Macrophage-mediated inflammation in metabolic disease

Abstract

Inflammation is a pathogenic link between obesity and insulin resistance. Adipose tissue macrophages display characteristics ranging from alternative to classical, and these reflect the nutritional state of the organism. Obesity leads to the recruitment of CCR2⁺LY6C⁺ monocytes, which give rise to pro-inflammatory, classically activated macrophages in white adipose tissue. Saturated fatty acids, potentially acting via Toll-like receptor 4, drive classical macrophage activation in the obese state. Alternatively activated macrophages populate lean adipose tissue and are associated with insulin sensitivity. Eosinophil-derived interleukin-4 supports alternative activation of adipose tissue macrophages to promote insulin sensitivity. Peroxisome proliferator-activated receptor-γ (PPARγ) and PPARδ, acting as fatty acid sensors in macrophages, cooperate with signal transducer and activator of transcription 6 and Krüppel-like factor 4 to sustain alternative macrophage activation. Chronic overnutrition results in the activation of adaptive immune responses, which synergize with macrophage-mediated inflammation to promote insulin resistance.