Convergence of Systemic and Cellular Immunometabolism

Figure: Example of systemic and intrinsic immunometabolic convergence

Lean adipose tissue is characterized by an enrichment of anti-inflammatory immune cells whose phenotype is driven by metabolic changes induced by the adipose microenvironment. Adipose tissue lipids bind to PPARg in regulatory T cells and alternatively activated (anti-inflammatory) macrophages and promote a regulatory program associated with oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Overfeeding and obesity induce multiple changes in the adipose microenvironment that can alter the metabolic program of adipose-resident immune cells and promote inflammation. Reduced oxygen levels can induce HIF-1a expression and a glycolytic program, which can shift the balance away from regulatory T cells and toward pathogenic Th17 cells. Free fatty acids from ruptured adipocytes can induce pro-inflammatory macrophage polarization through TLR signaling. Additionally, signaling from proinflammatory cytokines such as TNF and IFNγ can shift macrophage metabolism toward glycolysis, which further promotes their pro-inflammatory properties. The net effect of this pro-inflammatory response to obesity induces insulin resistance locally and systemically.