The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal research with no clinical trial data.
PubMed 28846098 · doi:10.1038/nm.4393
What was done
Researchers evaluated the orphan receptor GDNF-family receptor α-like (GFRAL) as a candidate receptor for growth/differentiation factor 15 (GDF15). The team assessed in vitro binding of GDF15 to GFRAL, tested the response to recombinant human GDF15 in Gfral knockout (Gfral -/-) mice compared to wild-type controls, evaluated an anti-GFRAL monoclonal antibody in rats treated with GDF15, and mapped Gfral mRNA expression in mouse, rat, and monkey brain tissue.
What was found
GFRAL bound to GDF15 with high affinity in vitro. In vivo, Gfral -/- mice were completely refractory to the body-weight, food-intake, and glucose-modulating effects of recombinant human GDF15. In rats, treatment with a monoclonal antibody targeting the GDF15-GFRAL interaction blocked GDF15-mediated metabolic effects. Gfral mRNA expression was localized to the area postrema across mouse, rat, and monkey brain samples. The abstract reports no numerical values, effect sizes, or confidence intervals.
Why it matters
Identifying GFRAL as the central receptor for GDF15 resolves the mechanism by which GDF15 controls energy intake and body weight, providing a specific target for therapies aimed at obesity, diabetes, or cancer cachexia.
Limits
All findings are restricted to in vitro assays and animal models (mice, rats, and tissue from monkeys); no clinical data in humans were collected. Specific sample sizes, effect magnitudes, and quantitative variance measures were omitted from the abstract.
Cited by
- supports Receptors for GDF15 are localized exclusively in the brain, while GDF15 itself is synthesized by non-brain peripheral tissues and tumors.