Central mechanisms of emesis: A role for GDF15

Abstract

Background: Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity.

Purpose: This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.

Keywords: CINV; GDF15; GFRAL; emesis; hyperemesis; malaise; nausea; vomiting.

FIGURE 1

Overview of the GDF15/GFRAL system in the central mediation of nausea and emesis. Circulating GDF15 levels are elevated in various medical conditions, including cancer, treatment with chemotherapeutic agents, exposure to toxins, pregnancy, and mitochondrial stress/dysfunctions. Bloodborne GDF15 can directly reach the area postrema (AP), the nucleus tractus solitarius (NTS), which are key hindbrain structures for the mediation of nausea and emesis. Within the AP/NTS there is a unique neuronal population which co‐expresses both the GDF15 receptor, GDNF family receptor α‐like (GFRAL) and its co‐receptor rearranged during transfection (RET) tyrosine kinase. Upon GDF15 binding to GFRAL, GFRAL conformational changes occurs that facilitates the dimerization of RET, leading to the subsequent phosphorylation (i.e., activation) of several downstream effectors (protein kinase B [Akt], extracellular signal‐related kinase ½ [Erk1/2] and phosphoinositide‐specific phospholipase C [PLC]) that ultimately alter neuronal activity and gene expression profile. Consequently, this activation extends to other upstream central targets implicated in regulation of anorexia, nausea and emesis (e.g., the parabrachial nucleus [PBN] and central nucleus of the amygdala [CeA]).