Current understanding and advances regarding the adipose-immune-metabolic axis in disease tolerance during sepsis

Sepsis remains a critical global health challenge characterized by high mortality and morbidity, primarily due to the limitations of current pathogen-centric therapies and a poor understanding of host-defense mechanisms. This review synthesizes the pivotal role of the adipose-immune-metabolic axis as a central regulator of disease tolerance-a host defense strategy that limits tissue damage without directly reducing pathogen load. We delineate how adipose tissue is reprogrammed from a passive energy reservoir into an active immunometabolic hub during sepsis. This functional shift is governed by three core hypotheses: "Metabolic Defense Priority," which describes the preferential mobilization of fat to spare skeletal muscle protein; "Bidirectional Immunometabolic Crosstalk," wherein immune cells such as macrophages and B cells precisely regulate lipolysis via specific cytokine signals (e.g., IL-1β and TGF-β); and "Stage-Specific Adaptation," which outlines the dynamic evolution of axis function from the acute to chronic phases of sepsis. We further dissect key molecular pathways, including the Insulin-INSR-Thermogenesis, TGFβ-PDE3b-cAMP, and STING-ER Stress-mtROS axes, that orchestrate this complex interplay. Finally, we discuss contemporary challenges in mechanistic understanding, model translatability, and clinical translation, while proposing future directions to leverage this axis for developing novel, tolerance-based therapeutic strategies to improve sepsis outcomes.