Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue

Abscisic acid (ABA) is a natural phytohormone and peroxisome proliferator-activated receptor γ (PPARγ) agonist that significantly improves insulin sensitivity in db/db mice. Although it has become clear that obesity is associated with macrophage infiltration into white adipose tissue (WAT), the phenotype of adipose tissue macrophages (ATMs) and the mechanisms by which insulin-sensitizing compounds modulate their infiltration remain unknown. We used a loss-of-function approach to investigate whether ABA ameliorates insulin resistance through a mechanism dependent on immune cell PPARγ. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80hi ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80lo ATMs. ABA significantly decreased CCR2+ F4/80hi infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARγ in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80hi ATMs into WAT, to repress WAT MCP-1 expression and to improve glucose tolerance. We provide molecular evidence in vivo demonstrating that ABA improves insulin sensitivity and obesity-related inflammation by inhibiting MCP-1 expression and F4/80hi ATM infiltration through a PPARγ-dependent mechanism.