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

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

Abbreviations: 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- converting enzyme; Timp, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; UCP, uncoupling protein; WAT, white adipose tissue

OBJECTIVE—Tumor necrosis factor (TNF)- is known to affect insulin sensitivity, glucose, and lipid metabolism through alternative and redundant mechanisms at both translational and post-translational levels. TNF- exerts its paracrine effects once the membrane-anchored form is shed and released from the cell membrane. TNF- cleavage is regulated by TNF- 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.

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