GDF15 Induces Anorexia through Nausea and Emesis

• Published in: Cell metabolism Vol. 31; no. 2; pp. 351 - 362.e5
• Main Authors: Borner, Tito, Shaulson, Evan D., Ghidewon, Misgana Y., Barnett, Amanda B., Horn, Charles C., Doyle, Robert P., Grill, Harvey J., Hayes, Matthew R., De Jonghe, Bart C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2020
• Subjects: anorexia; chemotherapy; emesis; GDF15; GFRAL; malaise; MIC-1; nausea; obesity; Suncus murinus; MIC-1; anorexia; GDF15; GFRAL; Suncus murinus; emesis; chemotherapy; malaise; obesity; nausea
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.12.004

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry. [Display omitted] •Chemotherapy-induced sickness involves GDF15•GDF15-GFRAL signaling causes emesis and nausea that precede the onset of anorexia•Anorexia triggered by GDF15 is associated with sickness in both lean and obese rats•GDF15-induced anorexia cannot be dissociated from GDF15-induced sickness This work assesses whether or not GDF15 produces emesis and/or emetic-like behaviors in the vomiting shrew (Suncus murinus) and non-vomiting rat. The results suggest that exogenous delivery of GDF15 produces either emesis or emetic-like behavior (i.e., pica) prior to the induction of anorexia in shrews and rats, respectively.