Uteroplacental insufficiency down regulates insulin receptor and affects expression of key enzymes of long-chain fatty acid (LCFA) metabolism in skeletal muscle at birth.
BACKGROUND
Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of insulin resistance and type 2 diabetes. Ligation of the uterine arteries in rats mimics uteroplacental insufficiency and serves as a model of intrauterine growth restriction (IUGR) and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia and adiposity in the offspring. The objective of this study was to investigate the effects of uterine artery ligation on the skeletal muscle expression of insulin receptor and key enzymes of LCFA metabolism.


METHODS
Bilateral uterine artery ligation was performed on day 19 of gestation in Sprague-Dawley pregnant rats. Muscle of the posterior limb was dissected at birth and processed by real-time RT-PCR to analyze the expression of insulin receptor, ACCalpha, ACCbeta (acetyl-CoA carboxylase alpha and beta subunits), ACS (acyl-CoA synthase), AMPK (AMP-activated protein kinase, alpha2 catalytic subunit), CPT1B (carnitine palmitoyltransferase-1 beta subunit), MCD (malonyl-CoA decarboxylase) in 14 sham and 8 IUGR pups. Muscle tissue was treated with lysis buffer and Western immunoblotting was performed to assay the protein content of insulin receptor and ACC.


RESULTS
A significant down regulation of insulin receptor protein (p < 0.05) and reduced expression of ACS and ACCalpha mRNA (p < 0.05) were observed in skeletal muscle of IUGR newborns. Immunoblotting showed no significant change in ACCalpha content.


CONCLUSIONS
Our data suggest that uteroplacental insufficiency may affect skeletal muscle metabolism down regulating insulin receptor and reducing the expression of key enzymes involved in LCFA formation and oxidation.
Germani
Daniela
D
Department of Public Health and Cell Biology, Tor Vergata University, 00133 Rome, Italy. germani@med.uniroma2.it
Puglianiello
Antonella
A
Cianfarani
Stefano
S
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D021041:Placental Circulation; D010927:Placental Insufficiency / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics*
D004798:Enzymes; D005227:Fatty Acids; D009097:Multienzyme Complexes; D002334:Carnitine O-Palmitoyltransferase; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat