Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis
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ABSTRACT:
PROVIDER: PRJNA948408 | ENA |
REPOSITORIES: ENA
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Project description: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-cre 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 dampen the expression of genes involved in thermogenesis, adipogenesis, and lipid uptake, storage and catabolism. Conclusion: 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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Project description:This study investigates the role of ADAM17 (a disintegrin and metalloproteinase 17) in skin homeostasis. Here, we show that mice lacking ADAM17 in keratinocytes have a normal epidermal barrier and skin architecture at birth, but develop pronounced defects in epidermal barrier integrity soon after birth and chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 days after birth, followed by transepidermal water loss and inflammatory immune cell infiltration. Our results identify a previously unappreciated critical role of the ADAM17/EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier. The genome-wide effects of ADAM17 deficiency were analyzed using Agilent Whole Mouse Genome microarrays. Conditional keratinocyte-specific ADAM17 knockout mice were generated by crossing Adam17flox/flox mice with keratin-14-Cre (Krt14-Cre) transgenic mice. Adam17flox/+Krt14-Cre mice were mated with Adam17flox/flox mice to generate pups of Adam17flox/flox Krt14-Cre positive (cKO) and Krt14-Cre negative (wild-type) control littermates. The genetic background was a mix of 129Sv and C57BL/6. As material, back skin tissue biopsies (postnatal day 10) from n = 2 wild-type skin and n = 2 ADAM17 epidermal KO skin (matched WT-cKO pairs from two different litters) were used in this study.
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Project description:Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalisation, including death. Despite the global health burden of pancreatitis, currently there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumour necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signalling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice – which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression – and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-week) and chronic (20-weeks) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was upregulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor; A17pro) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signalling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, upregulation of the ADAM17/IL-6 trans-signalling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
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