Uniting GDF15 and GFRAL: Therapeutic Opportunities in Obesity and Beyond

GDF15 is a hormone that is broadly expressed and is considered a biomarker the circulation of which positively correlates with the progression of many diseases. GDF15 administration leads to decreased food intake and body weight in obese rodents and nonhuman primates. GFRAL, a distant relative of receptors for a distinct class of the TGFβ superfamily ligands, has recently been identified as the high-affinity receptor binding and mediating the anorectic effects of GDF15. GDF15 and GFRAL are promising therapeutic targets for the treatment of disorders of energy homeostasis, including obesity and anorexia. Growth differentiation factor-15 (GDF15) is a circulating protein that has been implicated in multiple biological processes, including energy homeostasis, body weight regulation, and cachexia driven by cancer and chronic disease. The potential to target GDF15 in the treatment of energy-intake disorders, including obesity and anorexia, is an area of intense investigation, but has been limited by the lack of an identified receptor, signaling mechanism, and target tissue. GDNF family receptor α-like (GFRAL) was recently identified as the neuronal brainstem receptor responsible for mediating the anorectic actions of GDF15. Herein, we provide a brief overview of GDF15 biology with a focus on energy homeostasis, and highlight the implications of the recent receptor identification to this field and beyond. Growth differentiation factor-15 (GDF15) is a circulating protein that has been implicated in multiple biological processes, including energy homeostasis, body weight regulation, and cachexia driven by cancer and chronic disease. The potential to target GDF15 in the treatment of energy-intake disorders, including obesity and anorexia, is an area of intense investigation, but has been limited by the lack of an identified receptor, signaling mechanism, and target tissue. GDNF family receptor α-like (GFRAL) was recently identified as the neuronal brainstem receptor responsible for mediating the anorectic actions of GDF15. Herein, we provide a brief overview of GDF15 biology with a focus on energy homeostasis, and highlight the implications of the recent receptor identification to this field and beyond. decreased food intake because of diminished appetite or aversion to food. medullary brainstem structure at the base of the fourth ventricle with permeable capillaries allowing exposure to constituent neurons to peptides and hormones of the peripheral circulation. Functions include autonomic regulation of various homeostatic processes, including feeding behavior. disease-associated multiorgan wasting syndrome driving severe weight loss associated with muscle atrophy and appetite suppression in patients not actively trying to lose weight. forebrain nucleus with a role in physiological and behavioral responses to fear, stress, and drug-related stimuli, including that of noxious agents, via signaling emanating from the brainstem. anatomical region within the AP implicated in sensing blood-borne drugs or hormones that induce vomiting. tail region of antibody that interacts with cell surface Fc receptors to activate the immune system. Fusion of peptides to a modified non-immunogenic IgG Fc increases the half-life of the fusion partner in drug discovery efforts. neonatal Fc receptor (FcRN) expressed on immune and epithelial cells. Upon cellular uptake, serum albumin and immunoglobulin G bind to FcRN, which transports this cargo back to the plasma membrane, ultimately releasing it extracellularly. This process allows albumin and IgG to bypass lysosomal degradation and has been exploited in drug discovery efforts. subgroup of TGFβ superfamily with known roles in neuronal development and function. Signaling is mediated by GDNF family receptors (GFRα1–4) complexed with RET receptor tyrosine kinase. peptide hormone made by intestinal enteroendocrine cells that has many metabolic roles, including modulation of feeding behavior via signaling through the GLP-1 receptor located within the AP and NTS. collection of nuclei within the forebrain that coordinate autonomic processes, including homeostatic regulation of sleep, body temperature, thirst, and hunger, and hormonal signaling from the nearby pituitary gland. adipose-derived hormone that functions as a long-term mediator of energy balance by suppressing food intake upon binding to the leptin receptor located within the NTS, AP, and hypothalamus. located within the hypothalamus and brainstem, agonists of this receptor inhibit food intake. located adjacent to the AP in the brainstem, this is the primary visceral sensory relay station within the brain receiving and responding to stimuli from the respiratory, cardiovascular, and gastrointestinal systems to control homeostatic processes, including feeding behavior. neuronal relay center anatomically located between the brainstem and viscerosensory and autonomic centers in the forebrain, including the central amygdala. Functions include taste processing and regulation of feeding. weight-loss surgery reducing the size of the stomach restricting the amount of food a patient can eat and bypassing the upper portion of the small intestine, thus decreasing nutrient absorption. Surgery-subsequent changes in gut hormones also contribute to weight loss. suppression of ongoing eating; a signal to end a meal. model used in oncology research harboring the Transgenic Adenocarcinoma of the Mouse Prostate transgene that develop progressive forms of prostate cancer with distant site metastasis. structurally related molecules the active moiety of which is a dimer formed through an intermolecular disulfide bond; interact with a conserved family of transmembrane receptors to elicit intracellular signaling and regulate many biological processes.