TY - JOUR

T1 - Ionizing Radiation Potentiates High Fat Diet-Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells

AU - Nylander, Vibe

AU - Ingerslev, Lars R

AU - Andersen, Emil

AU - Fabre, Odile

AU - Garde, Christian

AU - Rasmussen, Morten

AU - Citirikkaya, Kiymet

AU - Bæk, Josephine

AU - Christensen, Gitte L

AU - Aznar, Marianne

AU - Specht, Lena

AU - Simar, David

AU - Barrès, Romain

N1 - © 2016 by the American Diabetes Association.

PY - 2016/9/20

Y1 - 2016/9/20

N2 - 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.

AB - 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.

U2 - 10.2337/db16-0364

DO - 10.2337/db16-0364

M3 - Journal article

C2 - 27650856

VL - 65

SP - 3573

EP - 3584

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 12

ER -