Increased tumor necrosis factor alpha-converting enzyme activity induces insulin resistance and hepatosteatosis in mice.
Tumor necrosis factor alpha-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.


CONCLUSIONS
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.
Fiorentino
Loredana
L
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Vivanti
Alessia
A
Cavalera
Michele
M
Marzano
Valeria
V
Ronci
Maurizio
M
Fabrizi
Marta
M
Menini
Stefano
S
Pugliese
Giuseppe
G
Menghini
Rossella
R
Khokha
Rama
R
Lauro
Renato
R
Urbani
Andrea
A
Federici
Massimo
M
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D040901:Proteomics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000502:physiology*
D004041:Dietary Fats; D019717:Tissue Inhibitor of Metalloproteinase-3; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse