Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation.
OBJECTIVE
Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)gamma agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARgamma are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARgamma activation in a non-genetic insulin-resistant animal model.


METHODS
Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg x kg(-1)) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARgamma, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3beta phosphorylation were assessed in rat liver.


RESULTS
Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-alpha and markers of neutrophil infiltration. Diet-induced PPARgamma expression was unaffected by the pioglitazone treatment.


CONCLUSIONS
Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.
Collino
Massimo
M
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy. massimo.collino@unito.it
Aragno
Manuela
M
Castiglia
Sara
S
Miglio
Gianluca
G
Tomasinelli
Chiara
C
Boccuzzi
Giuseppe
G
Thiemermann
Christoph
C
Fantozzi
Roberto
R
D000284:Administration, Oral; D000818:Animals; D002791:Cholesterol, Dietary; D004040:Dietary Carbohydrates; D004195:Disease Models, Animal; D005632:Fructose; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006505:Hepatitis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D050177:Overweight / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002791:Cholesterol, Dietary; D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526299:Irs2 protein, rat; D008055:Lipids; D047495:PPAR gamma; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D005632:Fructose; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000077205:Pioglitazone