TNF and obesity due to melanocortin 4 receptor deficiency: In individuals with obesity, lipid droplet accumulation, FFAs, local hypoxia, and lipopolysaccharide all polarize macrophages to the M1 pro-inflammatory phenotype (or more specifically, metabolism-activated macrophage phenotype) 156, secreting enormous inflammatory cytokines including IL-6, IL-1β, and TNF-α, and acting as key mediators of inflammation in AT 155.