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Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis

A. Amin, M. Badenes, J. Tüshaus, É. de Carvalho, E. Burbridge, P. Faísca, K. Trávníčková, A. Barros, S. Carobbio, PM. Domingos, A. Vidal-Puig, LF. Moita, S. Maguire, K. Stříšovský, FJ. Ortega, JM. Fernández-Real, SF. Lichtenthaler, C. Adrain

. 2023 ; 73 (-) : 101731. [pub] 20230428

Jazyk angličtina Země Německo

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc23010909

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.

Citace poskytuje Crossref.org

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$a Amin, Abdulbasit $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Nigeria
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$a 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.
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$a Badenes, Marina $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Faculty of Veterinary Medicine, Lusofona University, Lisbon, Portugal; Faculty of Veterinary Nursing, Polytechnic Institute of Lusofonia, Lisbon, Portugal
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$a Tüshaus, Johanna $u German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
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$a de Carvalho, Érika $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Instituto de Tecnologia Química da Universidade Nova de Lisboa (ITQB-Nova), Oeiras, Portugal
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$a Burbridge, Emma $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, N. Ireland
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$a Faísca, Pedro $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
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$a Trávníčková, Květa $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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$a Barros, André $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
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$a Carobbio, Stefania $u Centro de Investigacíon Principe Felipe (CIPF), Valencia, Spain; Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, UK
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$a Domingos, Pedro M $u Instituto de Tecnologia Química da Universidade Nova de Lisboa (ITQB-Nova), Oeiras, Portugal
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$a Vidal-Puig, Antonio $u Centro de Investigacíon Principe Felipe (CIPF), Valencia, Spain; Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, UK
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$a Moita, Luís F $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
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$a Maguire, Sarah $u Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, N. Ireland
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$a Stříšovský, Kvido $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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$a Ortega, Francisco J $u Girona Biomedical Research Institute (IDIBGI), Girona, Spain; Department of Medical Sciences, University of Girona, Girona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), and Institute of Salud Carlos III (ISCIII), Madrid, Spain
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$a Fernández-Real, José Manuel $u Girona Biomedical Research Institute (IDIBGI), Girona, Spain; Department of Medical Sciences, University of Girona, Girona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), and Institute of Salud Carlos III (ISCIII), Madrid, Spain
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$a Lichtenthaler, Stefan F $u German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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$a Adrain, Colin $u Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, N. Ireland. Electronic address: c.adrain@qub.ac.uk
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