Objectives Peripheral insulin resistance (IR) is one of the main side effects caused by glucocorticoid (GC)-based therapies, and the molecular mechanisms of GC-induced IR are not yet fully elucidated. Thus, we aimed to investigate the effects of dexamethasone treatment on the main components of insulin and inflammatory signaling in the adipose tissue of rats. Materials/methods Male Wistar rats received daily injections of dexamethasone (1 mg/kg body weight (b.w.), intraperitoneally (i.p.)) for 5 days (DEX), whereas control rats received saline (CTL). The metabolic status was investigated, and the epididymal fat fragments were collected for lipolysis and western blot analyses. Results The DEX rats became hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, compared with the CTL rats (P < 0.05). The basal glycerol release in the fat fragments was 1.5-fold higher in the DEX rats (P < 0.05). The phosphorylation of protein kinase B (PKB) at ser473 decreased by 44%, whereas, the phosphorylation of insulin receptor substrate (IRS)-1 at ser307 increased by 93% in the adipose tissue of the DEX rats after an oral bolus of glucose (P < 0.05). The basal phosphorylation of c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) proteins was reduced by 46% and 58%, respectively, in the adipose tissue of the DEX rats (P < 0.05). This was paralleled with a significant reduction (47%) in the glucocorticoid receptor (GR) protein content in the adipose tissue of the DEX rats (P < 0.05). Conclusion The insulin-resistant status of rats induced by dexamethasone administration have PKB and IRS-1 activity attenuated in epididymal fat without increases in the phosphorylation of the proinflammatory signals JNK and IKKβ.145 112Baxter, J.D., Forsham, P.H., Tissue effects of glucocorticoids (1972) Am. J. 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