Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans

• Published in: Nature communications Vol. 15; no. 1; pp. 5190 - 15
• Main Authors: Chrysafi, Pavlina, Valenzuela-Vallejo, Laura, Stefanakis, Konstantinos, Kelesidis, Theodoros, Connelly, Margery A., Mantzoros, Christos S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/443/319/1557; 692/163/2743/348; Adult; Animals; Deprivation; Energy; Energy balance; Energy Metabolism; Energy requirements; Female; Genetic diversity; Genetic variance; Growth Differentiation Factor 15 - blood; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Leptin; Leptin - blood; Leptin - metabolism; Lipid metabolism; Lipids; Lipoproteins; Male; Metabolism; Metabolites; Middle Aged; multidisciplinary; Science; Science (multidisciplinary); Starvation - metabolism; Stress response; Stress, Physiological; Triglycerides; Weight; Weight loss; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49366-y

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response. GDF15 is secreted my mitochondria and promotes weight loss in animals, but its effect in humans remain unclear. Here, they authors show that in humans, GDG15 is increase in females with chronic caloric deficit, independent of leptin levels, and that it’s positively correlated with triglyceride-rich particiles.