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Deficiency of TNF Converting Enzyme (TACE/ADAM17) Causes a Lean, Hypermetabolic Phenotype in Mice

Division of Metabolism, Endocrinology, and Nutrition (R.W.G., A.P., G.J.M., K.O., M.W.S., P.J.D.), Department of Medicine, University of Washington, Seattle, Washington 98195; Pacific Northwest Research Institute (S.A.-N., P.J.D.), Seattle, Washington 98122; and Departments of Molecular and Integrative Physiology and Pediatrics (W.Y., P.J.D.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Peter Dempsey, Departments of Pediatrics and Molecular and Integrative Physiology, University of Michigan, A520 MSRB1, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109. E-mail: petedemp{at}med.umich.edu.

Energy homeostasis involves central nervous system integration of afferent inputs that coordinately regulate food intake and energy expenditure. Here, we report that adult homozygous TNF converting enzyme (TACE)-deficient mice exhibit one of the most dramatic examples of hypermetabolism yet reported in a rodent system. Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. In the hypothalamus of these mice, neurons in the arcuate nucleus exhibit intact responses to reduced fat mass and low circulating leptin levels, suggesting that defects in other components of the energy homeostasis system explain the phenotype of Tace^Zn/Zn mice. Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace^Zn/Zn mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. These findings collectively identify a novel and potentially important role for TACE in energy homeostasis.

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