Role of retinoic acid in diet induced obesity

Obesity is a complex disease associated with chronic, low-grade inflammation of the adipose tissue, which promotes insulin resistance and type-2 diabetes. Adipose tissue macrophages (ATMs) with an inflammatory M1 profile are involved in the development and progression of obesity associated metabolic diseases. In contrast, alternatively activated M2 macrophages (AAMs) may promote anti-inflammatory responses and polarization of CD4+Foxp3+ regulatory T cells (Tregs), attenuating adipose tissue inflammation. We now show that AAMs in the adipose tissue promote the polarization and maintenance of Tregs, through expression of the enzyme retinal dehydrogenase 2 (Raldh2). Diet induced obesity reduces expression of Raldh2 by adipose tissue AAMs and disrupts the polarization of Tregs. Treatment of lean mice with a pan-retinoic acid receptor inverse agonist BMS493 disrupts polarization of Tregs in the adipose tissue. In contrast, retinoic acid (RA) treatment of obese mice reverses defects in Tregs. Induction of AAMs and Tregs in adipose tissue occurs through a Stat6 dependent mechanism. Conditional deletion of Raldh2 with LysM-Cre or CD11c-Cre resulted in the disruption of Treg polarization. These findings suggest that RA may be important for maintaining adipose tissue Tregs by AAMs under steady state non-obese conditions and could perhaps be used as a novel therapeutic agent for diet induced metabolic diseases.