Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice

Abstract

Glucocorticoids have been implicated as pathophysiological mediators of obesity and insulin resistance and are regulated by 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1). This enzyme regenerates active corticosterone from inactive 11-keto forms. To assess the role of 11␤-HSD1-mediated synthesis of active corticosterone in leptin-related obesity and diabetes, we examined the peripheral effect of leptin on 11␤-HSD1 activity and gene expression in vivo and in vitro in hepatocytes from ob/ob mice and in liver of streptozotocin (STZ)-treated ob/ob mice. We observed an inverse relationship between hepatic 11␤-HSD1 expression and body weight in ob/ob mice and lean littermates. Leptin treatment of ob/ob mice markedly increased hepatic 11␤-HSD1 activity and mRNA expression. This induction of 11␤-HSD1 expression corresponded to reduced levels of circulating corticosterone and weight loss in ob/ob mice treated with leptin, indicating that impaired hepatic 11␤-HSD1 expression may contribute to the pathogenesis of obesity in ob/ob mice. In addition, leptin treatment of STZ-treated ob/ob mice caused marked increases in hepatic 11␤-HSD1 levels associated with decreased body weight and a significant reduction in hyperglycemia due to pancreatic ␤-cell damage. Addition of leptin to ob/ob mouse primary hepatocytes led to a dose-dependent increase in 11␤-HSD1 mRNA expression. In contrast, leptin did not influence 11␤-HSD1 expression in primary hepatocytes from db/db mice, indicating that leptin regulation of 11␤-HSD1 expression is probably mediated by the functional leptin receptor. Thus, leptin appears to be an important metabolic signal that directly activates intrahepatic corticosterone production. These findings suggest that the liverspecific interaction of leptin with 11␤-HSD1 is involved in the development of obesity and insulin resistance in ob/ob mice.

The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

“…Centrally, leptin increases ACTH secretion while peripherally it suppresses ACTH-stimulated steroid production (Malendowicz et al 2007). However, leptin can also raise hepatic 11b-hydroxysteroid dehydrogenase (11b-HSD) type I activity in mice (Liu et al 2003). Therefore, our data suggest that in mice, obesity-related increases in leptin disrupts the feedback between central and peripheral branches of the HPA axis by increasing ACTH secretion and inhibiting ACTH-stimulated adrenal corticosterone release.…”

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

“…, and 18S RNA (Liu et al 2003(Liu et al , 2006. The amplification conditions of GR, 11b-HSD1, H6PDH, PEPCK, and G6Pase were optimized in preliminary studies to result in amplification within the linear range.…”

“…Analysis of 11b-HSD1 and H6PDH activity in primary hepatocytes 11b-HSD1 has been shown to be exclusively a 11b-reductase in primary cultures of mouse and rat hepatocytes (Jamieson et al 1995, Liu et al 2005 (Liu et al 2003(Liu et al , 2005. Steroids were extracted from 1 .…”

“…Primary hepatocytes were isolated from DIO mice by a two-step collagenase perfusion procedure as previously described (Liu et al 2003(Liu et al , 2006 and seeded onto collagencoated dishes in Dulbecco's Modified Eagle's Medium (DMEM)/F-12 medium (Invitrogen Life Technologies) with 10% FBS, 100 U/ml penicillin, and 100 mg/ml streptomycin supplemented with dexamethasone (10 K9 M) and insulin (10 K9 M). After 4 h incubation, the cells were then washed with PBS and treated with CBX (10 K7 -10 K4 M) for 12-72 h.…”

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

“…Conversely, 11HSD1 knockout mice on a high-fat diet are protected from obesity, hyperglycemia, and dyslipidemia and redistribute fat to peripheral rather than central fat depots (5-7). Moreover, inbred rodent models of obesity and diabetes show tissue-specific dysregulation of 11HSD1 (2,8,9); most commonly, 11HSD1 is reduced in liver but increased in adipose tissue. These findings substantiate the hypothesis that increased intra-adipose glucocorticoid regeneration by 11HSD1 contributes to obesity and its metabolic complications.…”