Deficiency of TNFα converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Endocrinology (Impact Factor: 4.5). 09/2008; 149(12):6053-64. DOI: 10.1210/en.2008-0775
Source: PubMed

ABSTRACT Energy homeostasis involves central nervous system integration of afferent inputs that coordinately regulate food intake and energy expenditure. Here, we report that adult homozygous TNFalpha 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(DeltaZn/DeltaZn) mice. Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace(DeltaZn/DeltaZn) 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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Available from: Richard Wayne Gelling, Sep 23, 2014
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    • "We and others have previously reported that the TIMP3/ADAM17 pathway is involved in the control of glucose homeostasis and adipose, hepatic, and vascular inflammation in both genetic and nutritional models of obesity in mice, as well as in patients with obesity-related T2DM and atherosclerosis (13–18). Adam17-null mice consistently show a hypermetabolic phenotype, and heterozygous Adam17+/− mice are protected from diet-induced obesity and inflammation (19,20). Furthermore, data from our and other laboratories have revealed that obesity is characterized by a deficiency of TIMP3 in white adipose tissue (WAT) and liver (14,21), suggesting that downregulation of TIMP3 in metabolic tissues may contribute to the deregulation of inflammatory pathways. "
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    • "Adult Adam17ΔZn/ΔZn mice have a lean and hypermetabolic phenotype characterized by reduced fat mass despite normal food intake. However, corticosterone (the major glucocorticoid in mice) was not altered in Adam17ΔZn/ΔZn mice [24]. Interestingly, plasma levels of leptin, a key factor in the energy homeostasis system, were reduced approximately 2-fold in Adam17ΔZn/ΔZn mice. "
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