8 research outputs found
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
<p>Abstract</p> <p>Background</p> <p>11Ī²-hydroxysteroid dehydrogenase type 1 (11Ī²-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 11Ī²-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 11Ī²-HSD1 activity in liver and visceral fat of WNIN/Ob lean and obese rats.</p> <p>Methods</p> <p>Male, 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 <it>ad libitum</it>. At the end of the experiment, tissues were collected and 11Ī²-HSD1 activity was assayed in liver and visceral fat.</p> <p>Results</p> <p>Vitamin A supplementation significantly decreased body weight, visceral fat mass and 11Ī²-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11Ī²-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein Ī± (C/EBPĪ±), the main transcription factor essential for the expression of 11Ī²-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver Ć receptor Ī± (LXRĪ±), a nuclear transcription factor which is known to downregulate 11Ī²-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes.</p> <p>Conclusions</p> <p>This study suggests that chronic consumption of vitamin A-enriched diet decreases 11Ī²-HSD1 activity in liver and visceral fat of WNIN/Ob obese rats. Decreased 11Ī²-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 11Ī²-HSD1 activity and expression will help in the evolving of dietary approaches to treat obesity and insulin resistance.</p
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Metabolic dysregulation in the Atp7bā/ā Wilsonās disease mouse model
Inactivating mutations in the copper transporter Atp7b result in Wilson's disease. The Atp7b -/- mouse develops hallmarks of Wilson's disease. The activity of several nuclear receptors decreased in Atp7b -/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b -/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography-mass spectrometry and correlated with transcriptomic data. Atp7b -/- mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b -/- mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b -/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b -/- mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b -/- mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b -/- mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b -/- mice
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Vitamin B2 enables regulation of fasting glucose availability.
Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARĪ±, including those required for gluconeogenesis. We also found PPARĪ± knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARĪ± agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs