Dynamic regulation of IL-33 in the obesity pathogenesis: Spatiotemporal specificity and functional paradoxes

Obesity is a complex chronic metabolic disease closely associated with inflammatory responses and insulin resistance. As a member of the IL-1 cytokine family, Interleukin-33(IL-33) binds to its receptor suppression of tumorigenicity 2 (ST2) and plays a crucial role in regulating the adipose tissue immune microenvironment and maintaining metabolic homeostasis. However, its role in obesity exhibits spatiotemporal specificity and functional paradoxes. Under physiological conditions, IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s), promoting anti-inflammatory factors secretion and adipose thermogenesis to maintain metabolic homeostasis. In obesity, despite increased IL-33 expression in obese adipose tissue, its protective effects are impaired by effector cell dysfunction, sST2-mediated neutralization, and non-classical pathway activation, collectively termed the “expression-function paradox”. Notably, IL-33 exhibits tissue-specific effects in distinct organs, including adipose tissue, cardiac tissue, liver and lungs under obese conditions. This review systematically analyzes the spatiotemporal regulatory mechanisms, functional paradoxes, and therapeutic potential of IL-33 in obesity, offering new insights for targeting obesity and related metabolic disorders.