A Nature-Derived Peptide Promotes Satiety Hormone Response and Weight Loss In Vivo

The global rise of obesity highlights the critical need for effective weight-management strategies. GLP-1 receptor agonists have transformed obesity care, yet gastrointestinal intolerance, high cost, and weight regain after discontinuation highlight the need for complementary, orally available options. An alternative is to stimulate the body’s own GLP-1 release through the nutrient-sensing GPCRs on enteroendocrine L cells that a meal engages. Using an AI-guided screen of common food proteins, we identified nature-derived peptides (NDPs): sequences native to edible proteins that were reproduced synthetically and engage these receptors. Unlike peptide drugs engineered for systemic exposure, NDPs are intended to act locally at the gut epithelium. Our lead, NDP-35 (from Coffea arabica), is a potent, selective GPR40 agonist (EC50 = 32.7 nM); in mice, it raised plasma GLP-1, GIP, and PYY while lowering hunger hormones, reproducing the coordinated satiety hormone response of a meal at minimal caloric cost. Over 28 days of oral dosing in diet-induced obese rats, NDP-35 reduced food intake and lowered body weight by ∼5%, versus a 3% gain in vehicle-treated animals; a subcutaneous semaglutide arm was included as a reference comparator and endpoint values were of similar magnitude to NDP-35. Terminal clinical chemistry and organ-weight markers showed no treatment-related changes over the dosing period. A structurally distinct peptide, NDP-45 (from banana), reproduced these effects. NDP-35 and NDP-45 are promising preclinical food-protein-derived peptide candidates that stimulate enteroendocrine hormone responses and reduce food intake and body weight in rodent models, warranting further evaluation as an oral approach to appetite and body-weight control.