associated with an increased risk of cardiovascular disease in healthy men. However, the association between treatment for ED and death or cardiovascular outcomes after a first myocardial infarction (MI) is unknown., Methods: In a Swedish nationwide cohort study all men <80 years of age without prior MI, or cardiac revascularisation, hospitalised for MI during 2007-2013 were included. Treatment for ED, defined as dispensed phosphodiesterase-5 inhibitors or alprostadil, was related to risk of death, MI, cardiac revascularisation or heart failure., Results: Forty-three thousand one hundred and forty-five men with mean age 64 (±10) years were included, of whom 7.1% had ED medication dispensed during a mean 3.3 years (141 739 person-years) of follow--up. Men with, compared with those without treatment for ED, had a 33% lower mortality (adjusted HR 0.67 (95%CI 0.55 to -0.81)), and 40% lower risk of hospitalisation for heart failure (HR 0.60 (95% CI 0.44 to 0.82)). There was no association between treatment with alprostadil and mortality. The adjusted risk of death in men with 1, 2-5 and >5 dispensed prescriptions of phosphodiesterase-5 inhibitors was reduced by 34% (HR 0.66 (95% CI 0.38 to 1.15), 53% (HR 0.47 (95% CI 0.26 to 0.87) and 81% (HR 0.19 (95% CI 0.08 to 0.45), respectively, when compared with alprostadil treatment., Conclusions: Treatment for ED after a first MI was associated with a reduced mortality and heart failure hospitalisation. Only men treated with phosphodiesterase-5 inhibitors had a reduced risk, which appeared to be dose-dependent., Competing Interests: Competing interests: MJH received consultancy honoraria from Actelion and Pfizer, (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: Omentectomy in addition to bariatric surgery has been suggested to improve metabolic outcome but short-term (6-24 months) studies have refuted this notion. We investigated whether there was any long-term impact of omentectomy., Methods: Forty-nine obese women underwent gastric bypass surgery and were randomly assigned to omentectomy (n = 26) or not (n = 23). They were re-examined after 5 years including dual-energy X-ray absorptiometry for body composition, blood pressure and blood sampling., Results: There were no significant differences between the two groups at baseline (p = 0.07-0.93) or 5 years post-operatively (p = 0.15-0.93) regarding weight, BMI, body composition, HOMA-IR, plasma cholesterol, HDL cholesterol, or triglycerides., Conclusion: In agreement with previous shorter studies, removal of the greater omentum in addition to GBP is not associated with metabolic benefits after long-term follow-up.

Aims/hypothesis: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes., Methods: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01)., Results: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes., Conclusion/interpretation: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.

Objective: Although long-term weight regain may occur after bariatric surgery, many patients are protected against relapse or development of type 2 diabetes. The study objective was to investigate whether this involves beneficial changes in adipose function., Research Design and Methods: Forty-nine obese women were investigated before and 2 and 5 years after Roux-en-Y gastric bypass (RYGB). At the 5-year follow-up, 30 subjects were pairwise matched for BMI and age to 30 control women. Clinical parameters and fine-needle biopsies from subcutaneous abdominal adipose tissue were obtained; fat cell size and number, lipolysis, adiponectin, and proinflammatory protein secretion were determined., Results: After 2 years, BMI decreased from 43 to 29 kg/m 2 , which was accompanied by improvements in insulin sensitivity (HOMA of insulin resistance [HOMA-IR]), increased circulating and adipose secreted adiponectin, and decreased adipose lipolysis and fat cell size but no change in adipocyte number. Between 2 and 5 years after surgery, BMI had increased to 31 kg/m 2 . This was associated with slightly increased HOMA-IR and unaltered circulating or adipose secreted adiponectin but higher secretion of tumor necrosis factor-α and increased lipolysis and number of fat cells but no change in adipocyte size. All these parameters, except lipolysis, were significantly more favorable compared with those in matched control subjects. Furthermore, the relationship between HOMA-IR and circulating adiponectin was less steep than in control subjects., Conclusions: RYGB improves long-term insulin sensitivity and adipose phenotypes beyond the control state despite weight regain. Postoperative beneficial alterations in adipose function may be involved in the diabetes-protective effect of bariatric surgery., (© 2017 by the American Diabetes Association.)

Context: Cardiometabolic complications in obesity may be linked to white adipose tissue (WAT) dysfunction. Transcriptomic studies of Sc WAT have reported that CCL18, encoding the CC chemokine ligand 18 (CCL18), is increased in obesity/insulin resistance but its functional role is unknown., Objective: Our objectives were to determine if CCL18 is secreted from Sc WAT and if secreted and/or serum levels associate with metabolic phenotypes. We also planned to define the primary cellular source and if CCL18 exerts effects on adipocytes., Design: This is a cohort study., Setting: The study took place in an outpatient academic clinic., Participants: A total of 130 obese women scheduled for bariatric surgery and 35 nonobese controls were included., Methods: Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp or homeostasis model assessment. CCL18 was analyzed in serum/WAT incubates by ELISA. Effects of recombinant CCL18 was determined in cultures of primary human adipocytes and the monocyte cell line THP-1 differentiated into M0/M1/M2 macrophages., Main Outcome Measure: Association with metabolic risk factors was measured., Results: CCL18 was secreted from WAT and the levels correlated positively with insulin resistance, Adult Treatment Panel III risk score and plasma triglycerides, independent of body mass index and better than other established adipocytokines. In 80 obese women, S-CCL18 levels were significantly higher in insulin resistant compared with insulin sensitive subjects. In WAT CCL18 mRNA was expressed in macrophages and correlated positively with immune-related genes, particularly those enriched in M2 macrophages. While CCL18 increased cyto-/chemokine expression in M0/M2-THP-1 cells, human adipocytes showed no responses in vitro., Conclusions: Circulating and WAT-secreted CCL18 correlates with insulin resistance and metabolic risk score. Because CCL18 is macrophage-specific and associates with adipose immune gene expression, it may constitute a marker of WAT inflammation.

Context: The adipokines chemerin, dipeptidyl peptidase 4, and adiponectin influence insulin sensitivity. Whether their circulating levels and adipose secretion are altered in nonobese individuals with type 2 diabetes mellitus (T2DM) is unknown., Objective: The objective of this study was to investigate SC adipose secretion and serum levels of the three adipokines in relation to T2DM features., Design: Fourteen nonobese T2DM and 13 healthy men were investigated. Insulin sensitivity and glucose control were assessed by hyperinsulinemic euglycemic clamp, homeostasis model assessment, and glycated hemoglobin., Main Outcome Measure: Association of circulating and adipose-secreted adipokines with fat cell volume and insulin sensitivity was measured., Participants: Volunteers in an outpatient academic clinic participated., Results: Although adipose secretion was similar between the groups, serum chemerin was higher (70 ± 10 vs 50 ± 1 ng/ml; P = .005), adiponectin lower (4.7 ± 1.3 vs 6.8 ± 2.2 μg/ml; P = .005), and dipeptidyl peptidase 4 unaltered in T2DM. Serum adiponectin (r = 0.53; P = .005) and chemerin (r = -0.42; P = .03) correlated with adipose secreted levels. Secreted and circulating chemerin correlated positively with adipocyte volume (r > 0.40; P < .05), whereas serum adiponectin correlated negatively with this measure (r = -0.61; P = .001). Adiponectin serum half-life was decreased in T2DM (168 ± 24 vs 186 ± 18 minutes; P = .029) and correlated negatively with glycated hemoglobin (r = -0.45; P = .03) and adipocyte volume (r = -0.56; P < .003). Serum adiponectin (r = 0.57; P = .017) and chemerin (r = -0.52; P = .03) associated with clamp measures independently of T2DM diagnosis., Conclusions: In nonobese men, circulating adiponectin and chemerin levels are altered in T2DM without changes in adipose secretion. Adipocyte volume is important for variations in serum chemerin and adiponectin and for serum clearance of adiponectin. In T2DM, poor glucose control also plays a role for adiponectin clearance.

Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response to insulin, which differed from the small effects observed in NO subjects. In the obese, 231 genes were altered; 71 were enriched in ISO subjects (e.g., phosphorylation processes), and 52 were enriched in IRO subjects (e.g., cellular stimuli). Common cardio-metabolic risk factors and gender do not influence these findings. This study demonstrates that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: We aimed to elucidate the impact of fat cell size and inflammatory status of adipose tissue on the development of type 2 diabetes in non-obese individuals., Methods: We characterised subcutaneous abdominal adipose tissue by examining stromal cell populations by 13 colour flow cytometry, measuring expression of adipogenesis genes in the progenitor cell fraction and determining lipolysis and adipose secretion of inflammatory proteins in 14 non-obese men with type 2 diabetes and 13 healthy controls matched for age, sex, body weight and total fat mass., Results: Individuals with diabetes had larger fat cells than the healthy controls but stromal cell population frequencies, adipose lipolysis and secretion of inflammatory proteins did not differ between the two groups. However, in the entire cohort fat cell size correlated positively with the ratio of M1/M2 macrophages, TNF-α secretion, lipolysis and insulin resistance. Expression of genes encoding regulators of adipogenesis and adipose morphology (BMP4, CEBPα [also known as CEBPA], PPARγ [also known as PPARG] and EBF1) correlated negatively with fat cell size., Conclusions/interpretation: We show that a major phenotype of white adipose tissue in non-obese individuals with type 2 diabetes is adipocyte hypertrophy, which may be mediated by an impaired adipogenic capacity in progenitor cells. Consequently, this could have an impact on adipose tissue inflammation, release of fatty acids, ectopic fat deposition and insulin sensitivity.

Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute ∼10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects., (Copyright © 2015 Elsevier Inc. All rights reserved.)