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

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.

On the track of intramembrane clippers: the SPPL2a/b proteases caught in the act in animal models.

In this issue, Ballin et al. report on their analysis of the substrate repertoire of SPPL2a and b intramembrane proteases. Based on the previous studies of their closest homologues, SPPL2c, SPPL3 and SPP, the authors hypothesized that SPPL2a/b proteases may cleave a subset of SNARE proteins. Indeed, four R-SNARE proteins, VAMP1, 2, 3 and 4, were cleaved by SPPL2a/b, both in overexpression assays and at endogenous levels. These findings have been validated by analysis of SPPL2a/b double knock-out mice tissues, which implicates these proteases in the regulation of SNARE protein turnover in vivo. The study of Ballin et al. also provides material for future studies of factors determining substrate specificity of SPPLs, as they cleave different subsets of the tail-anchored SNARE proteins. Comment on: https://doi.org/10.1111/febs.16610.