Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis.
OBJECTIVE
Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling.


METHODS
Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination.


RESULTS
Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation.


CONCLUSIONS
ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling.
Guri
Amir J
AJ
Nutritional Immunology and Molecular Nutrition Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Hontecillas
Raquel
R
Bassaganya-Riera
Josep
J
D000040:Abscisic Acid / Q000493:pharmacokinetics*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003625:Data Collection; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000493:pharmacokinetics*
D001786:Blood Glucose; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000040:Abscisic Acid; D017868:Cyclic AMP-Dependent Protein Kinases