This Article Full Text Full Text (PDF) All Versions of this Article: 149/2/758    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Gounarides, J. S. Articles by Laurent, D. PubMed PubMed Citation Articles by Gounarides, J. S. Articles by Laurent, D.

Effect of Dexamethasone on Glucose Tolerance and Fat Metabolism in a Diet-Induced Obesity Mouse Model

Discovery Technologies (J.S.G., M.K.-A., D.L.), Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139; and Safety Profiling and Assessment (K.K., G.A., O.T.), Novartis Pharmaceutical Corp., East Hanover, New Jersey 07936

Address all correspondence and requests for reprints to: Didier Laurent, Ph.D., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139. E-mail: didier.laurent{at}novartis.com.

Prolonged exposure to elevated glucocorticoid levels is known to produce insulin resistance (IR), a hallmark of diabetes mellitus. Although not fully elucidated, the underlying molecular mechanisms by which glucocorticoids induce IR may provide potential targets for pharmacological interventions. Here we characterized muscle lipid metabolism in a dexamethasone-aggravated diet-induced obesity murine model of IR. Male C57BL/6 mice on a high-fat diet for 2 months when challenged with dexamethasone showed elevated food consumption and weight gain relative to age and diet-matched animals dosed with saline only. Dexamethasone treatment impaired glucose tolerance and significantly increased the intramyocellular lipid content in the tibialis anterior muscle (TA). A good correlation (r = 0.76, P < 0.01) was found between accumulation in intramyocellular lipid content in the TA and visceral adiposity. The linoleic acid (18:2) to polyunsaturated acid ratio was increased in the dexamethasone-treated animals (+29%; P < 0.01), suggesting a possible increase in stearoyl-CoA desaturase 2 activity, as reported in Sertoli cells. The treatment was also accompanied by a reduction in the percent fraction of -3 and long-chain polyunsaturated fatty acids in the TA. Analysis of the low-molecular-weight metabolites from muscle extracts showed that there was no dysregulation of muscle amino acids, as has been associated with dexamethasone-induced muscle proteolysis. In conclusion, dexamethasone-induced insulin resistance in diet-induced obese mice is associated with a profound perturbation of lipid metabolism. This is particularly true in the muscle, in which an increased uptake of circulating lipids along with a conversion into diabetogenic lipids can be observed.