TNF as a mediator of metabolic inflammation and body-brain interaction in obesity-driven neuroinflammation and neurodegeneration

Abstract

Body–brain interaction (BBI) plays a critical role in coordinating the communication between peripheral organs and the brain, contributing to the comorbidity of metabolic disorders and neurological disorders. In the context of obesity, one of the key mediators driving systemic and neuroinflammatory responses is the soluble form of tumor necrosis factor (TNF), which primarily signals through TNF receptor 1 (TNFR1) to regulate inflammation and cell death. In this review, we examine how TNF/TNFR1-mediated metabolic inflammation in obesity disrupts cellular homeostasis across multiple organ systems, including the brain. In peripheral tissues, TNF is overproduced and secreted by activated macrophages, leading to lipid dysmetabolism, insulin resistance, and metabolic dysfunction in key cell types such as adipocytes and hepatocytes. Elevated circulating TNF also increases the permeability of the blood–brain barrier, enabling peripheral inflammatory mediators to infiltrate the brain and activate glial cells, thereby amplifying neuroinflammation. Within the brain, TNF induces metabolic and autolysosomal dysfunction in neurons, resulting in elevated reactive oxygen species, accumulation of toxic protein aggregates, and impaired insulin signaling, contributing collectively to neuronal death and the progression of neurodegeneration. We further highlight the metabolic-inflammatory crosstalk within the BBI as a potential therapeutic target, focusing on anti-inflammatory strategies that modulate TNF/TNFR1 signaling. Lastly, we provide future perspectives on the implications of body–brain axes, cell type–specific mechanisms, and disease comorbidities in the context of obesity.