Longevity & AgingHow Obesity Hijacks TNF Signaling to Inflame and Degenerate the Brain
Obesity triggers chronic overproduction of tumor necrosis factor (TNF) from adipose tissue macrophages and other peripheral organs. This soluble cytokine primarily signals through TNFR1 to drive insulin resistance, lipid dysmetabolism, and cell death in adipocytes and hepatocytes. Elevated circulating TNF also increases blood-brain barrier permeability, allowing inflammatory mediators to enter the brain, activate glial cells, and amplify neuroinflammation. Inside neurons, TNF/TNFR1 signaling disrupts autophagy, mitochondrial function, and insulin signaling, promoting toxic protein aggregation and necroptotic death—mechanisms implicated in Alzheimer's, Parkinson's, and multiple sclerosis. The review positions TNF as a central body-brain communication hub and highlights anti-TNF/TNFR1 strategies as promising therapeutic targets.
