title: Ionizing Radiation Potentiates High-Fat Diet-Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells.
abstract: Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes later in life. We hypothesized that irradiation reprograms the epigenome of metabolic progenitor cells, which could account for impaired metabolism after cancer treatment. C57Bl/6 mice were treated with a single dose of irradiation and subjected to high-fat diet (HFD). RNA sequencing and reduced representation bisulfite sequencing were used to create transcriptomic and epigenomic profiles of preadipocytes and skeletal muscle satellite cells collected from irradiated mice. Mice subjected to total body irradiation showed alterations in glucose metabolism and, when challenged with HFD, marked hyperinsulinemia. Insulin signaling was chronically disrupted in skeletal muscle and adipose progenitor cells collected from irradiated mice and differentiated in culture. Epigenomic profiling of skeletal muscle and adipose progenitor cells from irradiated animals revealed substantial DNA methylation changes, notably for genes regulating the cell cycle, glucose/lipid metabolism, and expression of epigenetic modifiers. Our results show that total body irradiation alters intracellular signaling and epigenetic pathways regulating cell proliferation and differentiation of skeletal muscle and adipose progenitor cells and provide a possible mechanism by which irradiation used in cancer treatment increases the risk for metabolic disease later in life.
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Vibe
authors.initials: V
authors.lastname: Nylander
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars R
authors.initials: LR
authors.lastname: Ingerslev
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Emil
authors.initials: E
authors.lastname: Andersen
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Odile
authors.initials: O
authors.lastname: Fabre
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Garde
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Rasmussen
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kiymet
authors.initials: K
authors.lastname: Citirikkaya
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Josephine
authors.initials: J
authors.lastname: Bæk
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gitte L
authors.initials: GL
authors.lastname: Christensen
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Aznar
authors.affiliation: Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lena
authors.initials: L
authors.lastname: Specht
authors.affiliation: Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Simar
authors.affiliation: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark barres@sund.ku.dk.
authors.forename: Romain
authors.initials: R
authors.lastname: Barrès
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D019295:Computational Biology; D059305:Diet, High-Fat / Q000009:adverse effects*; D057890:Epigenomics; D015151:Immunoblotting; D007333:Insulin Resistance / Q000528:radiation effects; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA
chemical_list: D017382:Reactive Oxygen Species