P Arner

Karolinska University Hospital, Tukholma, Stockholm, Sweden

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Publications (470)3019.79 Total impact

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    ABSTRACT: Obese subjects have increased number of enlarged fat cells which are reduced in size but not number in post-obesity. We performed DNA methylation profiling in fat cells with the aim of identifying differentially methylated DNA sites (DMS) linked to adipose hyperplasia (many small fat cells) in post-obesity. Genome-wide DNA methylation was analyzed in abdominal subcutaneous fat cells from 16 women examined two years after gastric bypass surgery at a post-obese state (BMI 26±2 kg/m(2), mean±s.d.) and 14 never-obese women (BMI 25±2 kg/m(2)). Gene expression was analyzed in subcutaneous adipose tissue from 9 women in each group. In a secondary analysis, we examined DNA methylation and expression of adipogenesis genes in 15 and 11 obese women, respectively. The average degree of DNA methylation of all analyzed CpG-sites was lower in fat cells from post-obese as compared to never-obese women (P=0.014). 8,504 CpG sites were differentially methylated in fat cells from post-obese versus never-obese women (false discovery rate 1%). DMS were under-represented in CpG-islands and surrounding shores. The 8,504 DMS mapped to 3,717 unique genes; these genes were over-represented in cell differentiation pathways. Notably, 27% of genes linked to adipogenesis (i.e. 35 of 130) displayed DMS (adjusted P=10(-8)) in post-obese versus never-obese women. Next, we explored DNA methylation and expression of genes linked to adipogenesis in more detail in adipose tissue samples. DMS annotated to adipogenesis genes were not accompanied by differential gene expression in post-obese compared to never-obese women. In contrast, adipogenesis genes displayed differential DNA methylation accompanied by altered expression in obese women,Conclusions:Global CpG hypomethylation and overrepresentation of DMS in adipogenesis genes in fat cells may contribute to adipose hyperplasia in post-obese women.International Journal of Obesity accepted article preview online, 18 March 2015. doi:10.1038/ijo.2015.31.
    International journal of obesity (2005) 03/2015; DOI:10.1038/ijo.2015.31 · 5.22 Impact Factor
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    ABSTRACT: Recently, in both human and murine white adipose tissue (WAT), transcription factor early B-cell factor 1 (EBF1) has been shown to regulate adipocyte differentiation, adipose morphology and triglyceride hydrolysis (lipolysis). This study investigated whether EBF1 expression and biological activity in WAT is related to different metabolic parameters. In this cross-sectional study of abdominal subcutaneous WAT, EBF1 protein levels were examined in 18 non-obese subjects, while biological activity was determined in 56 obese and non-obese subjects. Results were assessed by anthropometric measures and blood pressure as well as by plasma lipid levels and insulin sensitivity. EBF1 protein levels were negatively associated with waist circumference (r=-0.56; P=0.015), but not with body mass index (BMI) or body fat (P=0.10-0.29). Biological activity of EBF1 correlated negatively with plasma triglycerides (r=-0.46; P=0.0005) and plasma insulin (r=-0.39; P=0.0027), but positively with plasma HDL cholesterol (r=0.48; P=0.0002) and insulin sensitivity, as assessed by intravenous insulin tolerance test (r=0.64; P<0.0001). These relationships, except for plasma insulin, remained statistically significant after adjusting for BMI and adipose morphology. EBF1 activity was not associated with age, systolic/diastolic blood pressure or total plasma cholesterol (P=0.17-0.48). In contrast to EBF1 activity, after adjusting for BMI, EBF1 mRNA levels displayed only an association with plasma triglycerides. Low EBF1 protein expression and activity in abdominal subcutaneous WAT is a BMI-independent marker for several traits associated with the metabolic syndrome. However, whether EBF1 constitutes a novel treatment target remains to be demonstrated. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Diabetes & Metabolism 03/2015; DOI:10.1016/j.diabet.2015.02.004 · 2.85 Impact Factor
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    Peter Arner, Agné Kulyté
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    ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and, therefore, biological processes in different tissues. A major function of miRNAs in adipose tissue is to stimulate or inhibit the differentiation of adipocytes, and to regulate specific metabolic and endocrine functions. Numerous miRNAs are present in human adipose tissue; however, the expression of only a few is altered in individuals with obesity and type 2 diabetes mellitus or are differentially expressed in various adipose depots. In humans, obesity is associated with chronic low-grade inflammation that is regulated by signal transduction networks, in which miRNAs, either directly or indirectly (through regulatory elements such as transcription factors), influence the expression and secretion of inflammatory proteins. In addition to their diverse effects on signalling, miRNAs and transcription factors can interact to amplify the inflammatory effect. Although additional miRNA signal networks in human adipose tissue are not yet known, similar regulatory circuits have been described in brown adipose tissue in mice. miRNAs can also be secreted from fat cells into the circulation and serve as markers of disturbed adipose tissue function. Given their role in regulating transcriptional networks, miRNAs in adipose tissue might offer tangible targets for treating metabolic disorders.
    Nature Reviews Endocrinology 03/2015; DOI:10.1038/nrendo.2015.25 · 11.03 Impact Factor
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    ABSTRACT: Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.
    Science 02/2015; 347(6225):1010-4. · 31.48 Impact Factor
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    ABSTRACT: While it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then mRNAs encoding transcription factors dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously over-represented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation. Copyright © 2015, American Association for the Advancement of Science.
    Science 02/2015; 347(6225):1010-4. DOI:10.1126/science.1259418 · 31.48 Impact Factor
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    ABSTRACT: Background Cross-sectional studies show that white adipose tissue hypertrophy (few, large adipocytes), in contrast to hyperplasia (many, small adipocytes), associates with insulin resistance and increased risk of developing type 2 diabetes. We investigated if baseline adipose cellularity could predict improvements in insulin sensitivity following weight loss.Methods Plasma samples and subcutaneous abdominal adipose biopsies were examined in 100 overweight or obese individuals before and 10 weeks after a hypo caloric diet (7±3 % weight loss) and in 61 obese subjects before and two years after gastric by-pass surgery (33±9 % weight loss). The degree of adipose tissue hypertrophy or hyperplasia (termed the morphology value) in each individual was calculated based on the relationship between fat cell volume and total fat mass. Insulin sensitivity was determined by HOMAIR.ResultsIn both cohorts at baseline, subjects with hypertrophy displayed significantly higher fasting plasma insulin and HOMAIR values than subjects with hyperplasia (p<0.0001), despite similar total fat mass. Plasma insulin and HOMAIR were normalized in both cohorts following weight loss. The improvement (delta insulin or delta HOMAIR) was more pronounced in individuals with hypertrophy, irrespective of whether adipose morphology was used as a continuous (P=0.0002-0.027) or nominal variable (P=0.002-0.047). Absolute adipocyte size associated (although weaker than morphology) with HOMAIR improvement only in the surgery cohort. Anthropometric measures at baseline (fat mass, body mass index, waist-to-hip ratio or waist circumference) showed no significant association with delta insulin or delta HOMAIR.Conclusions In contrast to anthropometric variables or fat cell size, subcutaneous adipose morphology predicts improvement in insulin sensitivity following both moderate and pronounced weight loss in overweight/obese subjects.International Journal of Obesity accepted article preview online, 10 February 2015. doi:10.1038/ijo.2015.18.
    International journal of obesity (2005) 02/2015; DOI:10.1038/ijo.2015.18 · 5.22 Impact Factor
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    ABSTRACT: Previously, a healthy Nordic diet (ND) has been shown to have beneficial health effects close to those of Mediterranean diets. The objective was to explore whether the ND has an impact on gene expression in abdominal subcutaneous adipose tissue (SAT) and whether changes in gene expression are associated with clinical and biochemical effects. Obese adults with features of the metabolic syndrome underwent an 18- to 24-wk randomized intervention study comparing the ND with the control diet (CD) (the SYSDIET study, carried out within Nordic Centre of Excellence of the Systems Biology in Controlled Dietary Interventions and Cohort Studies). The present study included participants from 3 Nordic SYSDIET centers [Kuopio (n = 20), Lund (n = 18), and Oulu (n = 18)] with a maximum weight change of ±4 kg, highly sensitive C-reactive protein concentration <10 mg/L at the beginning and the end of the intervention, and baseline body mass index (in kg/m(2)) <38. SAT biopsy specimens were obtained before and after the intervention and subjected to global transcriptome analysis with Gene 1.1 ST Arrays (Affymetrix). Altogether, 128 genes were differentially expressed in SAT between the ND and CD (nominal P < 0.01; false discovery rate, 25%). These genes were overrepresented in pathways related to immune response (adjusted P = 0.0076), resulting mainly from slightly decreased expression in the ND and increased expression in the CD. Immune-related pathways included leukocyte trafficking and macrophage recruitment (e.g., interferon regulatory factor 1, CD97), adaptive immune response (interleukin32, interleukin 6 receptor), and reactive oxygen species (neutrophil cytosolic factor 1). Interestingly, the regulatory region of the 128 genes was overrepresented for binding sites for the nuclear transcription factor κB. A healthy Nordic diet reduces inflammatory gene expression in SAT compared with a control diet independently of body weight change in individuals with features of the metabolic syndrome. The study was registered at clinicaltrials.gov as NCT00992641. © 2015 American Society for Nutrition.
    American Journal of Clinical Nutrition 01/2015; 101(1):228-39. DOI:10.3945/ajcn.114.092783 · 6.50 Impact Factor
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    ABSTRACT: Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5' upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10(-5)) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat.European Journal of Human Genetics advance online publication, 19 November 2014; doi:10.1038/ejhg.2014.255.
    European journal of human genetics: EJHG 11/2014; DOI:10.1038/ejhg.2014.255 · 3.56 Impact Factor
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    ABSTRACT: Background:Cardiovascular disease is associated with multiple risk factors including stiff arteries and large adipocytes. Whether the latter two are interrelated is unknown. We aimed to determine whether arterial stiffness is associated with fat cell size and number in subcutaneous or visceral white adipose tissue (WAT).Methods:A cross-sectional study of 120 obese subjects scheduled for bariatric surgery in whom WAT mass and distribution was assessed by dual-X-ray absorptiometry. Biopsies from visceral (greater omentum) and subcutaneous (abdominal) WAT were obtained to calculate fat cell volume and number. Arterial stiffness was determined as aortic pulse wave velocity (PWV).Results:Visceral adipocyte volume, but not number, was strongly (P<0.0001) and positively correlated with PWV, explaining 20% of the inter-individual variations in this parameter. This relationship remained significant after correction for clinical confounders. PWV correlated positively (r=0.38, P<0.0001) with visceral (but not subcutaneous) WAT mass. Furthermore, PWV was also positively associated with subcutaneous adipocyte volume (r=0.20, P=0.031) and negatively with fat cell number (r=-0.26, P=0.006). However, the relationships between PWV and visceral WAT mass or subcutaneous fat cell size/number became non-significant when controlling for visceral fat cell volume. In a multiple regression analysis to determine the factors that explain variations in PWV, only visceral fat cell volume, age, pulse rate and diastolic blood pressure entered the model, together explaining 42% of the variation in PWV.Conclusions:Visceral fat cell volume was the only WAT parameter that constituted an independent and significant, positive regressor for arterial stiffness determined by PWV. Although a causal relationship is not established, visceral fat cell volume may explain the well-known correlation between central fat mass, arterial stiffness and cardiovascular risk, at least in severely/morbidly obese subjects. (291 words/Max 300)International Journal of Obesity accepted article preview online, 08 July 2014; doi:10.1038/ijo.2014.118.
    International journal of obesity (2005) 07/2014; 39(2). DOI:10.1038/ijo.2014.118 · 5.22 Impact Factor
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    ABSTRACT: Objective. White adipose tissue can expand by increasing the size and/or number of fat cells. While increased subcutaneous and visceral fat cell size associates with an adverse metabolic profile, the relationship with fat cell number in either depot is unknown. We hypothesized that adipocyte number and size displayed different relationships with clinically relevant metabolic variables. Methods. Cross-sectional study of 204 patients scheduled for gastric by-pass surgery. Fat cell size and number were determined in visceral and abdominal subcutaneous adipose tissue and related to insulin sensitivity (by hyperinsulinemic euglycemic clamp), fasting plasma levels of insulin, triglycerides and HDL cholesterol. Results. Visceral and subcutaneous fat cell volumes were positively correlated with insulin and triglyceride levels and negatively with insulin sensitivity and HDL cholesterol (p=0.0020 or better). In contrast, while visceral fat cell number did not associate with any metabolic parameter, subcutaneous adipocyte number displayed a positive association with insulin sensitivity and HDL cholesterol and a negative relationship with insulin and triglyceride levels (p=0.0014 or better). All results were independent of body fat mass. Conclusions. Variations in fat cell size and number correlate differently with metabolic parameters in obesity. Increased fat cell size in visceral and subcutaneous depots associates with a pernicious metabolic profile whereas increased subcutaneous, but not visceral fat cell number correlates with a more beneficial phenotype. Whether determination of subcutaneous fat cell number, in addition to adipocyte size, may have a predictive value for the risk of type 2 diabetes needs to be demonstrated in prospective or mechanistic studies.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(10):jc20141526. DOI:10.1210/jc.2014-1526 · 6.31 Impact Factor
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    ABSTRACT: White adipose tissue (WAT) morphology characterized by hypertrophy (i.e., fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance, and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation, and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High-fat diet intervention in Ebf1(+/-) mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy, and insulin resistance.
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    ABSTRACT: OBJECTIVE Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients.RESEARCH DESIGN AND METHODS Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed.RESULTSRYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass, insulin sensitivity, and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03).CONCLUSIONS After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity.
    Diabetes care 04/2014; 37(7). DOI:10.2337/dc13-2395 · 7.74 Impact Factor
  • Peter Arner, Dominique Langin
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    ABSTRACT: Triglycerides in adipose tissue are rapidly mobilized during times of energy needs via lipolysis, a catabolic process that plays important role in whole body triglyceride turnover. Lipolysis is regulated through cell surface receptors via neurotransmitters, hormones, and paracrine factors that activate various intracellular pathways. These pathways converge on the lipid droplet, the site of action of lipases and cofactors. Fat cell lipolysis is also involved in the pathogenesis of metabolic disorders, and recent human studies have underscored its role in disease states such as cancer cachexia and obesity-induced insulin resistance. We highlight here topics and findings with physiological and clinical relevance, namely lipid turnover in human fat cells and the role of lipolysis in cancer cachexia and obesity-induced insulin resistance.
    Trends in Endocrinology and Metabolism 04/2014; DOI:10.1016/j.tem.2014.03.002 · 8.87 Impact Factor
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    ABSTRACT: Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.
    PLoS ONE 03/2014; 9(3):e80274. DOI:10.1371/journal.pone.0080274 · 3.53 Impact Factor
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    ABSTRACT: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.
    Nature 03/2014; 507(7493):462-70. DOI:10.1038/nature13182. · 42.35 Impact Factor
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    ABSTRACT: Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
    Nature 03/2014; 507(7493):455-61. · 42.35 Impact Factor
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    ABSTRACT: Background Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear.Methods We studied this question in rare weight-discordant (intra-pair difference (?) BMI 3-10 kg/m(2), n=15) and concordant (?BMI 0-2 kg/m(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from ten birth cohorts of Finnish twins (n=5500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (DXA).ResultsThe concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs the obese co-twins (BMI 30.6±0.9 kg/m(2)) had significantly larger adipocytes (volume 547±59 pL), than the lean co-twins (24.9±0.9 kg/m(2); 356±34 pL, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), HOMA-index, CRP and LDL-cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, ?adipocyte volume correlated positively and ?cell number negatively with ?HOMA-index and ?LDL, independent of ?body fat. Transcripts most significantly correlating with ?adipocyte volume were related to reduced mitochondrial function, membrane modifications, to DNA-damage and cell death.Conclusions Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.International Journal of Obesity accepted article preview online, 19 February 2014; doi:10.1038/ijo.2014.31.
    International journal of obesity (2005) 02/2014; DOI:10.1038/ijo.2014.31 · 5.22 Impact Factor
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    ABSTRACT: Excess ectopic fat storage is linked to type 2 diabetes. The importance of dietary fat composition for ectopic fat storage in humans is unknown. We investigated liver fat accumulation and body composition during overfeeding saturated (SFA) or polyunsaturated (PUFA) fat. LIPOGAIN was a double-blind, parallel-group, randomized trial. Thirty-nine young and normal-weight individuals were overfed muffins high in SFA (palm oil) or n-6 PUFA (sunflower oil) for 7 weeks. Liver fat, visceral (VAT), subcutaneous abdominal (SAT), and total adipose tissue (TAT), pancreatic fat, and lean tissue was assessed by MRI. Transcriptomics were performed in SAT. Both groups gained similar weight. SFA however markedly increased liver fat compared with PUFA and caused 2-fold larger increase in VAT than PUFA. Conversely, PUFA caused a nearly 3-fold larger increase in lean tissue than SFA. Increase in liver fat directly correlated with changes in plasma SFA and inversely with PUFA. Genes involved in regulating energy dissipation, insulin resistance, body composition and fat cell differentiation in SAT were differentially regulated between diets, and associated with increased PUFA in SAT. In conclusion, overeating SFA promotes hepatic and visceral fat storage whereas excess energy from PUFA may instead promote lean tissue in healthy humans.
    Diabetes 02/2014; 63(7). DOI:10.2337/db13-1622 · 7.90 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have multiple effects in various tissues including adipose inflammation, a condition characterized by increased local release of the pro-lipolytic cytokine tumor necrosis factor-alpha (TNF-α). Whether miRNAs regulate adipocyte lipolysis is unknown. We set out to determine whether miRNAs affect adipocyte lipolysis in human fat cells. To this end, eleven miRNAs known to be present in human adipose tissue were over-expressed in human in vitro differentiated adipocytes followed by assessments of TNF-α and glycerol levels in conditioned media after 48 h. Three miRNAs (miR-145, -26a and let-7d) modulated both parameters in parallel. However, while miR-26a and let-7d decreased, miR-145 increased both glycerol release and TNF-α secretion. Further studies were focused therefore on miR-145 since this was the only stimulator of lipolysis and TNF-α secretion. Time-course analysis demonstrated that miR-145 over-expression up-regulated TNF-α expression/secretion followed by increased glycerol release. Increase in TNF-α production by miR-145 was mediated via activation of p65, a member of the NF-κB complex. In addition, miR-145 down-regulated the expression of the protease ADAM17, resulting in an increased fraction of membrane bound TNF-α, which is the more biologically active form of TNF-α. MiR-145 overexpression also increased the phosphorylation of activating serine residues in hormone sensitive lipase and decreased the mRNA expression of phosphodiesterase 3B, effects which are also observed upon TNF-α treatment in human adipocytes. We conclude that miR-145 regulates adipocyte lipolysis via multiple mechanisms involving increased production and processing of TNF-α in fat cells.
    PLoS ONE 01/2014; 9(1):e86800. DOI:10.1371/journal.pone.0086800 · 3.53 Impact Factor

Publication Stats

21k Citations
3,019.79 Total Impact Points

Institutions

  • 1988–2015
    • Karolinska University Hospital
      • • Obesity Unit
      • • Department of Surgery
      Tukholma, Stockholm, Sweden
  • 1979–2015
    • Karolinska Institutet
      • • Department of Medicine, Huddinge
      • • Department of Cell and Molecular Biology
      • • Clinical Research Center
      • • Department of Pediatric Surgery
      • • Department of Surgery
      Solna, Stockholm, Sweden
  • 2008
    • University of Helsinki
      Helsinki, Southern Finland Province, Finland
  • 2007
    • Maastricht University
      • Humane Biologie
      Maastricht, Provincie Limburg, Netherlands
  • 2005
    • Stockholm University
      Tukholma, Stockholm, Sweden
  • 1999–2005
    • Lund University
      Lund, Skåne, Sweden
  • 1993–2005
    • French Institute of Health and Medical Research
      • Institute of Metabolic and Cardiovascular Diseases I2MC
      Lutetia Parisorum, Île-de-France, France
  • 2001–2003
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 2002
    • Heinrich-Heine-Universität Düsseldorf
      • Brain Research Institute
      Düsseldorf, North Rhine-Westphalia, Germany
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 1998
    • McGill University
      Montréal, Quebec, Canada
  • 1996
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1990
    • University of Rochester
      • Department of Neurology
      Rochester, NY, United States
  • 1989
    • Capio S:t Görans sjukhus
      Tukholma, Stockholm, Sweden