The dairy-derived peptide Miltin exerts anti-obesity effects by increasing adipocyte thermogenesis

Growing research has highlighted that the consumption of dairy products improves the metabolic health in obese individuals by functioning as regulatory modulators. However, the molecular basis of this effect remains largely unknown. Herein, we report a dairy-derived peptide, which we named Miltin, that activates the thermogenesis of brown adipocytes and increases white adipocyte browning. Previously, Miltin was merely identified for its antioxidant capacity, although it is commonly present in different dairy products. In this study, we revealed the effect of Miltin in modulating adipose thermogenesis and further explored its potential in treating obesity through in vivo and in vitro strategies. The administration of Miltin in mice fed with a high-fat diet resulted in enhanced thermogenesis, improved glucose homeostasis, and reduced body mass and lipid accumulation, indicating the anti-obesity effect of Miltin. Genomic analysis revealed that Miltin modulates thermogenesis by inducing the activation of the MAPK signaling pathway by preferentially interacting with GADD45 gamma to promote its stability. Together, our findings indicate that Miltin's role in initiating the thermogenesis of adipocytes makes it a potential anti-obesity therapy for future development. Miltin, a dairy-derived peptide, activates the thermogenic programs in brown and white adipocytes by directly interacting with GADD45r.