title: Effect of dexamethasone on glucose tolerance and fat metabolism in a diet-induced obesity mouse model.
abstract: 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 omega-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.
authors.affiliation: Discovery Technologies, Novartis Institutes for BioMedical Research Inc, Cambridge, MA 02139, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Gounarides
authors.forename: Marion
authors.initials: M
authors.lastname: Korach-André
authors.forename: Karen
authors.initials: K
authors.lastname: Killary
authors.forename: Gregory
authors.initials: G
authors.lastname: Argentieri
authors.forename: Oliver
authors.initials: O
authors.lastname: Turner
authors.forename: Didier
authors.initials: D
authors.lastname: Laurent
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D050218:Body Fat Distribution; D001835:Body Weight / Q000187:drug effects; D002725:Chloroform; D003907:Dexamethasone / Q000494:pharmacology*; D004041:Dietary Fats / Q000378:metabolism*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000139:chemically induced / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010472:Perchlorates
chemical_list: D004041:Dietary Fats; D005938:Glucocorticoids; D010472:Perchlorates; D003907:Dexamethasone; D002725:Chloroform