The effect of pioglitazone on peroxisome proliferator-activated receptor-gamma target genes related to lipid storage in vivo.
OBJECTIVE
Pioglitazone is a member of the thiazolidinediones (TZDs), insulin-sensitizing agents used to treat type 2 diabetes. The aim of this study was to define the effect of pioglitazone on the expression of genes related to carbohydrate and lipid metabolism in subcutaneous fat obtained from type 2 diabetic patients.


METHODS
Forty-eight volunteers with type 2 diabetes were divided into two groups treated for 12 weeks with placebo or pioglitazone (30 mg/day). The expression of several genes was quantified by real-time RT-PCR.


RESULTS
Pioglitazone treatment increased the expression of genes involved in glycerol-3-phosphate synthesis. The mRNA expression of PEPCK-C and glycerol-3-phosphate dehydrogenase (GPDH) increased (P < 0.01) in patients treated with pioglitazone. There was no difference in glycerol kinase (GyK) mRNA levels. The expression of genes that regulate fatty acid availability in adipocytes, including lipoprotein lipase (LPL) and acetyl-CoA synthetase (ACS), was higher (P < 0.01) in pioglitazone-treated patients. Pioglitazone stimulated (P < 0.0001) expression of c-Cbl-associated protein (CAP), whereas tumor necrosis factor-alpha, leptin, resistin, angiopoietin like-4, and 11-beta-hydroxysteroid dehydrogenase type 1 (11beta HSD 1) were not affected by pioglitazone. The baseline peroxisome proliferator-activated receptor (PPAR)-gamma1 mRNA was significantly correlated with mRNA for LPL, CAP, ACS, 11beta HSD 1, GyK, fatty acid synthase, leptin, and GPDH, whereas PPAR-gamma2 mRNA was correlated with CAP, PEPCK-C, leptin, and GPDH.


CONCLUSIONS
Treatment with pioglitazone increased body weight, and this is associated with upregulation of some, but not all, genes previously demonstrated as "TZD responsive" in subcutaneous fat. The results suggest that TZDs might increase body weight through the upregulation of genes facilitating adipocyte lipid storage in vivo.
Bogacka
Iwona
I
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. bogackiu@pbrc.edu
Xie
Hui
H
Bray
George A
GA
Smith
Steven R
SR
D001823:Body Composition / Q000187:drug effects; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D000077205:Pioglitazone; D010919:Placebos; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045162:Thiazolidinediones / Q000627:therapeutic use*
D017931:DNA Primers; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D008055:Lipids; D047495:PPAR gamma; D010919:Placebos; D045162:Thiazolidinediones; D000077205:Pioglitazone