Mice Heterozygous for Tumor Necrosis Factor-α Converting Enzyme Are Protected From Obesity-Induced Insulin Resistance and
Diabetes
Matteo Serino 1 ,
Rossella Menghini 1 ,
Loredana Fiorentino 1 ,
Roberta Amoruso 1 ,
Alessandro Mauriello 2 ,
Davide Lauro 1 ,
Paolo Sbraccia 1 ,
Marta L. Hribal 1 ,
Renato Lauro 1 and
Massimo Federici 1
1 Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome “Tor Vergata,” Rome, Italy
2 Department of Biopathology, University of Rome “Tor Vergata,” Rome, Italy
Address correspondence and reprint requests to Massimo Federici, MD, Department of Internal Medicine, University of Rome “Tor
Vergata,” Via Montpellier 1, 00133 Rome, Italy. E-mail: federicm{at}uniroma2.it
Abstract
OBJECTIVE— Tumor necrosis factor (TNF)-α is known to affect insulin sensitivity, glucose, and lipid metabolism through alternative and
redundant mechanisms at both translational and post-translational levels. TNF-α exerts its paracrine effects once the membrane-anchored
form is shed and released from the cell membrane. TNF-α cleavage is regulated by TNF-α converting enzyme (TACE), which regulates
the function of several transmembrane proteins, such as interleukin-6 receptor and epidermal growth factor receptor ligands.
The role of TACE in high-fat diet (HFD)-induced obesity and its metabolic complications is unknown.
RESEARCH DESIGN AND METHODS— To gain insights into the role of TACE in metabolic disorders, we used Tace +/− mice fed a standard or high-fat diet for 16 weeks.
RESULTS— We observed that Tace +/− mice are relatively protected from obesity and insulin resistance compared with wild-type littermates. When fed an HFD, wild-type
mice exhibited visceral obesity, increased free fatty acid and monocyte chemoattractant protein (MCP)1 levels, hypoadiponectinemia,
glucose intolerance, and insulin resistance compared with Tace +/− mice. Interestingly, Tace +/− mice exhibited increased uncoupling protein-1 and GLUT4 expression in white adipose tissue.
CONCLUSIONS— Our results suggest that modulation of TACE activity is a new pathway to be investigated for development of agents acting
against obesity and its metabolic complications.
AMPK, AMP-activated protein kinase
HFD, high-fat diet
IL, interleukin
Insr, insulin receptor
IRS, insulin receptor substrate
MCP, monocyte chemoattractant protein
Pref, preadipocyte factor
TACE, tumor necrosis factor-α converting enzyme
Timp, tissue inhibitor of metalloproteinase
TNF, tumor necrosis factor
UCP, uncoupling protein
WAT, white adipose tissue
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 22 July 2007. DOI: 10.2337/db07-0360.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0360 .
M.S. and R.M. contributed equally to this work.
The costs of publication of this article were defrayed in part by...

Mice Heterozygous for Tumor Necrosis Factor-α Converting Enzyme Are Protected From Obesity-Induced Insulin Resistance and Diabetes

10.2337/db07-0360