REVIEW article
Front. Immunol.
Sec. Inflammation
Current Understanding and Advances Regarding the Adipose-Immune-Metabolic Axis in Disease Tolerance During Sepsis
Provisionally accepted
- The Second People's Hospital of Quzhou, Quzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Keywords: Adipo-Immune-MetabolicAxis, disease tolerance, Lipid Metabolism, Lipolysis, Sepsis
Received: 27 Nov 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 Du, He, Zhang, Lan, Pan and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jiajun Wang
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.