KPV attenuates adipogenesis and lipid metabolism through modulation of ROS-mediated AKT/mTORC1/PPARγ signaling.

Lysine-Proline-Valine (KPV), an endogenous tripeptide derived from α-melanocyte-stimulating hormone, has been recognized for its anti-inflammatory and antioxidant activities. However, its role in adipocyte differentiation has not been investigated. In this study, we investigated the regulatory effects of KPV on MDI-induced adipocyte differentiation in 3T3-L1 preadipocytes. KPV treatment dose-dependently suppressed adipocyte differentiation. Specifically, treatment with 100 μg/mL KPV reduced Oil Red O staining intensity by approximately 55% and intracellular triglyceride content by approximately 38% compared with the MDI-treated group. In addition, KPV decreased the expression of key adipogenic markers, including peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS). Mechanistically, KPV attenuated reactive oxygen species (ROS) production and was associated with reduced AKT-dependent mTOR signaling and altered PPARγ phosphorylation during adipocyte differentiation. This regulatory effect was accompanied by suppression of FAS expression. In addition, in a high-fat diet-induced obesity mouse model, oral administration of KPV alleviated body weight gain, white adipose tissue expansion, liver mass increase, and obesity-associated dyslipidemia, including elevated plasma total cholesterol levels. Collectively, these findings suggest that KPV suppresses adipocyte differentiation, at least in part, in association with the modulation of ROS-related AKT/mTOR/PPARγ signaling in vitro, while its in vivo administration mitigates diet-induced obesity-related metabolic alterations. These results highlight the potential of KPV as an endogenous peptide-based candidate for the prevention and management of obesity.