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Per-Arne Svensson,
Asa Anveden,
Stefano Romeo,
Markku Peltonen,
Sofie Ahlin,
Maria Antonella Burza, Björn Carlsson,
Peter Jacobson,
Anna-Karin Lindroos,
Hans Lönroth M D,
Cristina Maglio,
Ingmar Näslund M D,
Kajsa Sjöholm,
Hans Wedel Ph D,
Bo Söderpalm M D,
Lars Sjöström,
Lena M S Carlsson
[show abstract]
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ABSTRACT: OBJECTIVE: Increased sensitivity to alcohol after gastric bypass has been described. The aim of this study was to investigate whether bariatric surgery is associated with alcohol problems. DESIGN AND METHODS: The prospective, controlled Swedish Obese Subjects (SOS) study enrolled 2010 obese patients who underwent bariatric surgery (68% vertical banded gastroplasty (VBG), 19% banding and 13% gastric bypass) and 2037 matched controls. Patients were recruited between 1987 and 2001. Data on alcohol abuse diagnoses, self-reported alcohol consumption and alcohol problems were obtained from the National Patient Register and questionnaires. Follow-up time was 8-22 years. RESULTS: During follow-up, 93.1 % of the surgery patients and 96.0 % of the controls reported alcohol consumption classified as low risk by the World Health Organization (WHO). However, compared to controls, the gastric bypass group had increased risk of alcohol abuse diagnoses (adjusted hazard ratio [adjHR] = 4.97), alcohol consumption at least at the WHO medium risk level (adjHR = 2.69) and alcohol problems (adjHR = 5.91). VBG increased risk of these conditions with adjHRs of 2.23, 1.52 and 2.30, respectively, while banding was not different from controls. CONCLUSIONS: We conclude that alcohol consumption, alcohol problems and alcohol abuse are increased after gastric bypass and VBG.
Obesity 03/2013; · 4.28 Impact Factor
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Lena M S Carlsson,
Markku Peltonen,
Sofie Ahlin,
Åsa Anveden,
Claude Bouchard, Björn Carlsson,
Peter Jacobson,
Hans Lönroth,
Cristina Maglio,
Ingmar Näslund,
Carlo Pirazzi,
Stefano Romeo,
Kajsa Sjöholm,
Elisabeth Sjöström,
Hans Wedel,
Per-Arne Svensson,
Lars Sjöström
[show abstract]
[hide abstract]
ABSTRACT: Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.
In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.
During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.
Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.).
New England Journal of Medicine 08/2012; 367(8):695-704. · 53.30 Impact Factor
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ABSTRACT: The leptin system regulates body fat mass through a feedback loop between adipose tissue and the hypothalamus. To test if
leptin responsiveness may be regulated we assayed hypothalamic response to leptin during the estrous cycle; when changes in
food intake are known to occur. Immature rats were treated with pregnant mare’s serum gonadotropin (PMSG) to induce synchronized
follicular development, ovulation and corpus luteum formation. Leptin response was estimated by measuring the in vitro induction of tis11, a primary response gene activated by STAT3-dependent cytokines in hypothalamic explants after leptin stimulation. In addition,
mRNA levels of the suppressor cytokine signaling-3 (SOCS-3), a possible mediator of leptin resistance, were analyzed. Serum
leptin levels did not change between days 2 and day 3 (corresponding to proestrus and estrus, respectively) but the response
to leptin was higher on day 2 than on day 3 (p=0.05). Food intake displayed a tendency towards downregulation between day
1 and day 2 (p=0.057), and a tendency towards upregulation between day 2 and day 3 (p=0.072), although the body weight increased
on day of the study (p<0.0001). There was no significant difference in hypothalamic expression of SOCS-3 between day 2 and
day 3. In conclusion, we have shown that leptin responsiveness changes during a hormonally induced estrous cycle in rats.
Our data suggest that a change in the hypothalamic response to leptin may cause the cyclic feeding behavior seen in rats.
Central European Journal of Biology 04/2012; 1(2):221-234. · 1.00 Impact Factor
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Lars Sjöström,
Markku Peltonen,
Peter Jacobson,
C David Sjöström,
Kristjan Karason,
Hans Wedel,
Sofie Ahlin,
Åsa Anveden,
Calle Bengtsson,
Gerd Bergmark, [......], Björn Carlsson,
Sven Dahlgren,
Jan Karlsson,
Anna-Karin Lindroos,
Hans Lönroth,
Kristina Narbro,
Ingmar Näslund,
Torsten Olbers,
Per-Arne Svensson,
Lena M S Carlsson
[show abstract]
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ABSTRACT: Obesity is a risk factor for cardiovascular events. Weight loss might protect against cardiovascular events, but solid evidence is lacking.
To study the association between bariatric surgery, weight loss, and cardiovascular events.
The Swedish Obese Subjects (SOS) study is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2037 contemporaneously matched obese controls who received usual care. Patients were recruited between September 1, 1987, and January 31, 2001. Date of analysis was December 31, 2009, with median follow-up of 14.7 years (range, 0-20 years). Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Exclusion criteria were identical in surgery and control patients. Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system. Physical and biochemical examinations and database cross-checks were undertaken at preplanned intervals.
The primary end point of the SOS study (total mortality) was published in 2007. Myocardial infarction and stroke were predefined secondary end points, considered separately and combined.
Bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2010 patients in the surgery group vs 49 events among 2037 patients in the control group; adjusted hazard ratio [HR], 0.47; 95% CI, 0.29-0.76; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2010 patients) than in the control group (234 events among 2037 patients; adjusted HR, 0.67; 95% CI, 0.54-0.83; P < .001).
Compared with usual care, bariatric surgery was associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults.
JAMA The Journal of the American Medical Association 01/2012; 307(1):56-65. · 30.03 Impact Factor
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ABSTRACT: Obesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study.
SNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance.
Overall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R(2) = 3.7-5.2%, 3.9×10(-22)≤p≤7.7×10(-11)). One SNP (rs737267) showed a significant association (R(2) = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (-61.4 µmol/L) compared to minor allele carriers (A/X: -51.7 µmol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10.
SNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes.
PLoS ONE 01/2012; 7(12):e51658. · 4.09 Impact Factor
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ABSTRACT: Increased visceral fat, as opposed to subcutaneous/gluteal, most strongly relates to key metabolic dysfunctions including insulin resistance, hepatic steatosis, and inflammation. Mesenteric fat hypertrophy in patients with Crohn's disease and in experimental rodent models of gut inflammation suggest that impaired gut barrier function with increased leakage of gut-derived antigens may drive visceral lipid deposition. The aim of this study was to determine whether increased intestinal permeability is associated with visceral adiposity in healthy humans. Normal to overweight female subjects were recruited from a population-based cohort. Intestinal permeability was assessed using the ratio of urinary excretion of orally ingested sucralose to mannitol (S/M). In study 1 (n = 67), we found a positive correlation between waist circumference and S/M excretion within a time frame of urine collection consistent with permeability of the lower gastrointestinal tract (6-9 hours post-ingestion; P = 0.022). These results were followed up in study 2 (n = 55) in which we used computed tomography and dual energy X-ray absorptiometry to measure visceral and subcutaneous fat areas of the abdomen, liver fat content, and total body fat of the same women. The S/M ratio from the 6-12 h urine sample correlated with visceral fat area (P = 0.0003) and liver fat content (P = 0.004), but not with subcutaneous or total body fat. This novel finding of an association between intestinal permeability and visceral adiposity and liver fat content in healthy humans suggests that impaired gut barrier function should be further explored as a possible mediator of excess visceral fat accumulation and metabolic dysfunction.
Obesity 08/2011; 19(11):2280-2. · 4.28 Impact Factor
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ABSTRACT: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study.
Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance.
In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2-4.2% (P < 10(-14)) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R(2) = 0.4-1.1%; 3.8 × 10(-6) < P < 3 × 10(-3)), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10(-4) < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C.
SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.
The Journal of clinical endocrinology and metabolism 03/2011; 96(6):E953-7. · 6.50 Impact Factor
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Louise E Olofsson,
Bob Olsson,
Theodore Lystig,
Peter Jacobson,
Margareta Jernås,
Kajsa Sjöholm,
Anders Gummesson,
Lars Sjöström,
Per Eriksson,
Anders Hamsten,
Laura P Hale,
Dag S Thelle, Björn Carlsson,
Lena M S Carlsson
[show abstract]
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ABSTRACT: Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .00088) in healthy subjects and during weight loss (P = .059). The ZAG genotype was associated with total cholesterol (P = .014) and low-density lipoprotein cholesterol (P = .026) in healthy subjects, and the associations were replicated in an additional cohort (P = .0017 and P = .060, respectively). Our data indicate that ZAG plays a role in lipid metabolism.
Metabolism: clinical and experimental 09/2010; 59(9):1316-8. · 2.59 Impact Factor
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Lotta Delling,
Kristjan Karason,
Torsten Olbers,
David Sjöström,
Björn Wahlstrand, Björn Carlsson,
Lena Carlsson,
Kristina Narbro,
Jan Karlsson,
Carl Johan Behre,
Lars Sjöström,
Kaj Stenlöf
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ABSTRACT: Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD.
Journal of obesity 01/2010; 2010.
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Atsuhito Saiki,
Maja Olsson,
Margareta Jernås,
Anders Gummesson,
Philip G McTernan,
Johanna Andersson,
Peter Jacobson,
Kajsa Sjöholm,
Bob Olsson,
Shigeo Yamamura,
Andrew Walley,
Philippe Froguel, Björn Carlsson,
Lars Sjöström,
Per-Arne Svensson,
Lena M S Carlsson
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ABSTRACT: Tenomodulin (TNMD), a putative angiogenesis inhibitor, is expressed in hypovascular connective tissues. Global gene expression scans show that the TNMD gene also is expressed in human adipose tissue and that its expression is regulated in response to weight reduction; however, more detailed information is lacking.
The aim of this study was to investigate TNMD tissue distribution and TNMD gene expression in human adipose tissue in relation to obesity and metabolic disease.
TNMD gene expression, tissue distribution, and TNMD gene expression in adipose tissue from different depots, from lean and obese subjects, and during diet-induced weight reduction were analyzed by DNA microarray and real-time PCR.
We primarily measured TNMD gene expression.
The TNMD gene was predominantly expressed in sc adipose tissue. TNMD gene expression was higher in sc than omental adipose tissue both in lean (P = 0.002) and obese subjects (P = 0.014). In both women and men, TNMD gene expression was significantly higher in the obese subjects compared to the lean subjects (P = 1.1 x 10(-26) and P = 0.010, respectively). In a multiple linear regression analysis, BMI was a significant independent predictor of TNMD gene expression. TNMD gene expression was down-regulated during diet-induced weight loss, with a 65% decrease after 18 wk of diet (P < 0.0001).
We conclude that human adipose tissue TNMD gene expression is highly affected by obesity, adipose tissue location, and weight loss, indicating that TNMD may play a role in adipose tissue function.
The Journal of clinical endocrinology and metabolism 07/2009; 94(10):3987-94. · 6.50 Impact Factor
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Lars Sjöström,
Anders Gummesson,
C David Sjöström,
Kristina Narbro,
Markku Peltonen,
Hans Wedel,
Calle Bengtsson,
Claude Bouchard, Björn Carlsson,
Sven Dahlgren, [......],
Kristjan Karason,
Jan Karlsson,
Bo Larsson,
Anna-Karin Lindroos,
Hans Lönroth,
Ingmar Näslund,
Torsten Olbers,
Kaj Stenlöf,
Jarl Torgerson,
Lena M S Carlsson
[show abstract]
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ABSTRACT: Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data.
The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] >or=34 kg/m(2) in men, and >or=38 kg/m(2) in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99.9% and the median follow-up time was 10.9 years (range 0-18.1 years).
Bariatric surgery resulted in a sustained mean weight reduction of 19.9 kg (SD 15.6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1.3 kg (SD 13.7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0.67, 95% CI 0.53-0.85, p=0.0009). The sex-treatment interaction p value was 0.054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0.58, 0.44-0.77; p=0.0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0.97, 0.62-1.52; p=0.90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention.
Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men.
Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.
The lancet oncology 06/2009; 10(7):653-62. · 14.47 Impact Factor
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ABSTRACT: CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism.
The aim of the study was to test the hypothesis that adipose tissue C/EBPalpha regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPalpha and metabolic parameters.
Adipose tissue C/EBPalpha mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPalpha was used to identify genes regulated by C/EBPalpha in 3T3-L1 cells. Association between a genetic variation in C/EBPalpha (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4,866).
During caloric restriction, adipose tissue C/EBPalpha mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPalpha regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-beta dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPalpha mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041).
Adipose tissue C/EBPalpha regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPalpha is associated with triglycerides in two independent populations.
Journal of Clinical Endocrinology & Metabolism 10/2008; 93(12):4880-6. · 6.50 Impact Factor
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ABSTRACT: Members of the cell death-inducing DFF45-like effector (CIDE) gene family have been shown to regulate lipid metabolism. In this article, we report that the third member of the human CIDE family, CIDEC, is down-regulated in response to a reduced caloric intake. The down-regulation was demonstrated by microarray and real-time polymerase chain reaction analysis of subcutaneous adipose tissue in 2 independent studies on obese patients undergoing treatment with a very low calorie diet. By analysis of CIDEC expression in 65 human tissues, we conclude that human CIDEC is predominantly expressed in subcutaneous adipocytes. Together, these observations led us to investigate the effect of decreased CIDEC expression in cultured 3T3-L1 adipocytes. Small interfering RNA-mediated knockdown of CIDEC resulted in an increased basal release of nonesterified fatty acids, decreased responsiveness to adrenergic stimulation of lipolysis, and increased oxidation of endogenous fatty acids. Thus, we suggest that CIDEC is a regulator of adipocyte lipid metabolism and may be important for the adipocyte to adapt to changes in energy availability.
Metabolism: clinical and experimental 10/2008; 57(9):1307-13. · 2.59 Impact Factor
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Daniel A Hägg,
Margareta Jernås,
Olle Wiklund,
Dag S Thelle,
Björn Fagerberg,
Per Eriksson,
Anders Hamsten,
Bob Olsson, Björn Carlsson,
Lena M S Carlsson,
Per-Arne Svensson
[show abstract]
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ABSTRACT: Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
International Journal of Molecular Medicine 06/2008; 21(6):697-704. · 1.98 Impact Factor
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Anders Gummesson,
Margareta Jernås,
Per-Arne Svensson,
Ingrid Larsson,
Camilla A M Glad,
Erik Schéle,
Lena Gripeteg,
Kajsa Sjöholm,
Theodore C Lystig,
Lars Sjöström, Björn Carlsson,
Björn Fagerberg,
Lena M S Carlsson
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ABSTRACT: Cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings that CIDEA inhibits the brown adipose tissue uncoupling process in rodents.
Our objects were to investigate the putative link between CIDEA and basal metabolic rate in humans and to elucidate further the role of CIDEA in human obesity.
We have explored CIDEA gene expression in adipose tissue in two different human studies: a cross-sectional and population-based study assessing body composition and metabolic rate (Mölndal Metabolic study, n = 92); and a longitudinal intervention study of obese subjects treated with a very low calorie diet (VLCD) (VLCD study, n = 24).
The CIDEA gene was predominantly expressed in adipocytes as compared with other human tissues. CIDEA gene expression in adipose tissue was inversely associated with basal metabolic rate independently of body composition, age, and gender (P = 0.014). The VLCD induced an increase in adipose tissue CIDEA expression (P < 0.0001) with a subsequent decrease in response to refeeding (P < 0.0001). Reduced CIDEA gene expression was associated with a high body fat content (P < 0.0001) and high insulin levels (P < 0.01). No dysregulation of CIDEA expression was observed in individuals with the metabolic syndrome when compared with body mass index-matched controls. In a separate sample of VLCD-treated subjects (n = 10), uncoupling protein 1 expression was reduced during diet (P = 0.0026) and inversely associated with CIDEA expression (P = 0.0014).
The findings are consistent with the concept that CIDEA plays a role in adipose tissue energy expenditure.
Journal of Clinical Endocrinology & Metabolism 12/2007; 92(12):4759-65. · 6.50 Impact Factor
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Lars Sjöström,
Kristina Narbro,
C David Sjöström,
Kristjan Karason,
Bo Larsson,
Hans Wedel,
Ted Lystig,
Marianne Sullivan,
Claude Bouchard, Björn Carlsson, [......],
Peter Jacobson,
Jan Karlsson,
Anna-Karin Lindroos,
Hans Lönroth,
Ingmar Näslund,
Torsten Olbers,
Kaj Stenlöf,
Jarl Torgerson,
Göran Agren,
Lena M S Carlsson
[show abstract]
[hide abstract]
ABSTRACT: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality.
The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%).
The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29).
Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.
New England Journal of Medicine 09/2007; 357(8):741-52. · 53.30 Impact Factor
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ABSTRACT: The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS-) at baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS- subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase-polymerase chain reaction, and biochemical analyses. Serum adiponectin was also assessed in a sex- and age-matched healthy, nonobese reference group. Weight decreased by 26.3+/-9.8 kg in the MetS+ group and 28.2+/-8.4 kg in the MetS- group with concomitant reductions in insulin, hemoglobin A1c, and triglycerides that were more pronounced in the MetS+ group. Initially, the MetS+ subjects had lower serum adiponectin, but the differences disappeared at week 8, with a continuous increase in serum adiponectin throughout the study in both groups to a level that was higher than in the reference group. The expression of adiponectin and v-SNARE Vti1a did not differ between the groups or over time. In conclusion, obese subjects with the metabolic syndrome had lower circulating adiponectin than subjects without the syndrome. Weight loss increased serum levels of adiponectin without a parallel increase in adiponectin gene expression. The mechanisms involved in the regulation of adiponectin levels merits further investigation.
Metabolism 09/2007; 56(8):1022-8. · 2.66 Impact Factor
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ABSTRACT: We have previously identified nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1), an enzyme involved in the protection against oxidative stress, as a gene predominantly expressed in human adipocytes. Studies in mice deficient in NQO1 activity suggest that NQO1 may also play an important role in metabolism.
The aim of this study was to explore the expression and regulation of NQO1 in human adipose tissue (AT) and isolated adipocytes.
The high expression of NQO1 in adipocytes was verified in human adipocytes and AT by real-time PCR. DNA microarray analysis showed that NQO1 was expressed at higher levels in large compared with small adipocytes, isolated from the same fat biopsy. Furthermore, NQO1 mRNA levels were positively correlated with adipocyte size (n = 7; P < 0.002). During an 18-wk diet regime (n = 24; mean weight loss 27 kg), the NQO1 expression in human sc AT was down-regulated (P < 0.0001), and mRNA levels correlated with body mass index (P = 0.0005), sc, and total abdominal AT areas, as determined by computerized tomography (P < 0.0001, both) and metabolic parameters. NQO1 mRNA levels were also positively correlated with aspartate aminotransferase (P = 0.0028) and alanine aminotransferase (P = 0.0219), markers known to be associated with severity of hepatic steatosis.
NQO1 is highly expressed in human AT, particularly in large adipocytes. AT NQO1 expression is reduced during diet-induced weight loss, and the expression levels positively correlate with adiposity, glucose tolerance, and markers of liver dysfunction. Together, these findings indicate a role for NQO1 in the metabolic complications of human obesity.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(6):2346-52. · 6.50 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 626(1):169 - 176. · 3.15 Impact Factor
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Margareta Jernås,
Jenny Palming,
Kajsa Sjöholm,
Eva Jennische,
Per-Arne Svensson,
Britt G Gabrielsson,
Max Levin,
Anders Sjögren,
Mats Rudemo,
Theodore C Lystig, Björn Carlsson,
Lena M S Carlsson,
Malin Lönn
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ABSTRACT: Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+/-3.54 microm) and large cells (mean 100.1+/-3.94 microm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.
The FASEB Journal 08/2006; 20(9):1540-2. · 5.71 Impact Factor
