| 1. |
- Jiao, Hong, et al.
(author)
-
Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity
- 2011
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:6, s. E962-E966
-
Journal article (peer-reviewed)abstract
- Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
|
|
| 2. |
- Jiao, Hong, et al.
(author)
-
Genome wide association study identifies KCNMA1 contributing to human obesity
- 2011
-
In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4, s. 51-
-
Journal article (peer-reviewed)abstract
- Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
|
|
| 3. |
- Alastair, Kerr, et al.
(author)
-
The long noncoding RNA ADIPINT is a gatekeeper of pyruvate carboxylasefunction regulating human fat cell metabolism
-
Other publication (other academic/artistic)abstract
- The pleiotropic function of long noncoding RNAs (lncRNAs) is well recognized,but their direct role in governingmetabolic homeostasis is less understood. Herein,we describe a human adipocyte-specific lncRNA, ADIPINT, that regulatespyruvate carboxylase (PC) an enzyme pivotal to energy metabolism. With a novelapproach, Targeted RNA-protein identification using Orthogonal Organic PhaseSeparation (TROOPS) and validation with electron microscopy, we show thatADIPINT binds to PC. ADIPINT knockdown alters the interactome anddecreases the mitochondrial abundance and enzymatic activty of PC. Decreases inADIPINT or PC expression reduce adipocyte lipid synthesis, breakdown and lipidcontent. In human white adipose tissue, ADIPINT expression is increased inobesity, linked to fat cell size, adipose insulin resistance and PC activity. Thus, weidentify ADIPINT as a regulator of lipid metabolism in human white adipocytes,which at least in part is mediated through its interaction with PC.
|
|
| 4. |
- Anund, Anna, 1964-, et al.
(author)
-
Lessons learned from setting up a demonstration site with autonomous shuttle operation – based on experience from three cities in Europe
- 2022
-
In: Journal of Urban Mobility. - : Elsevier BV. - 2667-0917. ; 2
-
Journal article (peer-reviewed)abstract
- The interest in operating autonomous vehicles is growing and several demonstration sites using automated shuttles have been established all over the world. Major work is involved in setting up an automated shuttle operation that involves more than identifying the relevant site, including adhering to current regulations and obtaining approval, as well as a considerable amount of preparation and commissioning required at the site. The shuttle must pass relevant national vehicle regulations, and the operation site has to undergo a site assessment. This paper is based on lessons learned achieved from setting up automated shuttle operations in three different areas in Europe: Brussel (Belgium), Linköping (Sweden) and Turin (Italy). The focus is on the practical aspects of operation. Through the experience we have gained of setting up demonstration sites at three locations in Europe, we have identified the need to summarise the lessons learned from preparing AV shuttle operation sites in order to facilitate the implementation of other operation sites. Hence, this paper aims to consolidate lessons learned during preparation and implementation of automated shuttle operations in near urban environments and to identify the path toward future implementation The three sites operate different brands and number of shuttles, different types of infrastructure and varying local conditions. The focus here was on generic lessons learned and not to understand differences between brands and operators. It is clear that further development of the AV shuttles is vital to ensure that they operate smoothly in complex traffic situations considering lane and road width, shared spaces, snow, dust, rain, leaves, birds, etc. Adapting the road infrastructure to enable the shuttles to run in the autonomous mode should be avoided, instead the shuttle development should prioritise fitting into the existing traffic environment and eco system. Mitigation areas have been identified covering: road infrastructure, weather dependant operation, season dependent operation, improvement of localisation, digital infrastructure, design and working conditions, and citizens’ user experience.
|
|
| 5. |
|
|
| 6. |
- Bjermo, Helena, et al.
(author)
-
Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity : a randomized controlled trial
- 2012
-
In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 95:5, s. 1003-1012
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Replacing SFAs with vegetable PUFAs has cardiometabolic benefits, but the effects on liver fat are unknown. Increased dietary n-6 PUFAs have, however, also been proposed to promote inflammation-a yet unproven theory. OBJECTIVE: We investigated the effects of PUFAs on liver fat, systemic inflammation, and metabolic disorders. DESIGN: We randomly assigned 67 abdominally obese subjects (15% had type 2 diabetes) to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake. Liver fat was assessed by MRI and magnetic resonance proton (1H) spectroscopy (MRS). Proprotein convertase subtilisin/kexin type-9 (PCSK9, a hepatic LDL-receptor regulator), inflammation, and adipose tissue expression of inflammatory and lipogenic genes were determined. RESULTS: A total of 61 subjects completed the study. Body weight modestly increased but was not different between groups. Liver fat was lower during the PUFA diet than during the SFA diet [between-group difference in relative change from baseline; 16% (MRI; P < 0.001), 34% (MRS; P = 0.02)]. PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05). Adipose tissue gene expression was unchanged. CONCLUSIONS: Compared with SFA intake, n-6 PUFAs reduce liver fat and modestly improve metabolic status, without weight loss. A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress. Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs.
|
|
| 7. |
- Claussnitzer, Melina, et al.
(author)
-
Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms.
- 2014
-
In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 156:1-2, s. 343-358
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
|
|
| 8. |
- Dahlman, Ingrid, et al.
(author)
-
A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects
- 2005
-
In: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 90:10, s. 5834-5840
-
Journal article (peer-reviewed)abstract
- Context: Low-grade inflammation in adipose tissue may contribute to insulin resistance in obesity. However, the roles of individual inflammatory mediators in adipose tissue are poorly understood. Objectives: The objective of this study was to determine which inflammation markers are most overexpressed at the gene level in adipose tissue in human obesity and how this relates to corresponding protein secretion. Design: We examined gene expression profiles in 17 lean and 20 obese subjects. The secretory pattern of relevant corresponding proteins was examined in human sc adipose tissue or isolated fat cells in vitro and in vivo in several obese or lean cohorts. Results: In ranking gene expression, defined pathways associated with obesity and immune and defense responses scored high. Among seven markedly overexpressed chemokines, only monocyte chemoattractant protein 1 (MCP1) was released from adipose tissue and isolated fat cells in vitro. In obesity, the secretion and expression of MCP1 in adipose tissue pieces were more than 6- and 2-fold increased, respectively, but there was no change in circulating MCP1 levels. There was no net release of MCP1, but there was a net release of leptin, in vivo from adipose tissue into the circulation. Conclusions: Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.
|
|
| 9. |
- Dahlman, Ingrid
(author)
-
Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats
- 1999
-
Doctoral thesis (other academic/artistic)abstract
- Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) causing neurological deficits. The disease has a complex etiology comprising multiple unidentified susceptibility genes and environmental influences. Certain human leukocyte antigen (HLA) class 11 alleles are associated with an increased risk of developing MS, which provides important circumstantial evidence for a T-cell mediated autoimmune pathogenesis of the disease. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS which can be induced in a variety of species by immunisation with myelin antigens. EAE is a T-cell mediated disease and, like MS, both major histocompatibility complex (MHC) and non-MHC genes influence disease susceptibility. The causes of organ-specific inflammatory diseases such as MS and EAE are poorly understood. Identification of susceptibility genes should allow disclosure of mechanisms causing disease and not being a consequence of it. We have used linkage analysis to dissect genetic susceptibility to (1) spinal cordand (2) myelin oligodendrocyte glycoprotein (MOG)-induced EAE in Dark Agouti (DA) rats. Both of these disease models display a chronic/relapsing disease course and extensive demyelination in the CNS, thus offering the opportunity to dissect mechanisms causing these hallmarks of MS. We have identified several new susceptibility loci linked to phenotypes of EAE in three separate experimental crosses. Susceptibility loci for EAE are dependent on parental strains and immunisation protocol, which shows that EAE has multiple etiologies. Despite this, there is a striking colocalisation of susceptibility loci for EAE and for animal models of rheumatoid arthritis and Guillain Barré syndrome in DA rats. Such shared susceptibility loci for autoimmune diseases affecting different organs may control critical steps in the regulation of tolerance versus immunity. Genes regulating T helper (Th)-cell differentiation have been implicated in EAE. Two of the identified susceptibility loci for EAE are linked to immunological phenotypes compatible with an influence on Th-cell differentiation, suggesting that other mechanisms are also important in controlling susceptibility versus resistance to EAE. In conclusion, eight susceptibility loci for EAE in rats have been identified. Future work includes positional cloning of the underlying susceptibility genes by genetic finemapping, gene expression mapping, and sequencing studies. The biological role of specific genes in the disease process, and how different combinations of specific susceptibility genes for EAE contribute to overall disease susceptibility will be dissected in congenic strains. Together, this should allow definition of the different steps in the development of organ-specific neuroinflammatory disease. Such knowledge should potentially allow development of rationale treatment strategies for MS.
|
|
| 10. |
- Flanagan, John N., et al.
(author)
-
Role of follistatin in promoting adipogenesis in women
- 2009
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:8, s. 3003-9
-
Journal article (peer-reviewed)abstract
- CONTEXT: Follistatin is a glycoprotein that binds and neutralizes biological activities of TGFbeta superfamily members including activin and myostatin. We previously identified by expression profiling that follistatin levels in white adipose tissue (WAT) were regulated by obesity. OBJECTIVE: The objective of the study was to elucidate the role of follistatin in human WAT and obesity. DESIGN: We measured secreted follistatin protein from WAT biopsies and fat cells in vitro. We also quantified follistatin mRNA expression in sc and visceral WAT and in WAT-fractionated cells and related it to obesity status, body region, and cellular origin. We investigated the effects of follistatin on adipocyte differentiation of progenitor cells in vitro. PARTICIPANTS: Women (n = 66) with a wide variation in body mass index were recruited by advertisement and from a clinic for weight-reduction therapy. RESULTS: WAT secreted follistatin in vitro. Follistatin mRNA levels in sc but not visceral WAT were decreased in obesity and restored to nonobese levels after weight reduction. Follistatin mRNA levels were high in the stroma-vascular fraction of WAT and low in adipocytes. Recombinant follistatin treatment promoted adipogenic differentiation of progenitor cells and neutralized the inhibitory action of myostatin on differentiation in vitro. Moreover, activin and myostatin signaling receptors were detected in WAT and adipocytes. CONCLUSION: Follistatin is a new adipokine important for adipogenesis. Down-regulated WAT expression of follistatin in obesity may counteract adiposity but could, by inhibiting adipogenesis, contribute to hypertrophic obesity (large fat cells) and insulin resistance.
|
|
