GDF15-GFRAL signalling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis

Body weight loss is robustly associated with severe symptomatology and poor survival in Amyotrophic Lateral Sclerosis (ALS). Growth differentiation factor 15 (GDF15) regulates body weight under several pathological conditions, including cancer and metabolic disorders, acting through GDNF family receptor alpha-like (GFRAL). Our study reports sustained GDF15 levels in the serum of ALS patients and hSOD1G93A mice, together with the upregulation of GFRAL in the brainstem of our mouse model. Focal injection of GFRAL-shRNA in the AP/NTS delays body weight loss, modulating food intake and reducing adipose tissue wasting, with beneficial effects on motor function and survival. Moreover, we describe how microglia could partly regulate GDF15-GFRAL pathway since their depletion with PLX5622 decreases GDF15 levels in the brainstem, reducing body weight loss and the expression of lipolysis-associated genes in iWAT. Together, our results show how GDF15-GFRAL signalling plays a key role in ALS progression and symptomatology, regulating weight loss and lipid metabolism.