Carbenoxolone treatment ameliorated metabolic syndrome in WNIN/Ob obese rats, but induced severe fat loss and glucose intolerance in lean rats.

Abstract

BACKGROUND:

11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity.

METHODOLOGY/PRINCIPAL FINDINGS:

Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment.

CONCLUSIONS/SIGNIFICANCE:

We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions.

• Authors: Siva Sankara Vara Prasad Sakamuri, Mahesh Sukapaka, Vijay Kumar Prathipati, Harishankar Nemani, Uday Kumar Putcha, Shailaja Pothana, Swarupa Rani Koppala, Lakshmi Raj Kumar Ponday, Vani Acharya, Giridharan Nappan Veetill, Vajreswari Ayyalasomayajula
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e50216 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23284633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, HDL
• Enzyme Inhibitors
• Triglycerides
• Glycogen
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Carbenoxolone
• Corticosterone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• Adipocytes (drug effects, pathology)
• Adipose Tissue (drug effects, metabolism, pathology)
• Adrenal Glands (drug effects, pathology)
• Animals
• Body Composition (drug effects)
• Carbenoxolone (adverse effects, pharmacology, therapeutic use)
• Cholesterol, HDL (blood)
• Corticosterone (blood)
• Eating (drug effects)
• Enzyme Inhibitors (adverse effects, pharmacology, therapeutic use)
• Fibrosis (drug therapy)
• Gene Expression Regulation (drug effects)
• Glucose Intolerance (chemically induced, complications)
• Glycogen (metabolism)
• Hypertrophy (drug therapy)
• Liver (drug effects, metabolism, pathology)
• Male
• Metabolic Syndrome (blood, drug therapy, metabolism, pathology)
• Obesity (complications)
• Organ Size (drug effects)
• Rats
• Signal Transduction (drug effects)
• Thinness (complications)
• Triglycerides (blood, metabolism)