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Multiple genetic studies have linked copy number variation (CNV) in different genes to body mass index (BMI) and obesity. A CNV on chromosome 10q11.22 has been associated with body weight. This CNV region spans NPY4R, the gene encoding the pancreatic polypeptide receptor Y4, which has been described as a satiety-stimulating receptor. We have investigated CNV of the NPY4R gene and analysed its relationship to BMI, waist circumference and self-reported dietary intake from 558 individuals (216 men and 342 women) representing a wide BMI range. The copy number for NPY4R ranged from 2 to 8 copies (average 4.6 +/- 0.8). Rather than the expected negative correlation, we observed a positive correlation between NPY4R copy number and BMI as well as waist circumference (r = 0.267, p = 2.65x 10(-7) and r = 0.256, p = 8x10(-7), respectively). Each additional copy of NPY4R correlated with 2.6 kg/m(2) increase in BMI and 5.67 cm increase in waist circumference (p = 3.3x10(-7) and p = 1x10(-6), respectively) for women. For men, there was no statistically significant correlation between CNV and BMI. Our results suggest that NPY4R genetic variation influences body weight in women, but the exact role of this receptor appears to be more complex than previously proposed.

IMPORTANCE: Bariatric surgery is a life-changing treatment for patients with severe obesity, but little is known about its association with interpersonal relationships. OBJECTIVES: To investigate if relationship status is altered after bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: Changes in relationship status after bariatric surgery were examined in 2 cohorts: (1) the prospective Swedish Obese Subjects (SOS) study, which recruited patients undergoing bariatric surgery from September 1, 1987, to January 31, 2001, and compared their care with usual nonsurgical care in matched obese control participants; and (2) participants from the Scandinavian Obesity Surgery Registry (SOReg), a prospective, electronically captured register that recruited patients from January 2007 through December 2012 and selected comparator participants from the general population matched on age, sex, and place of residence. Data was collected in surgical departments and primary health care centers in Sweden. The current analysis includes data collected up until July 2015 (SOS) and December 2012 (SOReg). Data analysis was completed from June 2016 to December 2017. MAIN OUTCOMES AND MEASURES: In the SOS study, information on relationship status was obtained from questionnaires. In the SOReg and general population cohort, information on marriage and divorce was obtained from the Swedish Total Population Registry. RESULTS: The SOS study included 1958 patients who had bariatric surgery (of whom 1389 [70.9%] were female) and 1912 matched obese controls (of whom 1354 [70.8%] were female) and had a median (range) follow-up of 10 (0.5-20) years. The SOReg cohort included 29 234 patients who had gastric bypass surgery (of whom 22 131 [75.6%] were female) and 283 748 comparators from the general population (of whom 214 342 [75.5%] were female), and had a median (range) follow-up of 2.9 (0.003-7.0) years. In the SOS study, the surgical patients received gastric banding (n = 368; 18.8%), vertical b, Funding Agencies:National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health R01DK105948Sahlgrenska University Hospital Regional Agreement on Medical Education and Research research grants

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 2,010 obese patients who underwent bariatric surgery (68% vertical banded gastroplasty (VBG), 19% banding, and 13% gastric bypass) and 2,037 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 the risk of these conditions with adjHRs of 2.23, 1.52, and 2.30, respectively, while banding was not different from controls. Conclusions Alcohol consumption, alcohol problems, and alcohol abuse are increased after gastric bypass and VBG.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 inte, Funding Agencies:AstraZeneca New York Obesity Nutrition Research Center Pathway Genomics Weight Watchers Nike Human Kinetics and Informa Healthcare Pfizer Roche Novartis Johnson Johnson Swedish federal government under the LUA/ALF VINNOVA-VINNMER program Wenner-Gren Foundations Hoffmann-La Roche Cederroth Sanofi-Aventis

Using restriction fragment differential display (RFDD) technology, we have identified the imprinted gene neuronatin (Nnat) as a hypothalamic target under the influence of leptin. Nnat mRNA expression is decreased in several key appetite regulatory hypothalamic nuclei in rodents with impaired leptin signaling and during fasting conditions. Furthermore, peripheral administration of leptin to ob/ob mice normalizes hypothalamic Nnat expression. Comparative immunohistochemical analysis of human and rat hypothalami demonstrates that NNAT protein is present in anatomically equivalent nuclei, suggesting human physiological relevance of the gene product(s). A putative role of Nnat in human energy homeostasis is further emphasized by a consistent association between single nucleotide polymorphisms (SNPs) in the human Nnat gene and severe childhood and adult obesity.

OBJECTIVE-Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS-Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. RESULTS-SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight, loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. CONCLUSIONS-Our data suggest that SPARC Expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesit

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. FUNDING: 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.

Udgivelsesdato: 2008-Aug, Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.

The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.

Functional recovery after experimental stroke in rats is enhanced by environmental enrichment by stimulating plastic changes in brain regions outside the lesion, but the molecular mechanisms are not known. We investigated the effect of environmental enrichment after focal cerebral ischemia on cognitive recovery and hippocampal gene expression using microarray analysis. Rats placed in enriched environment (EE) for 1 month after middle cerebral artery occlusion (MCAo) showed significantly improved spatial memory in the Morris water maze compared to rats housed alone after MCAo. Microarray analysis suggested several EE-induced differences in neuronal plasticity-related genes, but these changes could not be confirmed by quantitative real-time PCR. This study highlights some of the potential problems associated with gene expression profiling of brain tissues. Further studies at earlier time points and in additional subregions of the brain are of interest in the search for molecular mechanisms behind EE-induced neuronal plasticity after ischemic stroke., Artikeln har vid publicering fått en annan titel än den hade vid publiceringen av avhandlingen.

OBJECTIVE: Macrophage-mediated oxidation of low-density lipoprotein (LDL) by enzymes, such as the lipoxygenases, is considered of major importance for the formation of oxidized LDL during atherogenesis. Macrophages have been identified in hypoxic areas in atherosclerotic plaques. METHODS AND RESULTS: To investigate the role of hypoxia in macrophage-mediated LDL oxidation, we incubated human monocyte-derived macrophages with LDL under normoxic (21% O2) or hypoxic (0% O2) conditions. The results showed that hypoxic macrophages oxidized LDL to a significantly higher extent than normoxic cells. Interestingly, the mRNA and protein expression of 15-lipoxygenase-2 (15-LOX-2) as well as the activity of this enzyme are elevated in macrophages incubated at hypoxia. Both the unspliced 15-LOX-2 and the spliced variant 15-LOX-2sv-a are found in macrophages. In addition, 15-LOX-2 was identified in carotid plaques in some macrophage-rich areas but was only expressed at low levels in nondiseased arteries. CONCLUSIONS: In summary, these observations show for the first time that 15-LOX-2 is expressed in hypoxic macrophages and in atherosclerotic plaques and suggest that 15-LOX-2 may be one of the factors involved in macrophage-mediated LDL oxidation at hypoxia.

Lack of neonatal angiotensin II type I receptor (AT1) stimulation produces renal abnormalities characterized by papillary atrophy and impaired urinary concentrating ability, but the mechanisms involved are still unclear. DNA microarray was used to identify genes that are differentially expressed in renal medulla in response to neonatal treatment with AT 1 receptor antagonist losartan (30 mg/kg per d), which commenced within 24 h after birth. The data showed that losartan treatment for 48 h downregulated 68 genes, ~30% of which encode various components of cytoskeleton and cytoskeleton-associated proteins, extracellular matrix, and enzymes involved in extracellular matrix maturation or turnover. With the use of immunohistochemistry and Western immunoblot, the microarray data were confirmed and it was demonstrated that losartan suppressed renal expression of syndecan 2, a-smooth muscle actin, MHC class II, and leukocyte type 12-lipoxygenase by day 4. In addition, losartan inhibited medullary expression of integrin a6 and caused relocalization of integrins a6 and a3. Moreover, losartan inhibited cell proliferation in medullary tubules by day 9, as detected by Ki-67 immunostaining. This study provides new data supporting the contention that a lack of AT1 receptor stimulation results in abnormal matrix assembly, disturbed cell-cell and cell-matrix interactions, and subsequent abnormal tubular maturation. Moreover, regulation of the expression of leukocyte type 12-lipoxygenase and a-smooth muscle actin by the renin-angiotensin system in the immature kidney adds new knowledge toward the understanding of renal vascular development.

Decreased activity of anti-inflammatory cytokines like transforming growth factor (TGF)-beta may contribute to allergic inflammation. In vivo effects of TGF-beta-effects are difficult to infer from local concentrations, since TGF-beta-effects depend on a complex system of regulatory proteins and receptors. Instead the effects of TGF-beta might be inferred by examining TGF-beta-inducible transcripts. In this study DNA microarrays were used to examine local expression of TGF-beta, TGF-beta-regulatory and -inducible transcripts in nasal biopsies from patients with symptomatic allergic rhinitis and healthy controls. In addition, nasal fluids were analysed with cytological and immunological methods. Nasal fluid eosinophils, albumin, eosinophil granulae proteins and IgE, but not TGF-beta, were higher in patients than in controls. DNA microarray analysis of nasal mucosa showed expression of transcripts encoding TGF-beta, TGF-beta-regulatory proteins and -receptors at variable levels in patients and controls. By comparison, analysis of 28 TGF-beta-inducible transcripts indicated that 23 of these had lower measurement values in patients than in controls, while one was higher, and the remaining four were absent in both patients and controls. In summary, TGF-beta and a complex system of regulatory genes and receptors are expressed in the nasal mucosa. Low expression of TGF-beta-inducible transcripts may indicate decreased TGF-beta activity in allergic rhinitis. DNA microarray analysis may be a way to study cytokine effects in vivo.

Increased vascular dilatation and permeability characterize allergic rhinitis. In this study oligonucleotide microarrays (Affymetrix HuGe95A) were used to identify differentially expressed vasoactive genes in nasal biopsies from 23 patients with symptomatic seasonal allergic rhinitis (SAR) and 12 healthy controls. RNA was extracted from the biopsies and pooled in three patient and three control pools. Out of 12,626 analysed transcripts, 39 were higher and 81 lower in the patients. Of these transcripts two have vasoactive effects: Vascular Endothelial Growth Factor-A (VEGF-A) and the Beta-1-Adrenergic Receptor. Both were higher in patients than in controls. The mean +/- SEM expression levels in arbitrary units of VEGF-A were 130 +/- 123 in the patients and 59 +/- 53 in the controls. The fold ratio in expression levels between patients/controls was 2.2. The corresponding values for the beta-1-adrenergic receptor were 129 +/- 123 in the patients and 40 +/- 31 in the controls. The fold ratio between patient/controls was 3.2. The role of VEGF-A was assessed by determining VEGF-A concentrations in nasal fluids from another 30 patients with SAR before and after allergen provocation. VEGF-A increased from 124.3 +/- 30.2 to 163.2 +/- 37.8 pg/ml after challenge, P < 0.05. In summary, oligonucleotide microarray analysis of nasal biopsies and protein analyses of nasal fluids indicate that VEGF-A may be an important mediator in SAR.