Total and Intact GDF-15 Increase with Caloric Deprivation Independently of Leptin and are Associated with Starvationinduced Metabolomic Responses

Growth differentiation factor 15 (GDF-15) is a stress-response cytokine expressed in various tissues including the liver, skeletal muscle, heart, kidney, and adipose tissue that has been proposed to have a role in several metabolic processes such as weight balance, obesity, diabetes, as well as anorexia, and cachexia. However, GDF-15’s role remains unclear largely due to genetic variants that may not be detected by the current assays and/or may interfere with the molecule’s bioactivity. We utilized two novel assays to measure intact (H202D allele non-detectable) and total (measured irrespectively of the allele presence) GDF-15 and evaluate their role in response to acute and chronic energy deprivation in humans. In this study, total and intact GDF-15 increased significantly in response to acute complete fasting in healthy controls, and total GDF-15 was higher by 70% in subjects with chronic mild caloric deficit due to relative energy deficiency in sports (RED-S) compared to controls, in a leptin independent manner. In addition, GDF-15 was positively correlated with very low-density lipoproteins (VLDLs), fatty-acids and ketone-bodies at baseline. No significant differences were detected between subjects with and without the variant at baseline. Still, principal component analyses suggest possible differential effects and bioactivity of intact and total GDF-15 during metabolic stress that need to be tested by future more extensive studies. In conclusion, total and intact GDF-15 increase as metabolic stress-related molecules in complete acute fasting and chronic mild caloric deprivation; and are independent of leptin as its administration does not change or restore their levels to normal.