Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

Objective: The beneficial metabolic actions of peroxisome proliferator- activated receptor gamma (PPAR gamma) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta- HSD1). This study aimed to assess the contribution of GC attenuation to PPAR gamma agonism action on gene expression in visceral adipose tissue and global metabolic profile. Design: Rats were treated (2 weeks) with the PPAR gamma agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPAR gamma- mediated GC attenuation. Measurements: mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. Results: Whereas HiCORT did not alter RWAT mass, RSG increased the latter (+33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPAR gamma agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORT-induced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. Conclusion: The GC and PPAR gamma pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPAR gamma agonism are retained under imposed high ambient GC, and are therefore independent from PPAR gamma effects on 11 beta-HSD1-mediated GC production.