Ionizing Radiation Potentiates High-Fat Diet-Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells

Diabetes. 2016 Dec;65(12):3573-3584. doi: 10.2337/db16-0364. Epub 2016 Sep 20.


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.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Body Weight / drug effects
  • Body Weight / radiation effects
  • Cells, Cultured
  • Computational Biology
  • Diet, High-Fat / adverse effects*
  • Epigenomics
  • Immunoblotting
  • Insulin Resistance / radiation effects
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Radiation, Ionizing*
  • Reactive Oxygen Species
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, RNA


  • Reactive Oxygen Species