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

Abstract

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