Through a combination of pharmacological, in vivo mouse model, and ex vivo brain explant studies, we demonstrated that the green leaf Rubisco-derived bioactive peptide YHIEPV acted on the hypothalamic metabolic circuitry to increase leptin responsiveness and protect against dietary obesity by inhibiting Epac-Rap1 signaling in the brain. The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.