GDF15 is a circulating divergent TGFb superfamily cytokine, most closely linked to the GDNFs. It is implicated in multiple biological processes including energy homeostasis, body weight and adiposity regulation, inflammatory diseases and cancer. It is overproduced in advanced cancer, causing anorexia/cachexia syndrome, mediated at least in large part by its actions on the brainstem appetite control centres, where its recently described receptor, glial derived neurotrophic factor receptor alpha like (GFRAL) is dominantly expressed. Preclinical studies suggest that therapeutics based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is less clear.
To investigate the physiological role of GDF15 in obese metabolism, we commenced mice concurrently on a HFD and administered a neutralising GDF15 monoclonal antibody. Mice treated with antibody displayed more rapid gain of body weight, adiposity and hepatic lipid deposition, which was accompanied by worsening of glucose metabolism and greater expression of adipose tissue pro-inflammatory cytokines.
To demonstrate the critical role of brainstem GFRAL-expressing neurons in the metabolic effect of physiological GDF15, we injected AAV-shControl or AAV-shGFRAL selectively into the area postrema (AP) and the nucleus of the solitary tract (NTS), and one week later commenced mice on a HFD. In these mice, the increase in body weight and adiposity were in direct proportion to the effectiveness of GFRAL knockdown. This data indicates that this region is crucial for the action of GDF15. We conclude that the GDF15–GFRAL axis plays an important role in resistance to obesity in HFD fed mice and that the major site of action of GDF15 is GFRAL expressing neurons in the AP and NTS.