GDF15 Induces Anorexia through Nausea and Emesis

Tito Borner; Evan D Shaulson; Misgana Y Ghidewon; Amanda B Barnett; Charles C Horn; Robert P Doyle; Harvey J Grill; Matthew R Hayes; Bart C De Jonghe

doi:10.1016/j.cmet.2019.12.004

GDF15 Induces Anorexia through Nausea and Emesis

Cell Metab. 2020 Feb 4;31(2):351-362.e5. doi: 10.1016/j.cmet.2019.12.004. Epub 2020 Jan 9.

Authors

Tito Borner¹, Evan D Shaulson¹, Misgana Y Ghidewon², Amanda B Barnett¹, Charles C Horn³, Robert P Doyle⁴, Harvey J Grill⁵, Matthew R Hayes⁶, Bart C De Jonghe⁷

Affiliations

¹ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA.
² School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁴ Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY 13244, USA.
⁵ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bartd@nursing.upenn.edu.

Abstract

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.

Keywords: GDF15; GFRAL; MIC-1; Suncus murinus; anorexia; chemotherapy; emesis; malaise; nausea; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anorexia / chemically induced*
Body Weight / drug effects*
Female
Growth Differentiation Factor 15* / administration & dosage
Growth Differentiation Factor 15* / adverse effects
Humans
Hypoglycemic Agents* / administration & dosage
Hypoglycemic Agents* / adverse effects
Male
Mice
Mice, Inbred C57BL
Nausea / chemically induced*
Rats
Rats, Sprague-Dawley
Recombinant Proteins / administration & dosage
Recombinant Proteins / adverse effects
Shrews
Vomiting / chemically induced*

Substances

GDF15 protein, human
Growth Differentiation Factor 15
Hypoglycemic Agents
Recombinant Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding