Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance.
Glucocorticoid therapy is often associated with impaired insulin sensitivity and cardiovascular disease. The present study was designed to evaluate cardiac fatty acid (FA) composition and metabolism following acute dexamethasone (Dex) treatment. Using the euglycemic hyperinsulinemic clamp, rats injected with Dex demonstrated a reduced glucose infusion rate. This whole body insulin resistance was also associated with a heart-specific increase in pyruvate dehydrogenase kinase 4 gene expression and a reduction in the rate of glucose oxidation. Dex treatment increased basal and postheparin plasma lipolytic activity. In the heart, palmitic and oleic acid levels were higher after 4 h of Dex and decreased to control (CON) levels within 8 h. Measurement of polyunsaturated FAs demonstrated a drop in linoleic and gamma-linolenic acid, with an increase in arachidonic acid (AA) after acute Dex injection. Tissue FA can be either oxidized or stored as triglyceride (TG). At 4 h, Dex augmented cardiac TG accumulation. However, this increase in tissue TG could not be maintained, such that at 8 h following Dex, TG declined to CON levels. AMP-activated protein kinase (AMPK) activation is known to promote FA oxidation through its control of acetyl-CoA carboxylase (ACC). Acute Dex promoted ACC phosphorylation, and increased cardiac palmitate oxidation, likely through its effects in increasing AMPK phosphorylation and total AMPK protein and gene expression. Whether these acute effects of Dex on FA oxidation, TG storage, and arachidonic acid accumulation can be translated into increased cardiovascular risk following chronic therapy has yet to be determined.
Qi
Dake
D
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
An
Ding
D
Kewalramani
Girish
G
Qi
Yadan
Y
Pulinilkunnil
Thomas
T
Abrahani
Ashraf
A
Al-Atar
Usama
U
Ghosh
Sanjoy
S
Wambolt
Richard B
RB
Allard
Michael F
MF
Innis
Sheila M
SM
Rodrigues
Brian
B
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage*; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D005227:Fatty Acids; D003907:Dexamethasone