Increased hepatic lipogenesis in insulin resistance and Type 2 diabetes is associated with AMPK signalling pathway up-regulation in Psammomys obesus.
AMPK (AMP-activated protein kinase) has been suggested to be a central player regulating FA (fatty acid) metabolism through its ability to regulate ACC (acetyl-CoA carboxylase) activity. Nevertheless, its involvement in insulin resistance- and TD2 (Type 2 diabetes)-associated dyslipidaemia remains enigmatic. In the present study, we employed the Psammomys obesus gerbil, a well-established model of insulin resistance and TD2, in order to appreciate the contribution of the AMPK/ACC pathway to the abnormal hepatic lipid synthesis and increased lipid accumulation in the liver. Our investigation provided evidence that the development of insulin resistance/diabetic state in P. obesus is accompanied by (i) body weight gain and hyperlipidaemia; (ii) elevations of hepatic ACC-Ser79 phosphorylation and ACC protein levels; (iii) a rise in the gene expression of cytosolic ACC1 concomitant with invariable mitochondrial ACC2; (iv) an increase in hepatic AMPKalpha-Thr172 phosphorylation and protein expression without any modification in the calculated ratio of phospho-AMPKalpha to total AMPKalpha; (v) a stimulation in ACC activity despite increased AMPKalpha phosphorylation and protein expression; and (vi) a trend of increase in mRNA levels of key lipogenic enzymes [SCD-1 (stearoyl-CoA desaturase-1), mGPAT (mitochondrial isoform of glycerol-3-phosphate acyltransferase) and FAS (FA synthase)] and transcription factors [SREBP-1 (sterol-regulatory-element-binding protein-1) and ChREBP (carbohydrate responsive element-binding protein)]. Altogether, our findings suggest that up-regulation of the AMPK pathway seems to be a natural response in order to reduce lipid metabolism abnormalities, thus supporting the role of AMPK as a promising target for the treatment of TD2-associated dyslipidaemia.
Research Centre, CHU-Sainte-Justine, Montreal, QC, Canada, H3T 1C5.
Ali
A
Ben Djoudi Ouadda
Emile
E
Levy
Ehud
E
Ziv
Geneviève
G
Lalonde
Alain T
AT
Sané
Edgar
E
Delvin
Mounib
M
Elchebly
D055372:AMP-Activated Protein Kinases / Q000032:analysis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005849:Gerbillinae; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D010743:Phospholipids / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
D001786:Blood Glucose; D007328:Insulin; D010743:Phospholipids; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases