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other·endocrinology, preclinical research, biomedical research, nutrition·PMC10197113

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

Molecular Metabolism · 18 authors, 15 centres

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The study used adipose tissue-specific ADAM17 knockout mice to investigate ADAM17's role in metabolic homeostasis.

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The study used adipose tissue-specific ADAM17 knockout mice to investigate ADAM17's role in metabolic homeostasis. ADAM17^adipoq-creΔ/Δ^ mice exhibited elevated energy consumption, increased thermogenic gene expression, and were protected from diet-induced weight gain, hepatosteatosis, and insulin resistance. SEMA4B acts in an autocrine manner in brown adipocytes to repress genes involved in adipogenesis, thermogenesis, and lipid metabolism. The findings reveal a negative regulatory loop where beta-adrenoceptor activation triggers ADAM17-mediated shedding of SEMA4B, which dampens adipogenesis and thermogenesis.

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other

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endocrinology

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ORIGINAL PAPER

PMC10197113

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

Molecular Metabolism

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ABSTRACT

Abstract 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 ADAM17 adipoq-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. Keywords: ADAM17/TACE, Metabolism, Adipose tissue, Thermogenesis, Semaphorin4B Sema4b, Obesity, Cold challenge, Beta-adrenoceptor signalling

CITATION EXPORT

Abdulbasit Amin, Marina Badenes, Johanna Tüshaus et al.. Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis. Molecular Metabolism. (2023). https://doi.org/10.1016/j.molmet.2023.101731

AUTHORS

18 · 15 CENTRES

Abdulbasit Amin, Marina Badenes, Johanna Tüshaus, Érika de Carvalho, Emma Burbridge, Pedro Faísca, Květa Trávníčková, André Barros, Stefania Carobbio, Pedro M Domingos, Antonio Vidal-Puig, Luís F Moita, Sarah Maguire, Kvido Stříšovský, Francisco J Ortega, José Manuel Fernández-Real, Stefan F Lichtenthaler, Colin Adrain

1Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
2Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Nigeria
3Faculty of Veterinary Medicine, Lusofona University, Lisbon, Portugal
4Faculty of Veterinary Nursing, Polytechnic Institute of Lusofonia, Lisbon, Portugal
5German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
6Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
7Instituto de Tecnologia Química da Universidade Nova de Lisboa (ITQB-Nova), Oeiras, Portugal
8Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, N. Ireland
9Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
10Centro de Investigacíon Principe Felipe (CIPF), Valencia, Spain
11Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, UK
12Girona Biomedical Research Institute (IDIBGI), Girona, Spain
13Department of Medical Sciences, University of Girona, Girona, Spain
14CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), and Institute of Salud Carlos III (ISCIII), Madrid, Spain
15Munich Cluster for Systems Neurology (SyNergy), Munich, Germany