Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in mature adipocytes

Tindall, Catherine A; Erkner, Estelle; Stichel, Jan; Beck‐Sickinger, Annette G.; Hoffmann, Anne; Weiner, Juliane; Heiker, John T.

doi:10.1080/21623945.2021.1910154

Cited by 5 publications

(9 citation statements)

References 61 publications

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“…Microarray analysis (Clariom S Assay, mouse, Thermo Fisher) of BAT gene expression in cold‐challenged (6 h at 8°C, n = 5 per group) male Mb‐KO and NMRI WT mice was conducted at the Core Unit DNA Technologies (Core Facilities of the Faculty of Medicine; University of Leipzig) and data processing and analysis were done as previously described. 65 Briefly, raw data were preprocessed according to the oligo Bioconductor R package (v1.50.0, 66 ). The R packages oligo, Biobase (v2.46, 67 ), and arrayQualityMetrics were used for data quality control (v3.42, 68 ).…”

Section: Methodsmentioning

confidence: 99%

Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

Christen

Broghammer

Rapöhn

et al. 2022

Clinical & Translational Med

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Background Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis. Methods and Results This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole‐body MB knockout resulted in impaired thermoregulation and cold‐ as well as drug‐induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential. Conclusions These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes.

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Section: Methodsmentioning

confidence: 99%

Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

Christen

Broghammer

Rapöhn

et al. 2022

Clinical & Translational Med

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“…A further example of an alternative endocytosis mechanism is seen with protein C inhibitor (PCI), where internalization is facilitated by a cell-penetrating N-terminal sequence [64]. Similarly, the N-terminal sequence of vaspin also contains a cell-penetrating peptide sequence, which is released upon cleavage by various vaspin target and non-target proteases [30]. However, assessing the specific contribution of this sequence to vaspin internalization is challenging due to the truncation induced in the vaspinDNT variant.…”

Section: Discussionmentioning

confidence: 99%

“…However, assessing the specific contribution of this sequence to vaspin internalization is challenging due to the truncation induced in the vaspinDNT variant. This truncation affects both heparin binding and LRP1 affinity and it is important to note that the vaspinDNT variant removes more residues than those proteolytically cleaved, and the processing of the N-terminus occurs rapidly in the presence of various proteases [30]. Furthermore, the ratio of N-terminally cleaved to uncleaved vaspin in the extracellular or circulating state remains unknown.…”

Section: Discussionmentioning

confidence: 99%

LRP1 is the cell‐surface endocytosis receptor for vaspin in adipocytes

Tindall,

Möhlis,

Rapöhn

et al. 2023

The FEBS Journal

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Vaspin is a serine protease inhibitor that protects against adipose tissue inflammation and insulin resistance, two key drivers of adipocyte dysfunction and metabolic disorders in obesity. Inhibition of target proteases such as KLK7 has been shown to reduce adipose tissue inflammation in obesity, while vaspin binding to cell surface GRP78 has been linked to reduced obesity‐induced ER stress and insulin resistance in the liver. However, the molecular mechanisms by which vaspin directly affects cellular processes in adipocytes remain unknown. Using fluorescently labeled vaspin, we found that vaspin is rapidly internalized by mouse and human adipocytes, but less efficiently by endothelial, kidney, liver, and neuronal cells. Internalization occurs by active, clathrin‐mediated endocytosis, which is dependent on vaspin binding to the LRP1 receptor, rather than GRP78 as previously thought. This was demonstrated by competition experiments and RNAi‐mediated knock‐down in adipocytes and by rescuing vaspin internalization in LRP1‐deficient Pea13 cells after transfection with a functional LRP1 minireceptor. Vaspin internalization is further increased in mature adipocytes after insulin‐stimulated translocation of LRP1. Although vaspin has nanomolar affinity for LRP1 clusters II‐IV, binding to cell surface heparan sulfates is required for efficient LRP1‐mediated internalization. Native, but not cleaved vaspin, and also vaspin polymers are efficiently endocytosed, and ultimately targeted for lysosomal degradation. Our study provides mechanistic insight into the uptake and degradation of vaspin in adipocytes, thereby broadening our understanding of its functional repertoire. We hypothesize the vaspin‐LRP1 axis to be an important mediator of vaspin effects not only in adipose tissue but also in other LRP1‐expressing cells.

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“…Interestingly, glycosylation has a significant effect on vaspin molecular weight, e.g., human unglycosylated vaspin migrates at 45 kDa, whereas glycosylation increases the molecular weight by around 7.5 kDa [ 19 ]. In addition, lower migrating vaspin bands may be connected to vaspin-derived peptides from the N terminal, which are released as a reason for protease cleavage [ 21 ]. These cell-penetrating peptides have biological effects connected to preadipocyte proliferation, and also present an additional aspect of vaspin action [ 21 ].…”

Section: Vaspin Structure and Expressionmentioning

confidence: 99%

“…In addition, lower migrating vaspin bands may be connected to vaspin-derived peptides from the N terminal, which are released as a reason for protease cleavage [ 21 ]. These cell-penetrating peptides have biological effects connected to preadipocyte proliferation, and also present an additional aspect of vaspin action [ 21 ].…”

Section: Vaspin Structure and Expressionmentioning

confidence: 99%

Review: Vaspin (SERPINA12) Expression and Function in Endocrine Cells

Kurowska

Mlyczyńska

Dawid

et al. 2021

Cells

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Proper functioning of the body depends on hormonal homeostasis. White adipose tissue is now known as an endocrine organ due to the secretion of multiple molecules called adipokines. These proteins exert direct effects on whole body functions, including lipid metabolism, angiogenesis, inflammation, and reproduction, whereas changes in their level are linked with pathological events, such as infertility, diabetes, and increased food intake. Vaspin-visceral adipose tissue-derived serine protease inhibitor, or SERPINA12 according to serpin nomenclature, is an adipokine discovered in 2005 that is connected to the development of insulin resistance, obesity, and inflammation. A significantly higher amount of vaspin was observed in obese patients. The objective of this review was to summarize the latest findings about vaspin expression and action in endocrine tissues, such as the hypothalamus, pituitary gland, adipose tissue, thyroid, ovary, placenta, and testis, as well as discuss the link between vaspin and pathologies connected with hormonal imbalance.

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Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in mature adipocytes

Abstract: 2021) Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in

Cited by 5 publications

References 61 publications

Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

LRP1 is the cell‐surface endocytosis receptor for vaspin in adipocytes

Review: Vaspin (SERPINA12) Expression and Function in Endocrine Cells

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