Metabolic action of peroxisome proliferator-activated receptor gamma agonism in rats with exogenous hypercorticosteronemia.
OBJECTIVE
The beneficial metabolic actions of peroxisome proliferator-activated receptor gamma (PPARgamma) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This study aimed to assess the contribution of GC attenuation to PPARgamma agonism action on gene expression in visceral adipose tissue and global metabolic profile.


METHODS
Rats were treated (2 weeks) with the PPARgamma agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARgamma-mediated GC attenuation.


METHODS
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. PPARgamma 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.


CONCLUSIONS
The GC and PPARgamma 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 PPARgamma agonism are retained under imposed high ambient GC, and are therefore independent from PPARgamma effects on 11beta-HSD1-mediated GC production.
Berthiaume
M
M
Faculty of Medicine, Laval Hospital Research Center, Laval University, Québec, Québec, Canada.
Laplante
M
M
Tchernof
A
A
Deshaies
Y
Y
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003345:Corticosterone / Q000097:blood* / Q000494:pharmacology / Q000502:physiology; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008066:Lipolysis / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D008071:Lipoprotein Lipase; D003345:Corticosterone