Luteolin, as a bidirectional ROS regulator, elevates mouse beige adipocyte browning

Abstract

In beige adipocytes, UCP1-dependent thermogenesis can be driven by intracellular reactive oxygen species (ROS) generation. While ROS elevation also induces mast cell activation, serotonin synthesis and release from mast cells inhibits beige progenitor cell proliferation and browning. As a natural antioxidant and mast cell stabilizer, luteolin promotes adipocyte thermogenesis and inhibits mast cell activation. Thus, to activate adipocyte thermogenesis, how luteolin regulates ROS level in beige adipocytes and mast cells needs to be further investigated. In this study, mouse subcutaneous stromal vascular fraction (SVF) cells are induced to differentiate into beige adipocytes, and mouse bone marrow-derived mast cells (BMMCs) are activated with hydrogen peroxide (H₂O₂). Intracellular ROS level is augmented in differentiated beige adipocytes and H₂O₂-activated BMMCs, and H₂O₂-activated BMMCs inhibited brown differentiation of SVF cells and thermogenesis of beige adipocytes. In beige adipocytes, unlike synthetic antioxidant N-acetylcysteine (NAC), luteolin elevates the expression of thermogenic and beige-selective marker genes and intracellular ROS generation. Contrarily, luteolin inhibits H₂O₂-induced mast cell activation and ROS generation. Further, luteolin partially reverses the inhibitory effects of H₂O₂-activated BMMCs on the brown differentiation of SVF cells and the thermogenesis of beige adipocytes. Molecular mechanistic studies demonstrate that luteolin regulates intracellular ROS level in beige adipocytes and mast cells via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Catalase pathway. Altogether, as a ROS regulator, luteolin contrarily affects intracellular ROS generation in beige adipocytes and mast cells, and hence elevates adipocyte browning.