Increased Tumor Necrosis Factor α–Converting Enzyme Activity Induces Insulin Resistance and Hepatosteatosis in Mice

Abstract

Tumor necrosis factor ␣-converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C 2 C 12 myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3 ؊/؊ mice have higher TACE activity compared with wild-type (WT) mice. Timp3 ؊/؊ mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3 ؊/؊ liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N-methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3 ؊/؊ compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE-Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice. (HEPATOLOGY 2010;51:103-110.) P andemic obesity is now considered the underlying basis for the increasing prevalence of chronic metabolic-inflammatory diseases including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. 1 Although NAFLD is an emerging metabolic complication of obesity, its pathogenic mechanisms are still unclear. 1 The contribution of insulin resistance to the development of fatty liver occurs in part by deficient control of lipid storage in white adipose tissue and in part by altered

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

“…sortilin reduction to be mediated at least partially through the post-translational modification (shedding) involving TACE activity (25), which could be activated by a PKC activator, TPA (26). Intriguingly, several recent studies have demonstrated that TACE activity is increased in the skeletal muscles of obese type 2 diabetes patients and in lipid-induced insulin resistance (43,44). In addition, increased TACE activity has been directly implicated in the pathogenesis of insulin resistance, which is generally explained by the augmented secretion of TNF-␣ (43,45,46).…”

“…Intriguingly, several recent studies have demonstrated that TACE activity is increased in the skeletal muscles of obese type 2 diabetes patients and in lipid-induced insulin resistance (43,44). In addition, increased TACE activity has been directly implicated in the pathogenesis of insulin resistance, which is generally explained by the augmented secretion of TNF-␣ (43,45,46). Thus, our findings provide an important connection between TACE activity and PKC-dependent sortilin reduction in skeletal muscle cells under palmitate-induced insulinresistant conditions, which appeared to be directly involved in the pathogenesis of impaired GLUT4 trafficking as discussed below.…”

Overexpression of TNF-α converting enzyme promotes adipose tissue inflammation and fibrosis induced by high fat diet

“…It was shown that TACE activity was significantly higher in mice fed with high fat diet (HFD) compared with chow controls (Fiorentino et al, 2010). In addition, TACE heterozygously knockout mice were protected against HFD-induced obesity (Serino et al, 2007).…”

“…In addition, TACE heterozygously knockout mice were protected against HFD-induced obesity (Serino et al, 2007). Furthermore, mice that lack tissue inhibitor of metalloproteinase 3, an endogenous inhibitor of ADAM families, showed an accelerated development of complications of obesity under HFD regimen (Menghini et al, 2009;Fiorentino et al, 2010). The collective findings suggested that TACE could be a possible therapeutic target of obesity-related diseases (Menghini et al, 2013).…”

Tumor Necrosis Factor-.ALPHA. Converting Enzyme Inactivation Ameliorates High-Fat Diet-Induced Insulin Resistance and Altered Energy Homeostasis

“…9, 10 Although neither TNF-α-nor TNF-α receptor-deficient mice show significant changes Tace Inactivation Ameliorates Insulin Resistance in body weight (BW) when fed a HFD, mice lacking functional Tace exhibit a lean phenotype and markedly increased energy expenditure, suggesting an important role of Tace in energy homeostasis. 11 To evaluate the pathogenic role of Tace in obesity-induced metabolic disorders, we generated Tace flox/flox /Mx1-Cre mice (TaceMx1) to allow temporal systemic deletion of Tace as previously reported, 12 because Tace-deficient mice die perinatally.…”