Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects – A Monozygotic Twin Study

et al (2007) Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects - A Monozygotic Twin Study. PLoS ONE 2(2): e218. doi:10.1371/journal.pone.0000218 Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects - A Monozygotic Twin Study Kirsi H. Pietil ainen 0 1 2 Marko Sysi-Aho 0 1 2 Aila Rissanen 0 1 2 Tuulikki Sepp anen-Laakso 0 1 2 Hannele Yki-J arvinen 0 1 2 Jaakko Kaprio 0 1 2 Matej Oresic 0 1 2 0 Funding: This work was supported by The National Institute on Alcohol Abuse and Alcoholism (grants AA-08315 and AA-12502) , the European Union Fifth Framework Program (QLRT-1999-00916, QLG2-CT-2002-01254) , the Academy of Finland (Grant 44069, 100499 and 201461), the Academy of Finland Centre of Excellence in Complex Disease Genetics, and Helsinki University Central Hospital grants. This work is part of the project ''Hepatic and adipose tissue and functions in the metabolic syndrome'' (HEPADIP, see http://www.hepadip.org/), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). KHP is supported by the following foundations: Yrjo Jahnsson, Jalmari & Rauha Ahokas, Juho Vainio, Finnish Cultural, Finnish Medical Foundation, and Research Foundation of the Orion Coorporation. The funding sources have not been involved in the design, analysis or interpretation of the results 1 Academic Editor: Alessandro Bartolomucci, University of Parma , Italy 2 1 Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital , Helsinki , Finland , 2 Department of Medicine, Division of Diabetes, Helsinki University Central Hospital , Helsinki, Finland, 3 Finnish Twin Cohort Study , Department of Public Health, University of Helsinki , Helsinki , Finland , 4 VTT Technical Research Centre of Finland , Espoo , Finland , 5 Department of Mental Health and Alcohol Research, National Public Health Institute , Helsinki , Finland Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance. - INTRODUCTION Obesity increases the risk of cardiovascular diseases and diabetes [1] especially when the extra fat is accumulated to central and intra-abdominal depots [2,3]. The increased cardiometabolic risk in obesity is at least partly mediated through atherogenic dyslipidemia characterized by an increase in plasma triglycerides, large very low density lipoprotein (VLDL) particles, small dense low density lipoprotein (LDL) particles as well as low concentrations of high density (HDL) cholesterol [4]. It is also recognized that changes in the function of individual lipids due to peroxidation, imbalanced fatty acid composition or their altered flux from peripheral tissues may contribute to development of atherosclerosis and diabetes [5]. The advent of novel analytical and information technologies for handling large volumes of data has made it feasible to characterize complex mixtures of lipids in body fluids and tissues and relate them to other entities of biological systems [5,6]. Therefore, lipidomics as a branch of metabolomics may provide powerful tools for characterization of global lipid profiles and identification of previously unknown changes in lipid metabolism in complex phenotypes such as those related to obesity [79]. The origin of obesity and related dyslipidemias is multifactorial [10]. Not all obese individuals develop dyslipidemia and not all dyslipidemic patients are obese. While environmental and lifestyle factors play a key role in the development of obesity, genetic variation may determine an individuals susceptibility to body fat accumulation and lipid disturbances [10]. Cross-sectional studies comparing lipid profiles in obese vs. non-obese humans do not permit unequivocal distinction between genetic versus environmental and life-style effects. This can best be done by studying monozygotic (MZ) twins discordant for obesity. MZ twins are genetically identical at the sequence level and any differences between the co-twins are thus attributable to environmental factors [11]. Environmental factors are here considered very broadly, including i.e. possible prenatal exposures and effects inducing epigenetic changes. The co-twin design controls for age, gender, childhood socioeconomic background and other environmental experiences and exposures. In a previous study of young adult obesity-discordant but otherwise healthy MZ twin pairs we have shown that the degree of obesity correlates with increases in visceral and liver fat deposition [12]. These adverse effects were associated with abnormalities in expression of fatty acid transport proteins [13] and increased expression of inflammation markers in the adipose tissue [14,15]. We then hypothesized that obesity-discordant twins would differ for the levels of specific serum lipid molecular species, and that these lipid species may provide further clues about the early mechanisms and biomarkers associated with acquired obesity and related complications. In this paper we report the results of lipidomics analyses of 14 pairs of MZ twins highly discordant for obesity. We show that acquired obesity primarily relates to increases in lysophosphatidylcholines, constituents of an atherogenic lipid profile and decreases in ether phospholipids, lipids with anti-oxidative properties. Sphingomyelins with long chain fatty acids remain very similar in the weight-discordant co-twins. Subjects The participants were recruited from a population-based longitudinal survey of five consecutive birth cohorts (19751979) of twins, (...truncated)