Editors' ChoiceObesity

Learning from cancer to promote weight loss

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Science Translational Medicine  20 Sep 2017:
Vol. 9, Issue 408, eaao6131
DOI: 10.1126/scitranslmed.aao6131


Growth differentiation factor 15 suppresses appetite and promotes weight loss by activating a receptor expressed in two brain regions.

Growth differentiation factor-15 (GDF15) is a protein associated with tumor-induced anorexia. First identified in mice with prostate tumors, concentrations of GDF15 were later found to correlate with BMI in patients with cancer. Administration of GDF15 to the brain of mice caused a decrease in body weight, and scientists proposed GDF15 as a centrally mediated weight loss drug target. Enthusiasm for this drug target was dampened by lack of knowledge of the mechanism of action and receptor targets.

Mullican and colleagues screened >4000 membrane proteins for binding with GDF15. Five hits were identified, but on further screening using fluorescence-activated cell sorting, only GDNF family receptor α–like (GFRAL) protein displayed specific binding to GDF15. GFRAL is an orphan receptor proposed to have a role in brain development. GFRAL alone, however, was not sufficient for the cell signaling effects of GDF15. The GDNF receptor family is known to form a complex with the coreceptor RET, and indeed cells overexpressing GFRAL treated with GDF15 had increased RET phosphorylation. RET mRNA depletion and chemical inhibition of RET tyrosine kinase activity both prevented GDF15-mediated signaling, confirming RET as a GFRAL coreceptor.

Mice with targeted deletions of Gfral had increased weight gain and worsened glucose intolerance when fed a high-fat diet and were resistant to the appetite suppressant effects of exogenous GDF15 administration. Researchers then fused recombinant human GDF15 to human serum albumin (HSA-GDF15) to extend the half-life of GDF15 to more than eight days. Nonhuman primates treated with a single dose of HSA-GDF15 had decreased food intake for two weeks. After four weeks’ exposure to HSA-GDF15, the monkeys had a dose-dependent weight loss of up to 4% of their body weight. In human brain sections, GDNF expression was localized to two areas of the brain: the area postrema and nucleus of the solitary tract. The area postrema is known as the brain’s “vomit center,” but clinically the monkeys did not demonstrate nausea or emesis.

The teams of Yang et al. and Emmerson et al. independently reached the same conclusions in simultaneously published studies. GDF15 and GFRAL are promising weight loss targets due to their specificity and ability to suppress appetite.

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