Frontiers in Immunology · Oct 30, 2026
Pathological mechanisms of the 'lifestyle–immunometabolic–neuroendocrine' crosstalk network in ectopic fat deposition and skeletal muscle decline
By Manli Yan, Zhiping Wang, Zhilin Ge et al.
Chronic low-grade systemic inflammation serves as a pivotal pathological link coupling unhealthy lifestyles with malignant remodeling of body composition. This review systematically constructs and elucidates the molecular mechanisms and pathological progression of the "lifestyle–immunometabolic–neuroendocrine" crosstalk network in ectopic fat deposition and skeletal muscle decline. Upstream multidimensional lifestyle stressors—including unhealthy diets, sleep deprivation, psychological stress, and sedentary behavior—disrupt the gut barrier, endocrine barriers, and mechanical contractile strain, thereby initiating immunometabolic reprogramming and triggering systemic chronic low-grade sterile inflammation. Acting as a core pathological driver, this low-grade inflammation impairs lipid and protein homeostasis, propels lipotoxic spillover and intramyocellular fat infiltration, and ultimately leads to the progressive decline of skeletal muscle mass and function. Concurrently, age-related neuroendocrine axis decline and dwindling sex hormone levels function as endogenous amplifiers, synergistically accelerating tissue microenvironmental remodeling and body composition imbalance in a distinctly dimorphic manner (e.g., postmenopausal estrogen deficiency accelerates muscle deterioration by inducing autophagy dysfunction in muscle stem cells). A deep mechanistic parsing of the regulatory nodes within this multidimensional network provides substantial academic value for deciphering the onset and progression of lifestyle-driven chronic inflammatory disorders.