A Novel Role for Fetuin-A in the Pathophysiology of Glucocorticoid-Mediated Insulin Resistance

Abstract

Fetuin-A (also called alpha2-HS glycoprotein), a phosphorylated protein secreted by the liver, is a physiological inhibitor of the insulin receptor tyrosine kinase (IR-TK). Elevated plasma levels of fetuin-A have been observed in animal models of obesity and diabetes, with fetuin-A null mice exhibiting improved insulin sensitivity and resistance to weight gain. In humans, increased plasma fetuin-A levels have been strongly correlated with insulin resistance, fatty liver, and metabolic syndrome. Increasing evidence indicate that insulin resistance and metabolic syndrome are associated with elevated circulating and/or tissue levels of cortisol, the principal active glucocorticoid in humans. Recently dexamethasone (DEX), a synthetic glucocorticoid, was shown to up-regulate fetuin-A gene expression and protein levels in primary mouse hepatocytes. Since DEX has been implicated in insulin resistance in animal models and humans, it was of significant interest to investigate the role of fetuin-A in DEX-induced insulin resistance. Treatment of Hep3B human hepatoma cells with DEX significantly increased the synthesis and secretion of fetuin-A, suggesting a possibility that glucocorticoids may regulate fetuin-A levels in humans. These findings were extended to the Zucker diabetic fatty (ZDF) rat, a model of extreme insulin resistance. ZDF rats exhibited a ~2-fold increase in corticosterone levels compared to age- (6 weeks old) and sex-matched lean controls. This increase was matched by a ~2-fold increase in plasma fetuin-A levels in ZDF rats. Consistent with these data, DEX treatment (1 mg/kg, i.p., once daily for 4 days) was associated with hyperinsulinemia and insulin resistance, analyzed by homeostasis model assessment (HOMA) in 4-week old, male Wistar rats. Concomitantly, DEX treatment significantly elevated hepatic fetuin-A gene expression and protein levels resulting in a ~2.2-fold increase in plasma fetuin-A levels. Administration of RU-486, a specific glucocorticoid receptor antagonist, restored insulin and HOMA-IR to normal and significantly decreased plasma fetuin-A levels in DEX-treated animals. Next, we sought to examine the role of endogenous glucocorticoids in regulating fetuin-A through the removal of adrenal glands. As expected, adrenalectomy significantly decreased circulating corticosterone and insulin levels, and effectively improved insulin sensitivity in Wistar rats. This improvement in insulin sensitivity was associated with a significant decrease in plasma fetuin-A levels. Furthermore, DEX-treated fetuin-A knockout mice showed improved insulin sensitivity compared to wild-type controls. Taken together, we demonstrate that circulating fetuin-A levels are regulated by glucocorticoids. Since fetuin-A is implicated in insulin resistance and metabolic syndrome, these studies suggest a novel role for fetuin-A in glucocorticoid-mediated insulin resistance.