The immunometabolic network in obesity-associated insulin resistance: a systemic multi-organ and multi-cellular perspective.

Obesity has escalated into a global pandemic, encompassing chronic low-grade inflammation-termed "meta-inflammation"-as a central pathophysiological nexus linking nutrient excess to insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cardiovascular complications. While adipose tissue was historically viewed as the primary origin of inflammation, accumulating evidence indicates that metabolic perturbation involves a broader and more intricate cross-organ immunometabolic network. This review provides a comprehensive synthesis of the mechanisms underlying obesity-induced IR from a systemic multi-organ and multi-cellular perspective. We elaborate on the infiltration dynamics and phenotypic remodeling of both innate and adaptive immune cells (including macrophages, T cells, B cells, and neutrophils) across critical metabolic tissues, including adipose tissue, liver, skeletal muscle, pancreatic islets, and the central nervous system (CNS). Furthermore, we dissect the remote regulation of systemic immune tone by the gut microbiota and its metabolites via the "gut-liver" and "gut-brain" axes. Crucially, this review highlights the pivotal molecular hubs bridging metabolism and immunity, with a focus on the crosstalk involving PI3K/AKT, MAPK, TLR4/NF-κB, NLRP3 inflammasome, and AMPK/mTOR signaling pathways, as well as inter-organ communication mediated by extracellular vesicles (EVs) and chemokines. This dysregulated immune-metabolic interplay establishes a self-reinforcing vicious cycle that persistently impairs insulin signaling. By integrating current mechanistic insights, we aim to underscore the therapeutic potential of targeting the immunometabolic network, offering precise intervention strategies to disrupt this vicious cycle and restore systemic metabolic homeostasis.