Vitamin A decreases pre-receptor amplification of glucocorticoids in obesity: study on the effect of vitamin A on 11beta-hydroxysteroid dehydrogenase type 1 activity in liver and visceral fat of WNIN/Ob obese rats

Abstract

Background11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and its inhibition ameliorates obesity and metabolic syndrome. So far, no studies have reported the effect of dietary vitamin A on 11β-HSD1 activity in visceral fat and liver under normal and obese conditions. Here, we studied the effect of chronic feeding of vitamin A-enriched diet (129 mg/kg diet) on 11β-HSD1 activity in liver and visceral fat of WNIN/Ob lean and obese rats.MethodsMale, 5-month-old, lean and obese rats of WNIN/Ob strain (n = 16 for each phenotype) were divided into two subgroups consisting of 8 rats of each phenotype. Control groups received stock diet containing 2.6 mg vitamin A/kg diet, where as experimental groups received diet containing 129 mg vitamin A/Kg diet for 20 weeks. Food and water were provided ad libitum. At the end of the experiment, tissues were collected and 11β-HSD1 activity was assayed in liver and visceral fat.ResultsVitamin A supplementation significantly decreased body weight, visceral fat mass and 11β-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11β-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein α (C/EBPα), the main transcription factor essential for the expression of 11β-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver × receptor α (LXRα), a nuclear transcription factor which is known to downregulate 11β-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes.ConclusionsThis study suggests that chronic consumption of vitamin A-enriched diet decreases 11β-HSD1 activity in liver and visceral fat of WNIN/Ob obese rats. Decreased 11β-HSD1 activity by vitamin A may result in decreased levels of active glucocorticoids in adipose tissue and possibly contribute to visceral fat loss in these obese rats. Studying the role of various nutrients on the regulation of 11β-HSD1 activity and expression will help in the evolving of dietary approaches to treat obesity and insulin resistance.

FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

“…Abnormally elevated pro-inflammatory cytokines from expanded adipose tissue in obesity can interfere with macrophages and peripheral tissues in an autocrine or paracrine manner [4,[6][7][8]. Elevated activities of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in fat and liver contribute to obesity and metabolic syndrome by catalyzing the conversion of inactive glucocorticoid to the active form [27,29,31]. Among the pro-inflammatory cytokines and hormones, TNF-a and DEX are well characterized to induce IR in cultured adipocytes and in mice [32].…”

Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats

“…This effect was retinoid specific as RA treatment reversed vitamin A deficiency effects on 11b-HSD1 expression. The inhibitory effect of retinoids on 11b-HSD1 expression has been already shown peripherally in liver and visceral fat of WNIN/Ob obese rats (Sakamuri et al 2011), in adipose tissue of mice (Sakuta et al 2006) and in vitro in myotubes (Aubry & Odermatt 2009) but never in central structures. Within the cell, 11b-HSD1 catalyses the regeneration of active glucocorticoid, thus amplifying glucocorticoid action.…”

“…Furthermore, RA treatment was shown to inhibit corticosterone (CORT) production in experimental Cushing's syndrome (Paez-Pereda et al 2001). The inhibitory effect of retinoids on 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) expression, an enzyme that regenerates active GCs within cells, has been reported in liver and visceral fat of WNIN/Ob obese rats (Sakamuri et al 2011), in adipose tissue of mice (Sakuta et al 2006) and in vitro in myotubes (Aubry & Odermatt 2009). This is interesting in regard to the fact that 11b-HSD1 increases in the aged hippocampus and its elevated expression correlates with impaired spatial memory (Holmes et al 2010).…”

Optimization of condition(s) towards establishment of primary islet cell cultures from WNIN/Ob mutant rat

“…The modifications we have made thus in the existing procedure were able to overcome the difficulties while trying to isolate islets from obese rats like WNIN/Ob, having high percentage of fat. This model is now increasingly being used (Reddy et al 2009;Bandaru et al 2011;Madhira et al 2011;Sakamuri et al 2011) and in the long run the establishment of a primary cell line from this model will be useful for studies related to obesity and diabetes.…”