Purmorphamine exerts anti-obesity effects by enhancing secretin-activated brown fat thermogenesis

Obesity necessitates effective therapeutics targeting energy-regulating pathways. Secretin (SCT) shows therapeutic promise but is limited by its short half-life and lack of potent agonists. We investigated purmorphamine, a small-molecule modulator of the SCT receptor (SCTR), for its ability to enhance the metabolic functions of SCT and promote weight loss. Chronic oral administration of purmorphamine reduced weight gain, improved glucose/lipid homeostasis, and increased energy expenditure in diet-induced obese mice of both sexes without suppressing daily food intake. Mechanistically, purmorphamine acts synergistically with SCT to amplify SCTR-cAMP-protein kinase A (PKA) signaling, stimulate lipolysis, and enhance mitochondrial respiration in mature brown adipocytes. Moreover, lentiviral SCTR knockdown eliminated the effect of purmorphamine in enhancing SCT-stimulated mitochondrial respiration and thermogenic gene expression. These findings demonstrate that purmorphamine promotes negative energy balance by potentiating SCT-activated brown adipose thermogenesis, establishing it as a promising therapeutic strategy against obesity.