Serum adiponectin as a biomarker for in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin sensitization/lipid lowering in rats.
BACKGROUND
PPARgamma agonists ameliorate insulin resistance and dyslipidemia in type 2 diabetic patients. Adiponectin possesses insulin sensitizing properties, and predicts insulin sensitivity of both glucose and lipid metabolism. In diet-induced insulin resistant rats and ZDF rats, the current studies determined the correlation between PPARgamma agonist-upregulated fatty acid binding protein(FABP3) mRNA in adipose tissue and PPARgamma agonist-elevated serum adiponectin, and the correlation between PPARgamma agonist-elevated serum adiponectin and PPARgamma agonist-mediated efficacy in insulin sensitization and lipid lowering.


RESULTS
Parallel groups of SD rats were fed a high fat/sucrose (HF) diet for 4 weeks. These rats were orally treated for the later 2 weeks with vehicle, either PPARgamma agonist GI262570 (0.2-100 mg/kg, Q.D.), or GW347845 (3 mg/kg, B.I.D). Rats on HF diet showed significant increases in postprandial serum triglycerides, free fatty acids (FFA), insulin, and area under curve (AUC) of serum insulin during an oral glucose tolerance test, but showed no change in serum glucose, adiponectin, and glucose AUC. Treatment with GI262570 dose-dependently upregulated adipose FABP3 mRNA, and increased serum adiponectin. There was a position correlation between adipose FABP3 mRNA and serum adiponectin (r = 0.7350, p < 0.01). GI262570 dose-dependently decreased the diet-induced elevations in triglycerides, FFA, insulin, and insulin AUC. Treatment with GW347845 had similar effects on serum adiponectin and the diet-induced elevations. There were negative correlations for adiponectin versus triglycerides, FFA, insulin, and insulin AUC (For GI262570, r = -0.7486, -0.4581, -0.4379, and -0.3258 respectively, all p < 0.05. For GW347845, r = -0.6370, -0.6877, -0.5512, and -0.3812 respectively, all p < 0.05). In ZDF rats treated with PPARgamma agonists pioglitazone (3-30 mg/kg, B.I.D.) or GW347845 (3 mg/kg, B.I.D.), there were also negative correlations for serum adiponectin versus glucose, triglycerides, FFA (for pioglitazone, r = -0.7005, -0.8603, and -0.9288 respectively; for GW347845, r = -0.9721, -0.8483, and -0.9453 respectively, all p < 0.01).


CONCLUSIONS
This study demonstrated that (a) PPARgamma agonists improved insulin sensitivity and ameliorated dyslipidemia in HF fed rats and ZDF rats, which were correlated with serum adiponectin; (b) Serum adiponectin was positively correlated with adipose FABP3 mRNA in GI262570-treated rats. These data suggest that serum adiponectin can serve as a biomarker for both in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin resistance and dyslipidemia in rats.
Yang
Baichun
B
Department of Molecular Pharmacology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. baichun.w.yang@gsk.com
Brown
Kathleen K
KK
Chen
Lihong
L
Carrick
Kevin M
KM
Clifton
Lisa G
LG
McNulty
Judi A
JA
Winegar
Deborah A
DA
Strum
Jay C
JC
Stimpson
Stephen A
SA
Pahel
Gregory L
GL
D052242:Adiponectin; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins; D007328:Insulin / Q000097:blood / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008055:Lipids / Q000097:blood*; D008297:Male; D009765:Obesity / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D052242:Adiponectin; D015415:Biomarkers; D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; D010080:Oxazoles; D047495:PPAR gamma; D045162:Thiazolidinediones; C422415:farglitazar; D014443:Tyrosine; D000077205:Pioglitazone