GDF15 is dispensable for the insulin-sensitizing effects of chronic exercise

Growth and differentiation factor 15 (GDF15) has recently emerged as a weight loss and insulin-sensitizing factor. Growing evidence also supports a role for GDF15 as a physiological, exercise-induced stress signal. Here, we tested whether GDF15 is required for the insulin-sensitizing effects of exercise in mice and humans. At baseline, both under a standard nutritional state and high-fat feeding, GDF15 knockout (KO) mice display normal glucose tolerance, systemic insulin sensitivity, maximal speed, and endurance running capacity when compared to wild-type littermates independent of sex. When submitted to a 4-week exercise training program, both lean and obese wild-type and GDF15 KO mice similarly improve their endurance running capacity, glucose tolerance, systemic insulin sensitivity, and peripheral glucose uptake. Insulin-sensitizing effects of exercise training were also unrelated to changes in plasma GDF15 in humans. In summary, we here show that GDF15 is dispensable for the insulin-sensitizing effects of chronic exercise. [Display omitted] •GDF15 deficiency has no effect on glucose homeostasis in mice irrespective of sex•GDF15 is not required for the insulin-sensitizing effects of chronic exercise•Plasma GDF15 negatively correlates with insulin sensitivity in humans with obesity•Changes in plasma GDF15 and insulin sensitivity with chronic exercise are unrelated Labour et al. demonstrate that the exerkine growth and differentiation factor 15 (GDF15) produced during exercise is dispensable for the insulin-sensitizing effects of chronic exercise both in lean and obese mice and in humans with obesity.