CHOP is dispensable for exercise-induced increases in GDF15

Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP homologous protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise, we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and Gdf15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP-deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole body level were intact in CHOP-deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP.NEW & NOTEWORTHY GDF15 is expressed in a wide range of tissues, is a marker of cellular stress, and has been shown to be regulated by the ER stress protein CHOP. Although exercise increases GDF15, the mechanisms mediating this effect have not been elucidated. Using various models of altered ER stress, we demonstrate that exercise-induced increases in GDF15 occur independent of ER stress/CHOP.