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GDF15 and its receptor GFRAL/RET form a non-homeostatic system that regulates food intake and body weight in preclinical species. Here, we describe a GDF15 analog, LY3463251, a potent agonist at the GFRAL/RET receptor with prolonged pharmacokinetics. In rodents and obese non-human primates, LY3463251 decreased food intake and body weight with no signs of malaise or emesis. In a first-in-human study in healthy participants, single subcutaneous LY3463251 injections showed a safety and pharmacokinetic profile supporting further clinical development with dose-dependent nausea and emesis in a subset of individuals. A subsequent 12-week multiple ascending dose study in overweight and obese participants showed that LY3463251 induced significant decreases in food intake and appetite scores associated with modest body weight reduction independent of nausea and emesis (clinicaltrials.gov : NCT03764774). These observations demonstrate that agonism of the GFRAL/RET system can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight-loss applications. [Display omitted] • LY3463251, a GDF15 fusion to monomeric IgG4-Fc, is a GFRAL/RET receptor agonist • LY3463251 decreased body weight in rodents and non-human primates • In humans, LY3463251 had prolonged PK and displayed an acceptable safety profile • LY3463251 dosed weekly in humans reduced food intake with a modest effect on body weight GDF15, a non-homeostatic regulator of food intake and body weight, has potential as a new therapeutic mechanism for obesity treatment. Here, Benichou et al. describe LY3463251 and its promising effects on food intake and body weight in rodents and non-human primates. However, findings in humans showed limited effect in lowering body weight. [ABSTRACT FROM AUTHOR]