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  • 1. Baek, Jeanha
    et al.
    Robert-Nicoud, Ghislaine
    Herrera Hidalgo, Carmen
    Borg, Melissa L.
    Iqbal, Muhammad Naeem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Sigrid Therapeutics AB, Sweden.
    Berlin, Roger
    Lindgren, Maria
    Waara, Erik
    Uddén, Anna
    Pietiläinen, Kirsi
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Engineered mesoporous silica reduces long-term blood glucose and HbA1c, and improves metabolic parameters in prediabetics2022Ingår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 17, nr 1, s. 9-22Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15®, on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

  • 2. Bao, Cuiping
    et al.
    Yang, Xilin
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Tianjin Med Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Tianjin, Peoples R China.
    Luo, Hongbin
    Xu, Zhongliang
    Su, Cheng
    Qi, Xiuying
    Diabetes mellitus and incidence and mortality of kidney cancer: A meta-analysis2013Ingår i: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 27, nr 4, s. 357-364Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Diabetes is associated with increased risk of a spectrum of cancers, but there are few meta-analyses on the association between diabetes and kidney cancer. We performed a meta-analysis of case-control studies and cohort studies to address the incidence and mortality of kidney cancer in diabetes. Methods: Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 24 studies were included. We found that diabetes was significantly associated with increased risk of kidney cancer (RR=1.40, 95% CI = 1.16 to 1.69), and the results were consistent between case-control and cohort studies. A slightly stronger positive relation was observed in women (RR = 1.47, 95% CI=1.18 to 1.83) than in men (RR=1.28, 95% CI=1.10 to 1.48). Additional analyses indicated that the increased risk of kidney cancer was independent of alcohol consumption, body mass index (BMI)/obesity and smoking. However, there was no association between diabetes and mortality of kidney cancer (RR=1.12, 95% CI=0.99 to 1.20), without heterogeneity (P = 0.419, I-2 = 1.8%). Conclusions: Diabetes mellitus may increase the risk of kidney cancer in both women and men.

  • 3. Barregard, Lars
    et al.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cooke, Marcus S.
    Human and Methodological Sources of Variability in the Measurement of Urinary 8-Oxo-7,8-dihydro-2 '-deoxyguanosine2013Ingår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, nr 18, s. 2377-2391Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r(p) 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.

  • 4. Brandão, Luiz Eduardo Mateus
    et al.
    Espes, Daniel
    Orzechowski Westholm, Jakub
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Martikainen, Teemu
    Westerlund, Nestori
    Lampola, Lauri
    Popa, Alexandru
    Vogel, Heike
    Schürmann, Annette
    Dickson, Suzanne L.
    Benedict, Christian
    Cedernaes, Jonathan
    Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial2022Ingår i: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 31, nr 2, artikel-id e13472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep–wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%–30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

  • 5. Böhm, Anja
    et al.
    Keuper, Michaela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Eberhard Karls University Tübingen, Germany.
    Meile, Tobias
    Zdichavsky, Marty
    Fritsche, Andreas
    Häring, Hans-Ulrich
    Hrabe de Angelis, Martin
    Staiger, Harald
    Franko, Andras
    Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals2020Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 12407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m(2)), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10(-9)). In adipocytes, a negative correlation of mitochondrial respiration with donors' insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.

  • 6.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    A PERKy way to make mitochondrial cristae2021Ingår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 32, nr 7, s. 417-419Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    PERK protein, that is canonically associated with the response to endoplasmic reticulum stress, may be acquiring a new role as a regulator of the growth of mitochondrial cristae. This role is pertinent not only to the recruitment of brown adipose tissue thermogenic capacity but probably also to directing cristae formation in highly metabolically active organs such as the heart.

  • 7. Cediel-Ulloa, Andrea
    et al.
    Lupu, Diana Loana
    Johansson, Ylva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hinojosa, Maria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Özel, Fatih
    Rüegg, Joëlle
    Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity2022Ingår i: Expert Review of Endocrinology & Metabolism, ISSN 1744-6651, Vol. 17, nr 2, s. 131-141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Brain development is highly dependent on hormonal regulation. Exposure to chemicals disrupting endocrine signaling has been associated with neurodevelopmental impairment. This raises concern about exposure to the suspected thousands of endocrine disruptors, and has resulted in efforts to improve regulation of these chemicals. Yet, the causal links between endocrine disruption and developmental neurotoxicity, which would be required for regulatory action, are still largely missing.

    Areas covered: In this review, we illustrate the importance of two endocrine systems, thyroid hormone and retinoic acid pathways, for neurodevelopment. We place special emphasis on TH and RA synthesis, metabolism, and how endocrine disrupting chemicals known or suspected to affect these systems are associated with developmental neurotoxicity.

    Expert opinion: While it is clear that neurodevelopment is dependent on proper hormonal functioning, and evidence is increasing for developmental neurotoxicity induced by endocrine disrupting chemicals, this is not grasped by current chemical testing. Thus, there is an urgent need to develop test methods detecting endocrine disruption in the context of neurodevelopment. Key to this development is further mechanistic insights on the involvement of endocrine signaling in neurodevelopment as well as increased support to develop and validate new test methods for the regulatory context.

  • 8. Chatterjee, Saion
    et al.
    Peters, Sanne A. E.
    Woodward, Mark
    Mejia Arango, Silvia
    Batty, G. David
    Beckett, Nigel
    Beiser, Alexa
    Borenstein, Amy R.
    Crane, Paul K.
    Haan, Mary
    Hassing, Linda B.
    Hayden, Kathleen M.
    Kiyohara, Yutaka
    Larson, Eric B.
    Li, Chung-Yi
    Ninomiya, Toshiharu
    Ohara, Tomoyuki
    Peters, Ruth
    Russ, Tom C.
    Seshadri, Sudha
    Strand, Bjørn H.
    Walker, Rod
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Tianjin Medical University, China .
    Huxley, Rachel R.
    Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia2016Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, nr 2, s. 300-307Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a metaanalysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001). CONCLUSIONS Individuals with type 2 diabetes are at similar to 60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

  • 9. Cheung, L.
    et al.
    Gertow, J.
    Werngren, O.
    Folkersen, L.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Franco-Cereceda, A.
    Eriksson, P.
    Fisher, R. M.
    Human mediastinal adipose tissue displays certain characteristics of brown fat2013Ingår i: Nutrition & Diabetes, E-ISSN 2044-4052, Vol. 3, nr UNSP e66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7 +/- 13.8 years, body mass index 29.3 +/- 5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry. RESULTS: The microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P < 0.001) and PPARGC1A (1.7-fold, P = 0.0047), and lower expression of SHOX2 (0.12-fold, P < 0.001) and HOXC8 (0.14-fold, P < 0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P < 0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400 +/- 810 versus 3260 +/- 980 mu m(2), P < 0.001). CONCLUSIONS: Human mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.

  • 10.
    Chungkham, Holendro Singh
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Indian Statistical Institute, India.
    Marbaniang, Strong P.
    Narzary, Pralip Kumar
    Childhood Anemia in India: an application of a Bayesian geo-additive model2021Ingår i: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 21, nr 1, artikel-id 529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The geographical differences that cause anaemia can be partially explained by the variability in environmental factors, particularly nutrition and infections. The studies failed to explain the non-linear effect of the continuous covariates on childhood anaemia. The present paper aims to investigate the risk factors of childhood anaemia in India with focus on geographical spatial effect.

    Methods Geo-additive logistic regression models were fitted to the data to understand fixed as well as spatial effects of childhood anaemia. Logistic regression was fitted for the categorical variable with outcomes (anaemia (Hb < 11) and no anaemia (Hb >= 11)). Continuous covariates were modelled by the penalized spline and spatial effects were smoothed by the two-dimensional spline.

    Results At 95% posterior credible interval, the influence of unobserved factors on childhood anaemia is very strong in the Northern and Central part of India. However, most of the states in North Eastern part of India showed negative spatial effects. A U-shape non-linear relationship was observed between childhood anaemia and mother's age. This indicates that mothers of young and old ages are more likely to have anaemic children; in particular mothers aged 15 years to about 25 years. Then the risk of childhood anaemia starts declining after the age of 25 years and it continues till the age of around 37 years, thereafter again starts increasing. Further, the non-linear effects of duration of breastfeeding on childhood anaemia show that the risk of childhood anaemia decreases till 29 months thereafter increases.

    Conclusion Strong evidence of residual spatial effect to childhood anaemia in India is observed. Government child health programme should gear up in treating childhood anaemia by focusing on known measurable factors such as mother's education, mother's anaemia status, family wealth status, child health (fever), stunting, underweight, and wasting which have been found to be significant in this study. Attention should also be given to effects of unknown or unmeasured factors to childhood anaemia at the community level. Special attention to unmeasurable factors should be focused in the states of central and northern India which have shown significant positive spatial effects.

  • 11. Dawed, Adem Y.
    et al.
    Mari, Andrea
    Brown, Andrew
    McDonald, Timothy J.
    Li, Lin
    Wang, Shuaicheng
    Hong, Mun-Gwan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Sharma, Sapna
    Robertson, Neil R.
    Mahajan, Anubha
    Wang, Xuan
    Walker, Mark
    Gough, Stephen
    Hart, Leen M 't
    Zhou, Kaixin
    Forgie, Ian
    Ruetten, Hartmut
    Pavo, Imre
    Bhatnagar, Pallav
    Jones, Angus G.
    Pearson, Ewan R.
    Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials2023Ingår i: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 11, nr 1, s. 33-41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment.

    Methods In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests.

    Findings 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol  [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response.

    Interpretation This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.

  • 12. Dixen, Karen
    et al.
    Basse, Astrid L.
    Murholm, Maria
    Isidor, Marie S.
    Hansen, Lillian H. L.
    Petersen, M. Christine H.
    Madsen, Lise
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Quistorff, Bjorn
    Hansen, Jacob B.
    ERR gamma Enhances UCP1 Expression and Fatty Acid Oxidation in Brown Adipocytes2013Ingår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, nr 3, s. 516-524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Estrogen-related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERR gamma impacts on differentiation and function of brown adipocytes. Design and Methods: We characterize the expression of ERR gamma in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes. Results: ERR gamma was preferentially expressed in brown compared to white fat depots, and ERR gamma was induced during cold-induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERR gamma positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERR gamma-induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1. Conclusions: Through its augmenting effect on expression of UCP1, ERR gamma may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.

  • 13. Dludla, Phiwayinkosi V.
    et al.
    Nkambule, Bongani B.
    Tiano, Luca
    Louw, Johan
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Helmholtz-Zentrum München, German Research Center for Environmental Health (GmbH), Germany; German Center for Diabetes Research (DZD), Germany.
    Mazibuko-Mbeje, Sithandiwe E.
    Uncoupling proteins as a therapeutic target to protect the diabetic heart2018Ingår i: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 137, s. 11-24Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.

  • 14.
    Eriksson, Birgitta S.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för socialt arbete.
    Ett år med diabetes: beskrivning av ett förlopp samt analys av faktorer som stött eller hindrat ett framgångsrikt behandlingsresultat1994Doktorsavhandling, monografi (Övrigt vetenskapligt)
  • 15.
    Ferraris, Jimena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Is prolactin receptor signaling a target in dopamine-resistant prolactinomas?2023Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, artikel-id 1057749Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The treatment of PRL-secreting tumors, formerly known as prolactinomas, has relied mainly on this physiological characteristic, making dopamine agonists the first therapeutic alternative. Nevertheless, the group of patients that do not respond to this treatment has few therapeutical options. Prolactin is another physiological regulator of lactotroph function, acting as an autocrine/paracrine factor that controls PRL secretion and cellular turnover, inducing apoptosis and decreasing proliferation. Furthermore, the signaling pathways related to these effects, mainly JAK/STAT and PI3K/Akt, and MAPK, have been extensively studied in prolactinomas and other tumors as therapeutic targets. In the present work, the relationship between PRL pathophysiology and prolactinoma development is explored, aiming to comprehend the value of PRL and PRLR-associated pathways as exploratory fields alternative to dopamine-related approaches, which are worth physiological characteristics that might be impaired and can be potentially restored or upregulated to provide more options to the patients.

  • 16.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Leptin: Is It Thermogenic?2020Ingår i: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 41, nr 2, s. 232-260Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin- receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred Aston mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.

  • 17.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study2018Ingår i: Molecular metabolism, ISSN 2212-8778, Vol. 7, s. 161-170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The laboratory mouse is presently the most common model for examining mechanisms of human physiology and disease. Housing temperatures can have a large impact on the outcome of such experiments and on their translatability to the human situation. Humans usually create for themselves a thermoneutral environment without cold stress, while laboratory mice under standard conditions (approximate to 20 degrees C) are under constant cold stress. In a well-cited, theoretical paper by Speakman and Keijer in Molecular Metabolism, it was argued that housing mice under close to standard conditions is the optimal way of modeling the human metabolic situation. This tenet was mainly based on the observation that humans usually display average metabolic rates of about 1.6 times basal metabolic rate. The extra heat thereby produced would also be expected to lead to a shift in the 'lower critical temperature' towards lower temperatures.

    Methods: To examine these tenets experimentally, we performed high time-resolution indirect calorimetry at different environmental temperatures on mice acclimated to different housing temperatures.

    Results: Based on the high time-resolution calorimetry analysis, we found that mice already under thermoneutral conditions display mean diurnal energy expenditure rates 1.8 times higher than basal metabolism, remarkably closely resembling the human situation. At any temperature below thermoneutrality, mice metabolism therefore exceeds the human equivalent: Mice under standard conditions display energy expenditure 3.1 times basal metabolism. The discrepancy to previous conclusions is probably attributable to earlier limitations in establishing true mouse basal metabolic rate, due to low time resolution. We also found that the fact that mean energy expenditure exceeds resting metabolic rate does not move the apparent thermoneutral zone (the lower critical temperature) downwards.

    Conclusions: We show that housing mice at thermoneutrality is an advantageous step towards aligning mouse energy metabolism to human energy metabolism.

  • 18.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Schlein, Christian
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Heeren, Joerg
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Intact innervation is essential for diet-induced recruitment of brown adipose tissue2019Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, nr 3, s. E487-E503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The possibility that recruitment and activation of brown adipose tissue (BAT) thermogenesis could be beneficial for curtailing obesity development in humans prompts a need for a better understanding of the control of these processes [that are often referred to collectively as diet-induced thermogenesis (DIT)]. Dietary conditions are associated with large changes in blood-borne factors that could be responsible for BAT recruitment, but BAT is also innervated by the sympathetic nervous system. To examine the significance of the innervation for DIT recruitment, we surgically denervated the largest BAT depot, i.e., the interscapular BAT depot in mice and exposed the mice at thermoneutrality to a high-fat diet versus a chow diet. Denervation led to an alteration in feeding pattern but did not lead to enhanced obesity, but obesity was achieved with a lower food intake, as denervation increased metabolic efficiency. Conclusively. denervation totally abolished the diet-induced increase in total UCP1 protein levels observed in the intact mice, whereas basal UCP1 expression was not dependent on innervation. The denervation of interscapular BAT did not discernably hyper-recruit other BAT depots, and no UCP1 protein could be detected in the principally browning-competent inguinal white adipose tissue depot under any of the examined conditions. We conclude that intact innervation is essential for diet-induced thermogenesis and that circulating factors cannot by themselves initiate recruitment of brown adipose tissue under obesogenic conditions. Therefore, the processes that link food intake and energy storage to activation of the nervous system are those of significance for the further understanding of diet-induced thermogenesis.

  • 19. García-Carrizo, Francisco
    et al.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Picó, Catalina
    Dols, Albert
    Rodríguez, Ana María
    Palou, Andreu
    Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate2020Ingår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 44, nr 3, s. 715-726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives High-esterified pectin (HEP) is a prebiotic able to modulate gut microbiota, associated with health-promoting metabolic effects in glucose and lipid metabolism and adipostatic hormone sensitivity. Possible effects regulating adaptive thermogenesis and energy waste are poorly known. Therefore, we aimed to study how physiological supplementation with HEP is able to affect microbiota, energy metabolism and adaptive thermogenic capacity, and to contribute to the healthier phenotype promoted by HEP supplementation, as previously shown. We also attempted to decipher some of the mechanisms involved in the HEP effects, including in vitro experiments.

    Subjects and experimental design We used a model of metabolic malprogramming consisting of the progeny of rats with mild calorie restriction during pregnancy, both under control diet and an obesogenic (high-sucrose) diet, supplemented with HEP, combined with in vitro experiments in primary cultured brown and white adipocytes treated with the postbiotic acetate.

    Results Our main findings suggest that chronic HEP supplementation induces markers of brown and white adipose tissue thermogenic capacity, accompanied by a decrease in energy efficiency, and prevention of weight gain under an obesogenic diet. We also show that HEP promotes an increase in beneficial bacteria in the gut and peripheral levels of acetate. Moreover, in vitro acetate can improve adipokine production, and increase thermogenic capacity and browning in brown and white adipocytes, respectively, which could be part of the protection mechanism against excess weight gain observed in vivo.

    Conclusion HEP and acetate stand out as prebiotic/postbiotic active compounds able to modulate both brown-adipocyte metabolism and browning and protect against obesity.

  • 20. García-Esquinas, Esther
    et al.
    Carballo-Casla, Adrián
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), Spain.
    Ortolá, Rosario
    Sotos-Prieto, Mercedes
    Olmedo, Pablo
    Gil, Fernando
    Plans-Beriso, Elena
    Fernández-Navarro, Pablo
    Pastor-Barriuso, Roberto
    Rodríguez-Artalejo, Fernando
    Blood Selenium Concentrations Are Inversely Associated with the Risk of Undernutrition in Older Adults2023Ingår i: Nutrients, E-ISSN 2072-6643, Vol. 15, nr 22, artikel-id 4750Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Selenium is an essential trace element with an antioxidant and anti-inflammatory capacity that has been associated in experimental studies with beneficial effects on appetite control, the regulation of the gut microbiota, and control of the anabolic–catabolic balance. The main aim of the present study was to evaluate the association between circulating selenium concentrations and the risk of developing undernutrition in older adults. Methods: This was a cohort study with 1398 well-nourished community-dwelling individuals aged ≥ 65 years residing in Spain in 2017, who were followed for a mean of 2.3 years. Whole blood selenium was measured at baseline using inductively coupled plasma-mass spectrometry. Undernutrition was assessed at baseline and at follow-up, and defined as having at least one of the three GLIM phenotypic criteria (involuntary weight loss, a low body mass index, and a reduced muscle mass) and at least one of the two etiologic criteria (reduced food consumption or nutrient assimilation and inflammation/disease burden). Results: During the follow-up, 142 participants (11%) developed moderate undernutrition and 113 (8.8%) severe undernutrition. The standardized relative risks of moderate and severe undernutrition at the 75th percentile of Se levels versus the 25th were 0.90 and 0.70, respectively. In dose–response analyses, the risk of severe undernutrition decreased linearly with increasing selenium concentrations. This association was independent of protein intake or diet quality and was stronger among participants with a diagnosis of a musculoskeletal disorder. Conclusions: The results suggest that an adequate dietary selenium status is needed to prevent undernutrition in older adults. Also, this may open the door for clinical trials with selenium supplementation, at doses considered as safe, to prevent undernutrition.

  • 21. Grandoch, Maria
    et al.
    Floegel, Ulrich
    Virtue, Sam
    Maier, Julia K.
    Jelenik, Tomas
    Kohlmorgen, Christina
    Feldmann, Kathrin
    Ostendorf, Yanina
    Castaneda, Tamara R.
    Zhou, Zhou
    Yamaguchi, Yu
    Nascimento, Emmani B. M.
    Sunkari, Vivekananda G.
    Goy, Christine
    Kinzig, Martina
    Soergel, Fritz
    Bollyky, Paul L.
    Schrauwen, Patrick
    Al-Hasani, Hadi
    Roden, Michael
    Keipert, Susanne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. German Center for Diabetes Research (DZD), Germany; Helmholtz Zentrum München, Germany.
    Vidal-Puig, Antonio
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. German Center for Diabetes Research (DZD), Germany; Helmholtz Zentrum München, Germany.
    Haendeler, Judith
    Fischer, Jens W.
    4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue2019Ingår i: Nature Metabolism, E-ISSN 2522-5812, Vol. 1, nr 5, s. 546-559Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Therapeutic increase in brown adipose tissue (BAT) thermogenesis is of great interest, as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, that is synthesized by HA synthases (HAS1, HAS2, and HAS3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here we show that inhibition of HA synthesis by 4-MU or genetic deletion of Has2 and Has3 improves the thermogenic capacity of BAT, reduces body-weight gain, and improves glucose homeostasis independently of adrenergic stimulation in mice on a diabetogenic diet. In this context, we validated a novel magnetic resonce T2 mapping approach for in vivo visualization of BAT activation. Inhibition of HA synthesis increases glycolysis, BAT respiration, and uncoupling protein 1 (UCP1) expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved, prescription-free drug, could be repurposed to treat obesity and diabetes.

  • 22.
    Gustafsson, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Söderdahl, Therése
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Jönsson, Gunn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Bratteng, Jan-Ove
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Forsby, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Insulin-like growth factor type 1 prevents hyperglycemia-induced uncoupling protein 3 down-regulation and oxidative stress2004Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 77, nr 2, s. 285-291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uncoupling proteins (UCPs) have been reported to decrease the mitochondrial production of reactive oxygen species (ROS) by lowering the mitochondrial inner membrane potential (MMP). We have previously shown that UCP3 expression is positively regulated by insulin-like growth factor-1 (IGF-1). The aim of this study was to investigate the role of UCPs in IGF-1-mediated protection from hyperglycemia-induced oxidative stress and neurodegeneration. Human neuroblastoma SH-SY5Y cells were differentiated with retinoic acid for 6 days, after which exposure to 8, 30, or 60 mM glucose with or without 10 nM IGF-1 was started. After 48-72 hr, the number of neurites per cell, UCP3 protein expression, MMP, and intracellular levels of ROS and total glutathione were examined. These studies showed that glucose concentration-dependently reduced the number of neurites per cell, with a 50% reduction at 60 mM. In parallel, the UCP3 protein expression was down-regulated, and the MMP was raised 3.5-fold, compared with those in cells incubated with 8 mM glucose. Also, the ROS levels were increased, showing a twofold maximum at 60 mM glucose. This was accompanied by a twofold elevation of total glutathione levels, confirming an altered cellular redox state. IGF-1 treatment prevented the glucose-induced neurite degeneration and UCP3 down-regulation. Furthermore, the MMP and the intracellular levels of ROS and glutathione were normalized to those of control cells. These data indicate that IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating MMP, possibly by the involvement of UCP3.

  • 23. Gyberg, Viveca
    et al.
    Hasson, Dan
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    Tuomilehto, Jaakko
    Rydén, Lars
    Measuring risk online-Feasibility of using FINDRISC in an online workplace survey2012Ingår i: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 6, nr 2, s. 103-107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: With the globally increasing prevalence of diabetes and the knowledge on how to prevent the disease there is a high demand for an effective way of identifying people at risk. The hypothesis behind this investigation was that incorporation of the FINnish Diabetes Risk SCore (FINDRISC) questionnaire in a regular workplace survey would be a feasible way to identify individuals and groups at risk for diabetes that could benefit from preventive interventions.

    METHOD: The eight FINDRISC questions were slightly modified and incorporated to Webb-QPS, an online work place survey, and distributed by e-mail to 5166 employees at Karolinska University Hospital (KUH).

    RESULTS: The total number of responders to Webb-QPS was 3581 (69%). Of those responding 3029 (84%) replied to the FINDRISC section which comprises 59% of the original population. A group of 1082 high risk individuals could be considered for intervention whereof 298 (9.8%) are expected to develop diabetes the upcoming 10 years if left without intervention.

    CONCLUSION: It is feasible to incorporate a diabetes risk score such as the FINDRISC in a workplace survey. A group that could be subject to preventive intervention programs was identified.

  • 24. Hagman, Emilia
    et al.
    Elimam, Amira
    Kupferschmidt, Natalia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ekbom, Kerstin
    Rössner, Stephan
    Naeem Iqbal, Muhammad
    Johnston, Eric
    Lindgren, Maria
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Sigrid Therapeutics AB, Sweden.
    Danielsson, Pernilla
    Oral intake of mesoporous silica is safe and well tolerated in male humans2020Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 15, nr 10, artikel-id e0240030Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Precisely engineered mesoporous silica has been shown to induce weight loss in mice, but whether it is safe to use in humans have not investigated.

    Objective

    The aim was to determine whether oral dosing, up to 9 grams/day, of precisely engineered mesoporous silica as a food additive can be used safely in male humans.

    Design

    This single blinded safety study consisted of two study arms including 10 males each (18-35 years). One arm consisted of participants with normal weight and one with obesity. After a placebo run-in period, all subjects were given porous silica three times daily, with increasing dose up to 9 grams/day (Phase 1). Subjects with obesity continued the study with highest dose for additional 10 weeks (Phase 2).

    Results

    All participants completed Phase 1 and 90% completed Phase 2, with approximately 1% missed doses. Participants reported no abdominal discomfort, and changes in bowel habits were minor and inconsistent. The side effects observed were mild and tolerable, biomarkers did not give any safety concern, and no severe adverse events occurred.

    Conclusion

    Mesoporous silica intake of up to 9 grams/day can be consumed by males without any major adverse events or safety concerns.

  • 25. Hedström, Anna Karin
    et al.
    Bellocco, Rino
    Hössjer, Ola
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen.
    Ye, Weimin
    Trolle Lagerros, Ylva
    Åkerstedt, Torbjörn
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    The relationship between nightmares, depression and suicide2021Ingår i: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 77, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Previous studies investigating the association between nightmares and suicide have yielded different results. We aimed to investigate whether nightmares, directly or indirectly, influence the incidence of suicide.

    Methods: We used a prospective cohort study, based on 40,902 participants with a mean follow-up duration of 19.0 years. Cox proportional hazards models with attained age as time-scale were fitted to estimate hazard ratios (HR) of suicide with 95% confidence intervals (CI) as a function of the presence or absence of depression and nightmares. Mediation analysis was used to asses to what extent the relationship between nightmares and the incidence rate of suicide could be mediated by depression.

    Results: No association was observed between nightmares and the incidence of suicide among participants without depression. Compared with non-depressed participants without nightmares, the incidence of suicide among participants with a diagnosis of depression was similar among those with and without nightmares (HR 12.3, 95% CI 5.55-27.2 versus HR 13.2, 95% CI 7.25-24.1). The mediation analysis revealed no significant effects of nightmares on suicide incidence. However, the incidence of depression during follow-up was higher among those who suffered from nightmares than among those who did not (p < 0.001).

    Conclusions: Our findings indicate that nightmares have no influence on the incidence rate of suicide, but may reflect pre-existing depression. This is supported by a recent discovery of a strong genetic correlation of nightmares with depressive disorders, with no evidence that nightmares would predispose to psychiatric illness or psychological problems. Interventions targeting both depression and nightmares, when these conditions co-occur, may provide additional therapeutic benefit.

  • 26. Hedström, Anna Karin
    et al.
    Katsoulis, Michail
    Hössjer, Ola
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen.
    Bomfim, Izaura L.
    Oturai, Annette
    Bach Sondergaard, Helle
    Sellebjerg, Finn
    Ullum, Henrik
    Wegner Thørner, Lise
    Wendel Gustavsen, Marte
    Harbo, Hanne F.
    Obradovic, Dragana
    Gianfrancesco, Milena A.
    Barcellos, Lisa F.
    Schaefer, Catherine A.
    Hillert, Jan
    Kockum, Ingrid
    Olsson, Tomas
    Alfredsson, Lars
    The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement2017Ingår i: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 32, nr 10, s. 909-919Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

  • 27.
    Hooshmand, Babak
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Ulm University Hospital, Germany.
    Rusanen, Minna
    Ngandu, Tiia
    Leiviskä, Jaana
    Sindi, Shireen
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    von Arnim, Christine A. F.
    Falkai, Peter
    Soininen, Hilkka
    Tuomilehto, Jaakko
    Kivipelto, Miia
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). University of Eastern Finland, Finland; Karolinska Institute, Sweden.
    Serum Insulin and Cognitive Performance in Older Adults: A Longitudinal Study2019Ingår i: American Journal of Medicine, ISSN 0002-9343, E-ISSN 1555-7162, Vol. 132, nr 3, s. 367-373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose

    The aim of this study was to examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning 7 years later in a longitudinal population-based study of Finnish older adults.

    Methods

    Serum glucose and insulin were measured at baseline in 269 dementia-free individuals aged 65-79 years, from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). Participants were reexamined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed, both at baseline and at follow-up. Multiple linear regression was used to investigate the associations with cognitive performance at follow-up, after adjusting for several potential confounders, including common vascular risk factors.

    Results

    In the multivariable-adjusted linear regression models, no associations of insulin resistance with cognitive functioning were observed. After excluding 19 incident dementia cases, higher baseline HOMA-IR values were related to worse performance in global cognition (beta [standard error (SE)] -.050 [0.02]; P =.043) and psychomotor speed (beta [SE] -.064 [. 03]; P = [.043]) 7 years later. Raised serum insulin levels were associated with lower scores on global cognition (b [SE] -.054 [.03]; P =.045) and tended to relate to poorer performance in psychomotor speed (beta [SE] -.061 [.03]; P =.070).

    Conclusions

    Serum insulin and insulin resistance may be independent predictors of cognitive performance 7 years later in elderly individuals without dementia. Randomized controlled trials are needed to determine this issue.

  • 28. Husdal, Rebecka
    et al.
    Adolfsson, Eva Thors
    Leksell, Janeth
    Eliasson, Björn
    Jansson, Stefan
    Jerdén, Lars
    Stålhammar, Jan
    Steen, Lars
    Wallman, Thorne
    Svensson, Ann-Marie
    Rosenblad, Andreas
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Organisation of primary diabetes care in people with type 2 diabetes in relation to all-cause mortality: A nationwide register-based cohort study2020Ingår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 167, artikel-id 108352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: To examine if personnel resources and organisational features in Swedish primary health-care centres (PHCCs) are associated to all-cause mortality (ACM) in people with type 2 diabetes mellitus (T2DM).

    Methods: A total of 187,570 people with T2DM registered in the Swedish National Diabetes Register (NDR) during 2013 were included in this nationwide cohort study. Individual NDR data were linked to data from a questionnaire addressing personnel resources and organisational features for 787 (68%) PHCCs as well as to individual data on socio-economic status and comorbidities. Furthermore, data on ACM were obtained and followed up until 30 January 2018. Hierarchical Cox regression analyses were applied.

    Results: After a median follow-up of 4.2 years, 27,136 (14.5%) participants had died. An association was found between number of whole-time-equivalent (WTE) general practitioner’s (GP’s) devoted to diabetes care/500 people with T2DM and lower risk of early death (hazard ratio 0.919 [95% confidence interval 0.895–0.945] per additional WTE GP; p = 0.002). No other personnel resources or organisational features were significantly associated with ACM.

    Conclusions: This nationwide register-based cohort study suggests that the number of WTE GPs devoted to diabetes care have an impact on the risk of early death in people with T2DM.

  • 29. Idrees, M.
    et al.
    Sohail, Ayesha
    Javed, Sana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Comsats University Islamabad, Pakistan.
    Forecasting the critical role of intermittent therapies for the control of bone resorption2019Ingår i: Clinical Biomechanics, ISSN 0268-0033, E-ISSN 1879-1271, Vol. 68, s. 128-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Osteoporosis is a chronic metabolic disease characterized by an imbalance of bone resorption and formation, leading to bone fragility and increased susceptibility to fracture. Parathyroid hormone is approved therapy for the treatment of osteoporosis.

    Methods: The intermittent therapy of parathyroid hormone requires accurate administration. Meta-analysis is conducted to draw a clear picture of the impact of intermittent therapy and dose rates relative to time, on the osteoporotic patients. A novel mathematical model is presented in this article synchronised with the parametric values, depicted from meta-analysis.

    Findings: Results obtained from the mathematical model are in close agreement with the results obtained from the clinical trials. The model can be used to forecast the drug potency and dosage rates, to control the vicious cycle of osteoporosis.

    Interpretations: The intermittent administration of parathyroid hormone, rather than the continuous administration, is more effective, furthermore it is also concluded that a mathematical model, linked with the extensive literature of clinical trials, using meta-analysis can help in drug administration and future clinical studies of drug development.

  • 30. Jespersen, Naja Z.
    et al.
    Feizi, Amir
    Andersen, Eline S.
    Heywood, Sarah
    Hattel, Helle B.
    Daugaard, Søren
    Peijs, Lone
    Bagi, Per
    Feldt-Rasmussen, Bo
    Schultz, Heidi S.
    Hansen, Ninna S.
    Krogh-Madsen, Rikke
    Pedersen, Bente K.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nielsen, Søren
    Scheele, Camilla
    Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells2019Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 24, s. 30-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective:

    Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity.

    Methods:

    We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet.

    Results:

    We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT.

    Conclusions:

    We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

  • 31.
    Kalinovich, Anastasia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Atrogi AB, Sweden.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Atrogi AB, Sweden.
    Åslund, Alice
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    van Beek, Sten
    Halleskog, Carina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Atrogi AB, Sweden.
    Olsen, Jessica
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Atrogi AB, Sweden.
    Forsberg, Elisabete
    Zacharewicz, Evelyn
    Schaart, Gert
    Rinde, Mia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sandström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Atrogi AB, Sweden.
    Berlin, Roger
    Östenson, Claes-Göran
    Hoeks, Joris
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity2020Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, nr 8, s. 1603-1615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis Chronic stimulation of beta(2)-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of beta(2)-adrenoceptors. In the current study we further explored the potential therapeutic relevance of beta(2)-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect.

    Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen.

    Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment,p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg(-1) day(-1)(40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%,p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%,p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 +/- 0.31%/min in comparison with 0.15 +/- 0.36%/min in control mice,p < 0.05) and drastically reduced hepatic steatosis (by 40%,p < 0.01) and glycogen (by 23%,p < 0.05).

    Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective beta(2)-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.

  • 32.
    Kalinovich, Anastasia V.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Lomonosov Moscow State University, Russian Federation.
    Mattsson, C. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Youssef, M. R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ost, M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Skulachev, V. P.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Lomonosov Moscow State University, Russian Federation.
    Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice2016Ingår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, nr 12, s. 1864-1874Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: A membrane-penetrating cation, dodecyltriphenylphosphonium (C12TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C12TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. METHODS: We investigated the metabolic effects of C12TPP in isolated brown-fat mitochondria, brown adipocyte cultures and mice in vivo. Experimental approaches included the measurement of oxygen consumption, carbon dioxide production, western blotting, magnetic resonance imaging and bomb calorimetry. RESULTS: In mice, C12TPP (50 mu mol per (day.kg body weight)) in the drinking water significantly reduced body weight (12%, P<0.001) and body fat mass (24%, P<0.001) during the first 7 days of treatment. C12TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C12TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pretreatment with C12TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C12TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C12TPP treatment increased the mitochondrial protein levels in the brown adipose tissue of both wild-type and UCP1-knockout mice. Pair-feeding revealed that one-third of the body weight loss in C12TPP-treated mice was due to reduced food intake. C12TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C12TPP reduced the respiratory exchange ratio, indicating enhanced fatty acid oxidation in mice. CONCLUSIONS: C12TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.

  • 33.
    Keipert, Susanne
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ost, Mario
    Stress-induced FGF21 and GDF15 in obesity and obesity resistance2021Ingår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 32, nr 11, s. 904-915Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are established as stress-responsive cytokines that can modulate energy balance by increasing energy expenditure or suppressing food intake, respectively. Despite their pharmacologically induced beneficial effects on obesity and comorbidities, circulating levels of both cytokines are elevated during obesity and related metabolic complications. On the other hand, endocrine crosstalk via FGF21 and GDF15 was also reported to play a crucial role in genetically modified mouse models of mitochondrial perturbations leading to diet-induced obesity (DIO) resistance. This review aims to dissect the complexities of endogenous FGF21 and GDF15 action in obesity versus DIO resistance for the regulation of energy balance in metabolic health and disease.

  • 34.
    Keuper, Michaela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Eberhard Karls University Tübingen, Germany; German Center for Diabetes Research (DZD), Germany.
    Häring, Hans-Ulrich
    Staiger, Harald
    Circulating FGF21 Levels in Human Health and Metabolic Disease2020Ingår i: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, E-ISSN 1439-3646, Vol. 128, nr 11, s. 752-770Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor betaKlotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21's role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.

  • 35.
    Keuper, Michaela
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The good and the BAT of metabolic sex differences in thermogenic human adipose tissue2021Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 533, artikel-id 111337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thermogenic adipose tissue, which comprises classical brown and beige adipose tissue, has the ability to improve systemic metabolism. Its identification in adult humans has fostered extensive investigations on the therapeutic value to counteract obesity and metabolic disorders. Sex and gender differences of human thermogenic adipose tissue, however, are still understudied despite their importance for personalized treatment options. Here, we review studies reporting human sex differences of thermogenic adipose tissue and related potential improvements of systemic energy metabolism. An increasing body of evidence suggests higher prevalence, mass and activity of thermogenic adipose tissue in women, but the consequences for metabolic disease progression and mechanisms are largely unknown. Therefore, we also discuss observations on sex-specific adipose metabolism in experimental mouse and rat studies that may assist to establish molecular mechanisms and instruct future investigations in humans.

  • 36. Khani, Sajjad
    et al.
    Topel, Hande
    Kardinal, Ronja
    Tavanez, Ana Rita
    Josephrajan, Ajeetha
    Larsen, Bjørk Ditlev Marcher
    Gaudry, Michael James
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Leyendecker, Philipp
    Meincke Egedal, Nadia
    Güller, Aylin Seren
    Stanic, Natasa
    Ruppert, Phillip M. M.
    Gaziano, Isabella
    Hansmeier, Nils Rouven
    Schmidt, Elena
    Klemm, Paul
    Vagliano, Lara-Marie
    Stahl, Rainer
    Duthie, Fraser
    Krause, Jens-Henning
    Bici, Ana
    Engelhard, Christoph Andreas
    Gohlke, Sabrina
    Frommolt, Peter
    Gnad, Thorsten
    Rada-Iglesias, Alvaro
    Pradas-Juni, Marta
    Schulz, Tim Julius
    Wunderlich, Frank Thomas
    Pfeifer, Alexander
    Bartelt, Alexander
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wachten, Dagmar
    Kornfeld, Jan-Wilhelm
    Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function2024Ingår i: Nature Metabolism, E-ISSN 2522-5812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation. 

  • 37.
    Klein Hazebroek, Marlou
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Keipert, Susanne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Adapting to the Cold: A Role for Endogenous Fibroblast Growth Factor 21 in Thermoregulation?2020Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, artikel-id 389Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Fibroblast growth factor 21 (FGF21) is in biomedical focus as a treatment option for metabolic diseases, given that administration improves metabolism in mice and humans. The metabolic effects of exogenous FGF21 administration are well-characterized, but the physiological role of endogenous FGF21 has not been fully understood yet. Despite cold-induced FGF21 expression and increased circulating levels in some studies, which co-occur with brown fat thermogenesis, recent studies in cold-acclimated mice demonstrate the dispensability of FGF21 for maintenance of body temperature, thereby questioning FGF21's role for thermogenesis. Here we discuss the evidence either supporting or opposing the role of endogenous FGF21 for thermogenesis based on the current literature. FGF21, secreted by brown fat or liver, is likely not required for energy homeostasis in the cold, but the nutritional conditions could modulate the interaction between FGF21, energy metabolism, and thermoregulation.

  • 38.
    Klein Hazebroek, Marlou
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Keipert, Susanne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue2022Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, artikel-id 909621Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.

  • 39. Kärvestedt, Lars
    et al.
    Mårtensson, Eva
    Grill, Valdemar
    Elofsson, Stig
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för socialt arbete - Socialhögskolan.
    von Wendt, Gunvor
    Hamsten, Anders
    Brismar, Kerstin
    The prevalence of peripheral neuropathy in a population-based study of patients with type 2 diabetes in Sweden2011Ingår i: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 25, nr 2, s. 97-106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims

    To assess peripheral neuropathy following a standardized foot examination protocol in a representative population-based cohort of subjects with type 2 diabetes.

    Methods

    In a geographically defined population, aged 40–70 years with diabetes prevalence of 3.5% according to medical records, we investigated 156 type 2 diabetic subjects, 95% Caucasian, mean age 61.7±7.2 years, duration of diabetes 7.0±5.7 years, and HbA1c 7.3±2.4% (6.4% Mono-S), by questionnaires, clinical examinations, blood sampling, and review of medical records. Foot examination included clinical signs of peripheral neuropathy and tests of sensibility with monofilament, tuning fork, and assessments of the vibration perception thresholds (VPT).

    Results

    Peripheral autonomic neuropathy (PAN) as judged by two or more signs of dysfunction was the most common and affected 43%. The prevalence of peripheral sensory neuropathy (PSN) was 15% by monofilament, 24% by tuning fork, and 28% by VPT expressed as ZscoreVPT ≥2.0 S.D. Twenty-nine percent had a VPT ≥25 V. Signs of peripheral motor neuropathy (PMN) affected 15%.

    Peripheral neuropathy, at least one variable, affected 67%, whereas 25% were affected by more than one variable of neuropathy, i.e., polyneuropathy. Exclusion of other identified causes for neuropathy than diabetes reduced the prevalence of diabetic polyneuropathy to 23%.

    Concurrent diabetic complications were 29% for retinopathy, 14% for incipient nephropathy, and 8% for overt nephropathy. The prevalence of macrovascular complications was 62% for CVD, 26% for PVD, and 11% for cerebrovascular lesion (CVL).

    Conclusion

    Peripheral neuropathy was common in this representative type 2 diabetes population. Clinical signs of PAN were the most frequent followed by diminished perception of vibration and touch.

  • 40. Langlet, Fanny
    et al.
    Tarbier, Marcel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Haeusler, Rebecca A.
    Camastra, Stefania
    Ferrannini, Eleuterio
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Accili, Domenico
    microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function2018Ingår i: Molecular metabolism, ISSN 2212-8778, Vol. 17, s. 49-60Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.

  • 41. Lennartsson, Anna-Karin
    et al.
    Theorell, Tores
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet.
    Rockwood, Alan L.
    Kushnir, Mark M.
    Jonsdottir, Ingibjorg H.
    Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress2013Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 9, s. 1650-1657Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to play a protective role during acute psychosocial stress, because they act as antagonists to the effects of the stress hormone cortisol. This study aims to investigate whether prolonged psychosocial stress, measured as perceived stress at work during the past week, is related to the capacity to produce DHEA and DHEA-S during acute psychosocial stress. It also aims to investigate whether prolonged perceived stress affects the balance between production of cortisol and DHEA-S during acute psychosocial stress. Method: Thirty-six healthy subjects (19 men and 17 women, mean age 37 years, SD 5 years), were included. Perceived stress at work during the past week was measured by using the Stress-Energy (SE) Questionnaire. The participants were divided into three groups based on their mean scores; Low stress, Medium stress and High stress. The participants underwent the Trier Social Stress Test (TSST) and blood samples were collected before, directly after the stress test, and after 30 min of recovery. General Linear Models were used to investigate if the Medium stress group and the High stress group differ regarding stress response compared to the Low stress group. Results: Higher perceived stress at work was associated with attenuated DHEA-S response during acute psychosocial stress. Furthermore, the ratio between the cortisol production and the DHEA-S production during the acute stress test were higher in individuals reporting higher perceived stress at work compared to individuals reporting low perceived stress at work. There was no statistical difference in DHEA response between the groups. Conclusions: This study shows that prolonged stress, measured as perceived stress at work during the past week, seems to negatively affect the capacity to produce DHEA-S during acute stress. Given the protective functions of DHEA-S, attenuated DHEA-S production during acute stress may Lead to higher risk for adverse effects on psychological and physiological health, particularly if stress exposure continues.

  • 42. Levie, Deborah
    et al.
    Derakhshan, Arash
    Shu, Huan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Broeren, Maarten A. C.
    de Poortere, Ralph A.
    Peeters, Robin P.
    Bornehag, Carl-Gustaf
    Demeneix, Barbara
    Korevaar, Tim I. M.
    The Association of Maternal Iodine Status in Early Pregnancy with Thyroid Function in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy Study2019Ingår i: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 29, nr 11, s. 1660-1668Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Severe maternal iodine deficiency can impact fetal brain development through effects on maternal and/or fetal thyroid hormone availability. The effects of mild-to-moderate iodine deficiency on thyroid function are less clear. The aim was to investigate the association of maternal urinary iodine concentration corrected for creatinine (UI/Creat) with thyroid function and autoantibodies in a mild-to-moderate iodine-deficient pregnant population.

    Methods: This study was embedded within the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Clinical reference ranges were determined by the 2.5th and 97.5th population-based percentile cutoffs. The associations of UI/Creat with thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), total T4 (TT4), and total T3 (TT3) were studied using multivariable linear regression in thyroid peroxidase antibody (TPOAb)-negative women. The association of UI/Creat with TPOAb and thyroglobulin antibody (TgAb) positivity was analyzed using multivariable logistic regression.

    Results: Urinary iodine and thyroid function were measured at a median (95% range) gestational age of 10 (6-14) weeks in 2009 women. The median (95% range) UI/Creat was 85 mu g/g (36-386) and the UI/Creat was below 150 mu g/g in 80.1% of women. Reference ranges did not differ substantially by UI/Creat. A lower UI/Creat was associated with a lower TSH (p = 0.027), a higher TT4 (p = 0.032), and with a corresponding trend toward slightly higher fT4 (p = 0.081), fT3 (p = 0.079), and TT3 (p = 0.10). UI/Creat was not associated with the fT4/fT3 (p = 0.94) or TT4/TT3 ratios (p = 0.63). Women with a UI/Creat of 150-249 mu g/g had the lowest prevalence of TPOAb positivity (6.1%), while women with a UI/Creat of <150 mu g/g had a higher prevalence (11.0%, odds ratio [OR] confidence interval [95% CI] 1.84 [1.07-3.20], p = 0.029). Women with a UI/Creat >= 500 mu g/g showed the highest prevalence and a higher risk of TPOAb positivity, however, only a small proportion of women had such a UI/Creat (12.5%, OR, [95% CI] 2.36 [0.54-10.43], p = 0.26).

    Conclusions: We could not identify any meaningful differences in thyroid function reference ranges. Lower iodine availability was associated with a slightly lower TSH and a higher TT4. Women with adequate iodine intake had the lowest risk of TPOAb positivity.

  • 43.
    Liang, Yajun
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Karolinska Institutet, Sweden.
    Yan, Zhongrui
    Hao, Yanlei
    Wang, Qiqi
    Zhang, Zuoji
    She, Rui
    Wang, Peng
    Du, Yifeng
    Lau, Joseph T. F.
    Dekker, Joost
    Bai, Bo
    Qiu, Chengxuan
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Shandong Provincial Hospital Affiliated to Shandong University, China.
    Metabolic syndrome in patients with first-ever ischemic stroke: prevalence and association with coronary heart disease2022Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikel-id 13042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The metabolic syndrome (MetS) has been well linked with coronary heart disease (CHD) in the general population, but studies have rarely explored their association among patients with stroke. We examine prevalence of MetS and its association with CHD in patients with first-ever ischemic stroke. This hospital-based study included 1851 patients with first-ever ischemic stroke (mean age 61.2 years, 36.5% women) who were hospitalized into two university hospitals in Shandong, China (January 2016–February 2017). Data were collected through interviews, physical examinations, and laboratory tests. MetS was defined following the National Cholesterol Education Program (NCEP) criteria, the International Diabetes Federation (IDF) criteria, and the Chinese Diabetes Society (CDS) criteria. CHD was defined following clinical criteria. Data were analyzed using binary logistic regression models. The overall prevalence of MetS was 33.4% by NECP criteria, 47.2% by IDF criteria, and 32.5% by CDS criteria, with the prevalence being decreased with age and higher in women than in men (p < 0.05). High blood pressure, high triglycerides, and low HDL-C were significantly associated with CHD (multi-adjusted odds ratio [OR] range 1.27–1.38, p < 0.05). The multi-adjusted OR of CHD associated with MetS defined by the NECP criteria, IDF criteria, and CDS criteria (vs. no MetS) was 1.27 (95% confidence interval 1.03–1.57), 1.44 (1.18–1.76), and 1.27 (1.03–1.57), respectively. In addition, having 1–2 abnormal components (vs. none) of MetS was associated with CHD (multi-adjusted OR range 1.66–1.72, p < 0.05). MetS affects over one-third of patients with first-ever ischemic stroke. MetS is associated with an increased likelihood of CHD in stroke patients.

  • 44. Liskiewicz, D.
    et al.
    Zhang, Q.
    Barthem, Clarissa S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jastroch, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Liskiewicz, A.
    Khajavi, N.
    Grandl, G.
    Coupland, C.
    Kleinert, M.
    Garcia-Caceres, C.
    Novikoff, A.
    Maity, G.
    Boehm, U.
    Tschöp, M. H.
    Müller, T. D.
    Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice2023Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 72, artikel-id 101714Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Mice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic phenotype of mice with either Nestin Cre-mediated neuronal loss of TRPM8, or with deletion of TRPM8 in Advillin Cre positive sensory neurons of the peripheral nervous system (PNS).

    Methods: Nestin Cre- and Advillin Cre-Trpm8 knock-out (KO) mice were metabolically phenotyped under chronic exposure to either chow or high-fat diet (HFD), followed by assessment of energy and glucose metabolism.

    Results: At room temperature, chow-fed neuronal Trpm8 KO are obese and show decreased energy expenditure when acutely treated with the TRPM8 selective agonist icilin. But body weight of neuronal Trpm8 KO mice is indistinguishable from wildtype controls at thermoneutrality, or when mice are chronically exposed to HFD-feeding. In contrast to previous studies, we show that the TRPM8 agonist icilin has no direct effect on brown adipocytes, but that icilin stimulates energy expenditure, at least in part, via neuronal TRPM8 signaling. We further show that lack of TRPM8 in sensory neurons of the PNS does not lead to a metabolically relevant phenotype.

    Conclusions: Our data indicate that obesity in TRPM8-deficient mice is centrally mediated and likely originates from alterations in energy expenditure and/or thermal conductance, but does not depend on TRPM8 signaling in brown adipocytes or sensory neurons of the PVN.

  • 45.
    Luijten, Ineke H. N.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Feldmann, Helena M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    von Essen, Gabriella
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain2019Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, nr 5, s. E729-E740Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57B1/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 w.k. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly. high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.

  • 46. Maroto-Rodriguez, Javier
    et al.
    Ortolá, Rosario
    Carballo-Casla, Adrián
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Universidad Autónoma de Madrid, Spain; CIBERESP (CIBER of Epidemiology and Public Health), Spain.
    Iriarte-Campo, Víctor
    Salinero-Fort, Miguel Ángel
    Rodríguez-Artalejo, Fernando
    Sotos-Prieto, Mercedes
    Association between a mediterranean lifestyle and Type 2 diabetes incidence: a prospective UK biobank study2023Ingår i: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 22, artikel-id 271Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background There is mounting evidence that the Mediterranean diet prevents type 2 diabetes, but little is known about the role of Mediterranean lifestyles other than diet and among non-Mediterranean populations. This work aimed to examine the association between a comprehensive Mediterranean-type lifestyle and type 2 diabetes incidence in a British adult population.

    Methods We used data from 112,493 individuals free of cardiovascular disease and type 2 diabetes mellitus, aged 40–69 years, from the UK Biobank cohort, who were followed from 2009 to 2010 to 2021. The Mediterranean lifestyle was assessed through the 25-item MEDLIFE index, which comprises three blocks: (a) “Mediterranean food consumption”, (b) “Mediterranean dietary habits”, (c) “Physical activity, rest, social habits, and conviviality”. Diabetes incidence was obtained from clinical records. Cox proportional-hazards regression models were used to analyze associations and adjusted for the main potential confounders.

    Results After a median follow-up of 9.4 years, 2,724 cases of type 2 diabetes were ascertained. Compared to the first quartile of MEDLIFE adherence, the hazard ratios (95% confidence interval) for increasing quartiles of adherence were 0.90 (0.82–0.99), 0.80 (0.72–0.89) and 0.70 (0.62–0.79) (p-trend < 0.001). All three blocks of MEDLIFE were independently associated with lower risk of diabetes.

    Conclusions Higher adherence to the MEDLIFE index was associated with lower risk of type 2 diabetes in the UK Biobank. A Mediterranean-type lifestyle, culturally adapted to non-Mediterranean populations, could help prevent diabetes.

  • 47. Marqueze, Elaine C.
    et al.
    Nogueira, Luciana F. R.
    Vetter, Céline
    Skene, Debra J.
    Cipolla-Neto, José
    Moreno, Claudia R. C.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. University of São Paulo, Brazil.
    Exogenous melatonin decreases circadian misalignment and body weight among early types2021Ingår i: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 71, nr 2, artikel-id e12750Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real-life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3 mg) or placebo was administered on non-night shift nights for 12 weeks in 27 female nurses (37.1 yo, +/- 5.9 yo; BMI 29.9 kg/m(2), +/- 3.3 kg/m(2)). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days off). Composite Phase Deviations (CPD) of actigraphy-based mid-sleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction in circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants' calorie intake or physical activity levels.

  • 48.
    Marseglia, Anna
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Fratiglioni, Laura
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholm Gerontology Research Center, Sweden.
    Kalpouzos, Grégoria
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Wang, Rui
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Bäckman, Lars
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Tianjin Medical University, China.
    Prediabetes and diabetes accelerate cognitive decline and predict microvascular lesions: A population-based cohort study2019Ingår i: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, nr 1, s. 25-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The impact of prediabetes and diabetes on cognitive decline and the potential underlying mechanisms remain unclear. We investigated whether prediabetes and diabetes accelerate cognitive decline and brain aging, and the initial pathological changes linked to microvascular processes.

    Methods: Nine-year longitudinal data from the Swedish National Study on Aging and Care-Kungsholmen (n = 2746, age >= 60 years) and the magnetic resonance imaging subsample (n = 455) were used. Cognitive function was assessed with Mini-Mental State Examination. Brain magnetic resonance imaging markers included total brain tissue, white matter, gray matter, white matter hyperintensities, and hippocampal volumes.

    Results: Compared with diabetes-free status, prediabetes and diabetes were independently associated with accelerated cognitive decline. Prediabetes was cross-sectionally associated with smaller total brain tissue volume (P < .01), particularly smaller white matter volume. Diabetes was associated with larger white matter hyperintensities volume. Longitudinally, diabetes was associated with faster white matter hyperintensities accumulation. No associations between prediabetes or diabetes and hippocampal volume were found.

    Discussion: Diabetes and prediabetes accelerate cognitive decline and might predict microvascular lesions among dementia-free older adults.

  • 49.
    Marseglia, Anna
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Wang, Hui-Xin
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet.
    Rizzuto, Debora
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Fratiglioni, Laura
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholm Gerontology Research Center, Sweden.
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Tianjin Medical University, China.
    Participating in Mental, Social, and Physical Leisure Activities and Having a Rich Social Network Reduce the Incidence of Diabetes-Related Dementia in a Cohort of Swedish Older Adults2019Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 42, nr 2, s. 232-239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE

    The effect of a healthy lifestyle on diabetes-related dementia remains unknown. We examined whether an active lifestyle and rich social network may counteract the increased risk of dementia in people with diabetes.

    RESEARCH DESIGN AND METHODS

    Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) (n = 2,650) were followed up for 10 years. Diabetes was ascertained on the basis of medical history, medication use, medical records, or glycated hemoglobin (HbA(1c)) 6.5% and prediabetes as HbA(1c) between 5.7 and 6.5%. Dementia was diagnosed by specialists following standard criteria. An active lifestyle was defined as a moderate to high (vs. low) level of engagement in leisure activities or a rich social network (having moderate to rich [vs. poor] social connections and support). Hazard ratios (HRs) of dementia risk were derived from Cox regression models.

    RESULTS

    There were 246 incident dementia cases during follow-up. Those with diabetes (n = 243), but not those with prediabetes (n = 921), had greater risk of dementia (adjusted HR 2.0 [95% CI 1.4-2.9]) than diabetes-free participants. Participants with diabetes but low level of engagement in leisure activities (HR 4.2 [95% CI 2.2-8.2]) or a poor social network (HR 3.4 [95% CI 1.9-6.1]) had greater dementia risk than diabetes-free participants with moderate to high levels of leisure activity engagement or a moderate to rich social network. In participants with diabetes, an active lifestyle (high level of engagement in leisure activities or a rich social network) was associated with less of a raised risk (HR 1.9 [95% CI 1.1-3.4]).

    CONCLUSIONS

    An active and socially integrated lifestyle may significantly counteract the detrimental effect of diabetes on dementia risk.

  • 50.
    Marseglia, Anna
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Tianjin Medical University, China.
    Fratiglioni, Laura
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholm Gerontology Research Center, Sweden.
    Fabbri, Cristina
    Berendsen, Agnes A. M.
    Bialecka-Debek, Agata
    Jennings, Amy
    Gillings, Rachel
    Meunier, Nathalie
    Caumon, Elodie
    Fairweather-Tait, Susan
    Pietruszka, Barbara
    De Groot, Lisette C. P. G. M.
    Santoro, Aurelia
    Franceschi, Claudio
    Effect of the NU-AGE Diet on Cognitive Functioning in Older Adults: A Randomized Controlled Trial2018Ingår i: Frontiers in Physiology, E-ISSN 1664-042X, Vol. 9, artikel-id 349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Findings from animal and epidemiological research support the potential neuroprotective benefits from healthy diets. However, to establish diet neuroprotective causal relations, evidence from dietary intervention studies is needed. NU-AGE is the first multicenter intervention assessing whether a diet targeting health in aging can counteract the age-related physiological changes in different organs, including the brain. In this study, we specifically investigated the effects of NU-AGE's dietary intervention on age related cognitive decline.

    Materials and Methods: NU-AGE randomized trial (NCT01754012, clinicaltrials.gov) included 1279 relatively healthy older-adults, aged 65-79 years, from five European centers. Participants were randomly allocated into two groups: control (n = 638), following a habitual diet; and, intervention (n = 641), given individually tailored dietary advice (NU-AGE diet). Adherence to the NU-AGE diet was measured over follow-up, and categorized into tertiles (low, moderate, high). Cognitive function was ascertained at baseline and at 1-year follow-up with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-Neuropsychological Battery and five additional domain-specific single cognitive tests. The raw scores from the CERAD subtests [excluding the Mini-Mental State Examination (MMSE)] and the single tests were standardized into Z-scores. Global cognition (measured with MMSE and CERAD total score), and five cognitive domains (perceptual speed, executive function, episodic memory, verbal abilities, and constructional praxis) were created. Cognitive changes as a function of the intervention were analyzed with multivariable mixed effects models.

    Results: After the 1-year follow-up, 571 (89.1%) controls and 573 (89.8%) from the intervention group participated in the post-intervention assessment. Both control and intervention groups showed improvements in global cognition and in all cognitive domains after 1 year, but differences in cognitive changes between the two groups were not statistically significant. However, participants with higher adherence to the NU-AGE diet showed statistically significant improvements in global cognition [beta 0.20 (95%CI 0.004, 0.39), p-value = 0.046] and episodic memory [beta 0.15 (95%Cl 0.02, 0.28), p-value = 0.025] after 1 year, compared to those adults with lower adherence.

    Discussion: High adherence to the culturally adapted, individually tailored, NU-AGE diet could slow down age-related cognitive decline, helping to prevent cognitive impairment and dementia.

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