OBJECTIVE: 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. 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.
OBJECTIVE: 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. 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.
Authors: Janice M Zabolotny; Young-Bum Kim; Laura A Welsh; Erin E Kershaw; Benjamin G Neel; Barbara B Kahn Journal: J Biol Chem Date: 2008-02-14 Impact factor: 5.157
Authors: Bridget M Ford; Assaad A Eid; Monika Göőz; Jeffrey L Barnes; Yves C Gorin; Hanna E Abboud Journal: Am J Physiol Renal Physiol Date: 2013-05-15
Authors: A Monroy; S Kamath; A O Chavez; V E Centonze; M Veerasamy; A Barrentine; J J Wewer; D K Coletta; C Jenkinson; R M Jhingan; D Smokler; S Reyna; N Musi; R Khokka; M Federici; D Tripathy; R A DeFronzo; F Folli Journal: Diabetologia Date: 2009-07-25 Impact factor: 10.122