title: Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity.
abstract: Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.
authors.affiliation: Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Mette J
authors.initials: MJ
authors.lastname: Jacobsen
authors.affiliation: Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Caroline M Junker
authors.initials: CM
authors.lastname: Mentzel
authors.affiliation: Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Ann Sofie
authors.initials: AS
authors.lastname: Olesen
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S 1166, Integrative Biology of Atherosclerosis Team, 75013 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.affiliation: Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Claus B
authors.initials: CB
authors.lastname: Jørgensen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Romain
authors.initials: R
authors.lastname: Barrès
authors.affiliation: Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
authors.forename: Merete
authors.initials: M
authors.lastname: Fredholm
authors.affiliation: Inflammation and Infection Research, School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: David
authors.identifier: 0000-0002-3862-1932
authors.initials: D
authors.lastname: Simar
mesh_terms: D050154:Adiposity; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000097:blood*; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000378:metabolism*; D008055:Lipids / Q000097:blood*; D008297:Male; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000276:immunology; D015434:Panniculitis / Q000097:blood / Q000235:genetics* / Q000276:immunology; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D008055:Lipids