Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.

Claire Laurens ,Virginie Bourlier ,Geneviève Tavernier ,Coralie Fontaine ,Enda Murphy ,Claire Thalamas ,Fabrice Bertile ,Nathalie Boulet ,I Harant ,Donal J O'gorman ,Anne Bouloumié ,Nathalie Viguerie ,Pauline Maes ,Dominique Larrouy ,Isabelle De Glisezinski ,Julie Vion ,J L Grolleau ,Dominique Langin ,Émilie Montastier ,Deborah Carper ,Stéphane Blanc ,Anisha Parmar ,Benjamin Lair ,Marie-Adeline Marquès ,Sylvie Caspar-Bauguil ,Cédric Moro

doi:10.1172/jci.insight.131870

Abstract

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 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. CM and human plasma samples were analyzed using unbiased proteomic screening 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. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Highlights

Exercise improves metabolic health and prevents the complications of obesity and type 2 diabetes [1, 2]
We investigated the effect of recombinant human Growth and differentiation factor 15 (GDF15) protein on lipolysis in human abdominal adipose tissue explants. rhGDF15 significantly modestly increased lipolysis at the physiological concentration of 1 ng/ml (~10%, P < 0.05), reflected by both glycerol (Figure 5A) and NEFA release (Figure 5B)
We demonstrate that blocking GDF15 with a neutralizing IgG antibody of hGDF15 completely abrogates the lipolytic response of EPS24h Conditioned media (CM) (Figure 5E), indicating that GDF15 likely triggers most, if not all, the EPS24h CM lipolytic effect in human multipotent adipose-derived stem (hMADS) adipocytes

Summary

Introduction

Exercise improves metabolic health and prevents the complications of obesity and type 2 diabetes [1, 2] This is partly due to the release of secreted factors by skeletal muscle, i.e., myokines, which can virtually target all organs remotely [3]. In a previous clinical study, we observed a remarkably enhanced in situ and systemic lipolytic response in lean healthy endurance-trained subjects performing a high-intensity exercise the day after an exhaustive glycogen-depleting exercise compared with participants that rested [8]. This greater lipolytic response could not be explained by significant changes in classically known lipolytic stimuli, such as increased catecholamines, atrial natriuretic peptide, growth hormone, cortisol, and IL-6 or a decrease in circulating insulin during exercise. We hypothesized that skeletal muscle contraction in the context of acute high-intensity exercise and chronic moderate exercise may produce a cellular stress signal capable of increasing adipose tissue lipolysis to sustain fuel availability and delay muscle glycogen depletion

Methods

Results

Conclusion