Immunometabolic mechanisms of osteosarcopenic obesity: chronic inflammation, trained immunity, and systemic immune dysregulation

Osteosarcopenic obesity (OSO)-the co-occurrence of osteoporosis/osteopenia, sarcopenia, and excess adiposity-is increasingly recognized in ageing populations and is strongly linked to frailty, fractures, disability, and cardiometabolic complications. However, heterogeneous operational definitions and population-specific cut-offs complicate risk stratification and mechanistic inference. Here, we propose a systems immunometabolic framework to explain coordinated deterioration of adipose tissue, skeletal muscle, and bone, focusing on chronic low-grade inflammation, trained immunity (innate immune memory), and senescence-associated signaling. Dysfunctional visceral adipose tissue emerges as an immune-active endocrine organ that sustains low-grade systemic inflammation through release of cytokines, adipokines, lipotoxic mediators, and damage-associated molecular patterns. A key mechanism potentially underpinning inflammatory persistence is trained immunity-epigenetic and metabolic reprogramming of innate immune cells and their progenitors-which establishes maladaptive inflammatory memory and amplifies inter-organ immune crosstalk. In skeletal muscle, this pro-inflammatory milieu promotes catabolic signaling and anabolic resistance, including NF-κB activation and mTOR pathway dysregulation, thereby driving impaired proteostasis, fibrosis, and fatty infiltration. In bone, inflammatory and senescence-associated signals converge on osteoclastogenic pathways and disrupt the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) axis, leading to uncoupled bone remodeling and net bone loss. Collectively, we argue that OSO can be conceptualized as a fat-initiated, system-level immunometabolic remodeling process across the adipose-muscle-bone axis. This framework supports stratified, multimodal interventions combining lifestyle modification with mechanism-based anti-inflammatory and anti-resorptive therapies, while immuno-epigenetic and senescence-targeted approaches warrant further study. Notably, OSO-specific longitudinal and interventional evidence integrating immune phenotyping and multi-omics remains limited and is needed to test causality and validate actionable biomarkers and targets.