Loss of PPAR gamma 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 gamma (PPARgamma) 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 PPARgamma. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80(hi) ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80(lo) ATMs. ABA significantly decreased CCR2(+) F4/80(hi) infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARgamma in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80(hi) 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 F4/80(hi) ATM infiltration through a PPARgamma-dependent mechanism.
Guri
Amir J
AJ
Laboratory of Nutritional Immunology and Molecular Nutrition, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Hontecillas
Raquel
R
Ferrer
Gerardo
G
Casagran
Oriol
O
Wankhade
Umesh
U
Noble
Alexis M
AM
Eizirik
Decio L
DL
Ortis
Fernanda
F
Cnop
Miriam
M
Liu
Dongmin
D
Si
Hongwei
H
Bassaganya-Riera
Josep
J
D000040:Abscisic Acid / Q000494:pharmacology*; D052436:Adipose Tissue, White / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D018932:Chemokine CCL2; D047495:PPAR gamma; D014280:Triglycerides; D000040:Abscisic Acid