Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice

Loredana Fiorentino, Alessia Vivanti, Michele Cavalera, Valeria Marzano, Maurizio Ronci, Marta Fabrizi, Stefano Menini, Giuseppe Pugliese, Rossella Menghini, Rama Khokha, Renato Lauro, Andrea Urbani, Massimo Federici

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Tumor necrosis factor α-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, C2C12 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 withWTmice. 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.

Original languageEnglish
Pages (from-to)103-110
Number of pages8
JournalHepatology
Volume51
Issue number1
DOIs
Publication statusPublished - Jan 2010

Fingerprint

Tissue Inhibitor of Metalloproteinase-3
Insulin Resistance
Tumor Necrosis Factor-alpha
Enzymes
Hepatocytes
High Fat Diet
Insulin
Methionine
Glycine N-Methyltransferase
Liver
Adenosine Kinase
Glucose
Fatty Acid-Binding Proteins
White Adipose Tissue
Proteins
Palmitic Acid
Firearms
Fatty Liver
Adipocytes
Adenoviridae

ASJC Scopus subject areas

  • Hepatology

Cite this

Fiorentino, L., Vivanti, A., Cavalera, M., Marzano, V., Ronci, M., Fabrizi, M., ... Federici, M. (2010). Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice. Hepatology, 51(1), 103-110. https://doi.org/10.1002/hep.23250

Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice. / Fiorentino, Loredana; Vivanti, Alessia; Cavalera, Michele; Marzano, Valeria; Ronci, Maurizio; Fabrizi, Marta; Menini, Stefano; Pugliese, Giuseppe; Menghini, Rossella; Khokha, Rama; Lauro, Renato; Urbani, Andrea; Federici, Massimo.

In: Hepatology, Vol. 51, No. 1, 01.2010, p. 103-110.

Research output: Contribution to journalArticle

Fiorentino, L, Vivanti, A, Cavalera, M, Marzano, V, Ronci, M, Fabrizi, M, Menini, S, Pugliese, G, Menghini, R, Khokha, R, Lauro, R, Urbani, A & Federici, M 2010, 'Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice', Hepatology, vol. 51, no. 1, pp. 103-110. https://doi.org/10.1002/hep.23250
Fiorentino, Loredana ; Vivanti, Alessia ; Cavalera, Michele ; Marzano, Valeria ; Ronci, Maurizio ; Fabrizi, Marta ; Menini, Stefano ; Pugliese, Giuseppe ; Menghini, Rossella ; Khokha, Rama ; Lauro, Renato ; Urbani, Andrea ; Federici, Massimo. / Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice. In: Hepatology. 2010 ; Vol. 51, No. 1. pp. 103-110.
@article{b05d4a0f2dfb42069602973aab374515,
title = "Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice",
abstract = "Tumor necrosis factor α-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, C2C12 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 withWTmice. 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.",
author = "Loredana Fiorentino and Alessia Vivanti and Michele Cavalera and Valeria Marzano and Maurizio Ronci and Marta Fabrizi and Stefano Menini and Giuseppe Pugliese and Rossella Menghini and Rama Khokha and Renato Lauro and Andrea Urbani and Massimo Federici",
year = "2010",
month = "1",
doi = "10.1002/hep.23250",
language = "English",
volume = "51",
pages = "103--110",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice

AU - Fiorentino, Loredana

AU - Vivanti, Alessia

AU - Cavalera, Michele

AU - Marzano, Valeria

AU - Ronci, Maurizio

AU - Fabrizi, Marta

AU - Menini, Stefano

AU - Pugliese, Giuseppe

AU - Menghini, Rossella

AU - Khokha, Rama

AU - Lauro, Renato

AU - Urbani, Andrea

AU - Federici, Massimo

PY - 2010/1

Y1 - 2010/1

N2 - Tumor necrosis factor α-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, C2C12 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 withWTmice. 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.

AB - Tumor necrosis factor α-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, C2C12 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 withWTmice. 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.

UR - http://www.scopus.com/inward/record.url?scp=73449086315&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73449086315&partnerID=8YFLogxK

U2 - 10.1002/hep.23250

DO - 10.1002/hep.23250

M3 - Article

C2 - 19877183

AN - SCOPUS:73449086315

VL - 51

SP - 103

EP - 110

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 1

ER -