Maladaptive trained immunity of adipose tissue macrophages unraveling the link to obesity, T2DM, and beyond.

Maladaptive trained immunity and associated chronic low-grade inflammation contribute to metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and cardiometabolic disorders. The heterogeneity and plasticity of adipose tissue macrophages (ATMs) are essential for preserving adipose tissue (AT) homeostasis. The obese AT microenvironment trains ATMs to undergo adaptive changes, especially transition to a maladaptive state, and exacerbates the inflammation associated with obesity and T2DM. This review focuses on the pivotal role of ATMs in propagating local inflammation from AT to distant organs, a process that is central to the systemic effects of obesity. In addition, we emphasize the potential of targeted therapeutic interventions that leverage the axes of maladaptive trained immunity. The advancement of interleukin-1β and NLR family pyrin domain containing 3 targeted agents represents an innovative and promising research frontier, with the potential to transform immunotherapy for metabolic disorders.