Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Abstract

Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11b-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11b-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11b-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11b-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1,[2][3] H] deoxy-D-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11b-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.

Transgenic overexpression of hexose-6-phosphate dehydrogenase in adipose tissue causes local glucocorticoid amplification and lipolysis in male mice

“…The protein concentration was measured by Bradford assay (Bio-Rad Protein Assay Kit). 11␤-HSD1 activity was evaluated by addition of 1 mM NADPH and 250 nmol/l 11-dehydrocorticosterone (11-DHC) with 11-[ 3 H]DHC as tracer to microsomes in KRB solution at 37°C for 1-2 h, as done in our previous study (26). Steroids were separated by TLC, and the percentage of conversion of 11-[…”

Role of glucocorticoids and the glucocorticoid receptor in metabolism: Insights from genetic manipulations

“…On the other hand, changes in liver GR expression are not evident in other models of insulin resistance, as long-term (i.e. >30 wk) treatment with high-fat diet does not alter liver GR expression and expression of GR target genes [119], indicating that liver GC sensitivity is not always altered under conditions of low whole-body insulin action.…”

“…On this, while studies have shown that a diabetic-like metabolic phenotype can be partially reversed by GR antagonists and reducing systemic GC levels by adrenalectomy [119][120][121][122], the conclusions from these studies are clouded by the potential off-target effects of these treatments. While whole-body GR deficiency in mice does not alter body-weight gain, impaired glucose tolerance and liver triglyceride accumulation associated with administration of a high-fat diet [89], a recent study has shown that the downregulation of GR mRNA and activity via administration of an 11␤-HSD inhibitor reduced the weight gain, hyperglycemia and insulin resistance in response to high-fat diet feeding in mice [119]. In accordance with this, inhibition of GR expression by agonists for nuclear receptor liver X receptor (LXR) results in an amelioration of the diabetic phenotype in obese, db/db mice [121].…”

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

“…11βHSD1 is expressed at high levels in the major organs underpinning metabolism such as liver and adipose tissue. Hepatic overexpression of 11βHSD1 leads to insulin resistance in mice with increased lipogenesis (14), consistent with increased intrahepatic glucocorticoid action, whereas 11βHSD1 inhibition or deficiency leads to decreased hepatic gluconeogenesis (and decreased PCK1), improved insulin sensitivity, and correction of hyperglycemia in rodent models of insulin resistance and patients with T2DM (15)(16)(17)(18).…”