Adipocyte aryl hydrocarbon receptors mediate sex differences in pyocyanin-induced weight loss

Pyocyanin (PYO) is a Pseudomonas aeruginosa virulence factor metabolite that is an aryl hydrocarbon receptor (AhR) ligand. In addition to liver, adipocytes express AhR that regulates adipocyte differentiation and inflammatory adipokines. Previous studies demonstrated that PYO administration reduced body weight and adipose mass of mice. The purpose of this study was to define the role of AhR in PYO-induced regulation of 3T3-L1 adipocyte differentiation in vitro, and body weight and fat mass in vivo in male and female mice. PYO-induced reductions in adipocyte differentiation were not abolished by AhR antagonists. However, a competitive AhR antagonist reduced PYO-induced increases in adipocyte CYP1a1 mRNA abundance. PYO-induced reductions in body weight of male and female mice were not abolished in AhR^+/- mice. In contrast, male mice with adipocyte AhR deficiency exhibited reductions in PYO-induced regulation of body weight, whereas female adipocyte AhR-deficient mice exhibited augmented PYO-induced body weight reductions. Adipocyte AhR deficiency reduced PYO-induced elevations of adipose tissue CYP1a1 mRNA abundance in both sexes. PYO increased glycerol release from adipose explants of females, but not males, an effect that was abolished in explants from female adipocyte AhR-deficient mice. These results demonstrate that PYO regulates adipocyte differentiation through AhR-independent mechanisms. In males, PYO effects on body weight are partially adipocyte AhR-mediated. However, adipocyte AhR-deficient females exhibit potentiation of PYO regulation of body weight. These findings suggest that adipocyte AhR may differentially regulate susceptibility to P. aeruginosa-induced cachexia in males and females.NEW & NOTEWORTHY We examined effects of AhR antagonists on adipocyte differentiation and adipocyte AhR receptors in effects of pyocyanin to induce weight loss in male and female mice. In males, adipocyte AhR mediated pyocyanin-induced regulation of body weight, whereas in females, removal of adipocyte AhR potentiated pyocyanin-induced reductions of body weight. These results suggest cachexia from systemic P. aeruginosa infections may differ between males and females due to sex differences in pyocyanin effects at adipocyte AhR.