4.7 Article

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

Journal

DIABETES
Volume 65, Issue 12, Pages 3573-3584

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db16-0364

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Funding

  1. European Foundation for the Study of Diabetes (EFSD Research Programme in Diabetes and Cancer)
  2. Novo Nordisk Foundation
  3. Danish Diabetes Academy
  4. Cancer Research UK [21133] Funding Source: researchfish
  5. NNF Center for Basic Metabolic Research [Barres Group] Funding Source: researchfish

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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. C57BI/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.

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