Editors' ChoicePhysiology

Protection from vomiting and β-cell death

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Science Signaling  03 Mar 2020:
Vol. 13, Issue 621, eabb4981
DOI: 10.1126/scisignal.abb4981

The roles of the cytokine GDF15 in emesis and inflammation-induced pancreatic β-cell death are elucidated.

Growth differentiation factor 15 (GDF15) is a widely distributed cytokine, and its role in two different systems was explored in a pair of papers. GDF15 and its receptor GFRAL-RET (GDNF family receptor α-like; GFRAL) have been proposed as targets for anti-obesity treatments, and GFRAL-deficient mice do not develop anorexia or lose weight when treated with the chemotherapeutic cisplatin, an emetic (a substance that causes vomiting). Borner et al. investigated the relationship between the anorexic and emetic effects of GDF15. They found that mice injected with cisplatin had increased circulating concentrations of GDF15, which was produced in the liver, and showed activation of GFRAL-positive neurons in the brain. Intracerebroventricular infusion of GDF15 into rats induced anorexia and a behavior that is a proxy for nausea. The serotonin receptor antagonist Ondansetron is given to patients receiving cisplatin to combat its emetic effects, and administration of this drug suppressed anorexia but not the nausea-proxy behavior. In rats that were obese due to a high-fat and sucrose diet and given GDF15 centrally or systemically, the appearance of the nausea-proxy behavior preceded decreased food intake. Injection of GDF15 into musk shrews induced vomiting, and GDF15-treated musk shrews ate less food and lost weight. These results suggest that blockade of GFRAL could be an anti-emetic treatment and that GFRAL agonists may not be desirable as anti-obesity treatments because they would be expected to induce nausea.

In the second paper, Nakayasu et al. searched for cytokines that are regulated by the inflammatory signals that promote the progression of type 1 diabetes. These authors treated pancreatic islets from nondiabetic cadaveric donors with the proinflammatory cytokines interleukin-1β (IL-1β) and IFN-γ. Their proteomics analysis of the treated pancreatic islets resulted in the identification of GDF15 as a cytokine that was suppressed by IL-1β and IFN-γ due to a block in the translation of its mRNA. IL-1β and IFN-γ decreased GDF15 abundance in EndoC-βH1 human β-cells and mouse MIN6 β-cells. Furthermore, in nonobese diabetic (NOD) mice, which are a model of autoimmune diabetes, the abundance of GDF15 was decreased in mice with insulitis (immune cell infiltration into the pancreas). Application of GDF15 to EndoC-βH1 or MIN6 cells or human islets attenuated cell death triggered by IL-1β and IFN-γ, and treatment of NOD mice with GDF15 before the development of hyperglycemia decreased insulitis and the incidence of diabetes. GDF15 protein abundance was reduced in pancreases from donors with type 1 diabetes (T1D) compared with those from normal donors or from patients with T2D. These results suggest that GDF15 is a factor that protects pancreatic β-cells from inflammation-induced cell death and could be targeted to limit the progression of T1D.

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