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


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.
Serino
Matteo
M
Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Menghini
Rossella
R
Fiorentino
Loredana
L
Amoruso
Roberta
R
Mauriello
Alessandro
A
Lauro
Davide
D
Sbraccia
Paolo
P
Hribal
Marta L
ML
Lauro
Renato
R
Federici
Massimo
M
D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics*; D000072198:ADAM17 Protein; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D003920:Diabetes Mellitus / Q000517:prevention & control*; D004041:Dietary Fats / Q000494:pharmacology; D006580:Genetic Carrier Screening; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification
D004041:Dietary Fats; D012313:RNA; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse