Abstract 13654: Temporal Systemic Deletion of Tumor Necrosis Factor-α Converting Enzyme Prevents Development of High-Fat Diet-induced Insulin Resistance, Hepatosteatosis, Adipose Tissue Remodeling with Ameliorating Energy Expenditure
Background: Tumor Necrosis Factor (TNF)-α is known to play a pivotal role in obesity-induced metabolic disorders. However, the role of TNF-α converting enzyme (Tace) in the development of obesity-induced metabolic disorders is unclear.
Methods and Results: Temporal systemic Tace inactivation mice (Mx1/Cre) and their wild-type littermates were fed standard-diet (STD/Cre or STD/CON, n=8 each) or high-fat diet (HFD/Cre or HFD/CON, n=8 each) at the age of 6 weeks. At 18 weeks, oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were performed. Body, EAT and liver weight was significantly increased in HFD/CON than STD/Cre and STD/CON (all p<0.05), but not increased in HFD/Cre. HFD/Cre had ameliorated glucose tolerance (p<0.01) and insulin sensitivity (p<0.01) compared with HFD/CON. Histological analysis of liver showed that hepatocellular ballooning (HE stain), oil-drops (Oil-Red O stain) and perisinusoidal fibrosis (Masson-Trichrome stain) were more prominent in HFD/CON compared with STD/CON. However, these changes were attenuated in HFD/Cre compared with HFD/CON. Increased hepatic triglyceride content in HFD/Cre was also attenuated in HFD/Cre (132±26 vs. 476±114mg/g, p<0.01). The mean adipocyte area in EAT was larger in HFD/CON compared with STD/CON and STD/CRE (both p<0.01). Enlargement of adipocytes in HFD/Cre was restored compared with HFD/CON (2973±557 vs. 5167±1110μm2, p<0.01). Immunohistochemistry of EAT showed infiltration of macrophage and expression of MCP-1were increased in HFD/CON than in STD/CON (both p<0.05) and these differences were attenuated in HFD/Cre (both p<0.05). Moreover, decreased serum adiponectin level in HFD/CON was preserved in HFD/Cre (37±7 vs. 18±2μg/mL p<0.01). Indirect calorimetry showed that energy expenditure of HFD/Cre was significantly higher than that of HFD/CON and that both fat and carbohydrate oxidation was higher in HFD/Cre than HFD/CON.
Conclusion: Post-natal inactivation of Tace protected from high-fat diet induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with ameliorating energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.
- © 2010 by American Heart Association, Inc.