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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
Adipocyte ( IF 3.3 ) Pub Date : 2021-04-19 , DOI: 10.1080/21623945.2021.1910154
Catherine A Tindall 1 , Estelle Erkner 1 , Jan Stichel 1 , Annette G Beck-Sickinger 1 , Anne Hoffmann 2 , Juliane Weiner 3 , John T Heiker 1, 2
Affiliation  

ABSTRACT

Vaspin expression and function is related to metabolic disorders and comorbidities of obesity. In various cellular and animal models of obesity, diabetes and atherosclerosis vaspin has shown beneficial, protective and/or compensatory action. While testing proteases for inhibition by vaspin, we noticed specific cleavage within the vaspin N-terminus and sequence analysis predicted cell-penetrating activity for the released peptides. These findings raised the question whether these proteolytic peptides exhibit biological activity.

We synthesized various N-terminal vaspin peptides to investigate cell-penetrating activity and analyse uptake mechanisms. Focusing on adipocytes, we performed microarray analysis and functional assays to elucidate biological activities of the vaspin–derived peptide, which is released by KLK7 cleavage (vaspin residues 21-30; VaspinN). Our study provides first evidence that proteolytic processing of the vaspin N-terminus releases cell-penetrating and bioactive peptides with effects on adipocyte biology. The VaspinN peptide increased preadipocyte proliferation, interfered with clonal expansion during the early stage of adipogenesis and blunted adrenergic cAMP-signalling, downstream lipolysis as well as insulin signalling in mature adipocytes.

Protease-mediated release of functional N-terminal peptides presents an additional facet of vaspin action. Future studies will address the mechanisms underlying the biological activities and clarify, if vaspin-derived peptides may have potential as therapeutic agents for the treatment of metabolic diseases.



中文翻译:

vaspin N 端的裂解释放细胞穿透肽,影响脂肪生成的早期阶段并抑制成熟脂肪细胞的脂肪分解

摘要

Vaspin 的表达和功能与肥胖的代谢紊乱和合并症有关。在肥胖、糖尿病和动脉粥样硬化的各种细胞和动物模型中,vaspin 已显示出有益、保护和/或补偿作用。在测试蛋白酶对 vaspin 的抑制作用时,我们注意到 vaspin N 末端内的特异性裂解,序列分析预测了释放肽的细胞穿透活性。这些发现提出了这些蛋白水解肽是否具有生物活性的问题。

我们合成了各种 N 端 vaspin 肽来研究细胞穿透活性并分析摄取机制。针对脂肪细胞,我们进行了微阵列分析和功能分析,以阐明 vaspin 衍生肽的生物活性,该肽由 KLK7 裂解(vaspin 残基 21-30;VaspinN)释放。我们的研究提供了第一个证据,即 vaspin N 端的蛋白水解过程会释放细胞穿透性和生物活性肽,并对脂肪细胞生物学产生影响。VaspinN 肽增加前脂肪细胞增殖,在脂肪生成的早期干扰克隆扩增,并减弱成熟脂肪细胞中的肾上腺素能 cAMP 信号、下游脂肪分解以及胰岛素信号。

蛋白酶介导的功能性 N 端肽的释放提供了 vaspin 作用的另一个方面。未来的研究将解决生物活性的潜在机制,并阐明 vaspin 衍生肽是否具有作为治疗代谢疾病的治疗剂的潜力。

更新日期:2021-04-19
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