Elevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patients

Growth and differentiation factor 15 (GDF15) is a significant player in cellular stress and energy homeostasis. GDF15 is elevated in cancer cachexia, chemotherapy-induced anorexia, hyperemesis gravidarum, and mitochondrial disorders. Here we analyze GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by low weight and persistent restriction of food intake. While no significant difference in plasma GDF15 concentration was seen across the three included groups; active AN, recovered AN, and healthy controls, a subgroup of study participants with high GDF15 plasma was noted to a significantly higher extent in the AN groups. Sparse partial least squares discriminant analysis (sPLS-DA) identified six markers related to inflammatory processes or cellular stress from a set of 74 markers that distinguished AN with high GDF15 from the rest, with fibroblast growth factor 21 (FGF21) being the most important contributor. Moreover, FGF21 plasma concentration was significantly higher in the group with high GDF15, suggesting an involvement of mitochondrial dysfunction. In fact, mitochondrial polygenic risk score (PRS) was significantly associated with AN risk in a large AN case-control cohort. In line with this, we also report elevated liver expression of GDF15 in the anx/anx mouse displaying anorexia associated with mitochondrial dysfunction. We conclude that mitochondrial dysfunction should be further explored in AN. Clinical trials of GDF15 immunoneutralization in patients with AN and high levels of GDF15 are worthy of consideration.