Mice heterozygous for tumor necrosis factor-α converting enzyme are protected from obesity-induced insulin resistance and diabetes

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 wildtype 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. © 2007 by the American Diabetes Association.