Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.
OBJECTIVE
High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice.


METHODS
Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined.


RESULTS
HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity.


CONCLUSIONS
This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance.
Department of Biochemistry and Biotechnology, Annamalai University, Tamil Nadu, India.
Emayavaramban
E
Priyadarshini
Department of Biochemistry and Biotechnology, Annamalai University, Tamil Nadu, India. Electronic address: cvaradha@yahoo.com.
Carani Venkatraman
CV
Anuradha
D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000008:administration & dosage / Q000633:toxicity*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology*; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D008055:Lipids; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D005632:Fructose; D015735:Mifepristone
11β-hydroxysteroid dehydrogenase type 1; 11β-hydroxystéroïde déshydrogénase de type 1; RU 486; RU486; accumulation des lipides; glucocorticoid; glucocorticoid receptor; glucocorticoïdes; insulin resistance; insulinorésistance; lipid accumulation; récepteur des glucocorticoïdes