A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism

Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D) and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low grade inflammatory environment through the production of inflammatory cytokines. NF-?B signaling is a central coordinator of these inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. To understand the role of inflammatory macrophages in insulin resistance and T2D development, we fed myeloid-specific A20 deficient mice (A20myel-KO mice) with a high fat diet, and demonstrate that these mice are completely protected from diet-induced obesity and insulin resistance, despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. Given the increased macrophage numbers in A20myel-KO mice, we hypothesize that A20 deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal an unexpected role for A20 in regulating macrophage immunometabolism. Overall design: Bulk RNA sequencing of FACS-purified CD206+ and CD11c+ adipose tissue macrophage subclasses isolated from epididymal adipose tissue (eWAT) of A20myel-KO and wild-type C57BL/6J mice.