Growth and Differentiation Factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans

We hypothesized that skeletal muscle contraction produces a cellular stress signal triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying novel exercise-regulated myokines, also known as exerkines, able to promote lipolysis.Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. Conditioned media and human plasma samples were analyzed using unbiased proteomic and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples.CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes (1.3 to 8 fold, p<0.001). Growth and Differentiation Factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was up-regulated in CM from both acute and chronic exercise-stimulated myotubes. We further show that physiological concentrations of recombinant GDF15 protein increase lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogates EPS CM-mediated lipolysis.We herein provide the first evidence that GDF15 is a novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.