OBJECTIVE: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. METHODS: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. RESULTS: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to repress the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism. CONCLUSIONS: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

Centro de Investigacíon Principe Felipe Valencia Spain; Metabolic Research Laboratories Institute of Metabolic Science Addenbrooke's Hospital University of Cambridge UK

German Center for Neurodegenerative Diseases Munich Germany

German Center for Neurodegenerative Diseases Munich Germany; Neuroproteomics School of Medicine Klinikum rechts der Isar Technical University of Munich 81675 Munich Germany

Girona Biomedical Research Institute Madrid Spain

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czech Republic

Instituto de Tecnologia Química da Universidade Nova de Lisboa Oeiras Portugal

Instituto Gulbenkian de Ciência Oeiras Portugal

Instituto Gulbenkian de Ciência Oeiras Portugal; Department of Physiology Faculty of Basic Medical Sciences University of Ilorin Nigeria

Instituto Gulbenkian de Ciência Oeiras Portugal; Faculty of Veterinary Medicine Lusofona University Lisbon Portugal; Faculty of Veterinary Nursing Polytechnic Institute of Lusofonia Lisbon Portugal

Instituto Gulbenkian de Ciência Oeiras Portugal; Patrick G Johnston Centre for Cancer Research Queen's University Belfast N Ireland

Patrick G Johnston Centre for Cancer Research Queen's University Belfast N Ireland

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