基因缺失 ITIH5 会导致小鼠脂肪组织发育加快。

IF 4.3 2区 生物学 Q1 BIOLOGY Biological Research Pub Date : 2024-08-29 DOI:10.1186/s40659-024-00530-0
Thomas M Sessler, Justus P Beier, Sophia Villwock, Danny Jonigk, Edgar Dahl, Tim Ruhl
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引用次数: 0

摘要

背景:脂肪细胞因子通过调节细胞的新陈代谢、增殖、分化和分泌活性,在维持脂肪组织平衡方面发挥着关键作用。这些可溶性因子是健康脂肪组织的相关成分,而它们的缺乏则与肥胖和相关代谢疾病(如慢性炎症)的发生密切相关。在人体脂肪组织中,α-胰蛋白酶间抑制物重链 5(ITIH5)的表达与脂肪组织的发育(即个人的体重指数)成正比。因此,ITIH5 被认为是人类肥胖的惰性标志物。然而,当应用于体外脂肪干细胞时,重组(r)ITIH5 蛋白会抑制增殖和脂肪生成,这表明 ITIH5 对脂肪量的发展有负面影响。我们现在测试了 ITIH5 在体内的作用,并比较了 ITIH5+/+ 野生型与 ITIH5-/- 基因敲除小鼠:结果:相对于动物体重,遗传性缺失 ITIH5 会显著增加脂肪组织质量(p -/-细胞表现出增殖和成脂分化增加(p -/-动物对炎症介质刺激的反应更强,即这些细胞释放出更多的 IL-6 和 MCP-1(p 结论):我们的数据表明,ITIH5 可通过调节小鼠 ASC 的生物学特性来有效调节脂肪组织的发育和稳态。此外,rITIH5 蛋白的作用还强调了其作为一种治疗剂的潜力,可纠正通常与肥胖和代谢紊乱相关的脂肪组织失调。
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Genetic deletion of ITIH5 leads to increased development of adipose tissue in mice.

Background: Adipocytokines play a pivotal role in maintaining adipose tissue homeostasis by regulating cellular metabolism, proliferation, differentiation, and secretory activity. These soluble factors are relevant components for healthy adipose tissue, while their deficiency is closely associated with the development of obesity and related metabolic diseases, e.g., chronic inflammation. In human adipose tissue, inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is expressed in proportion to the development of adipose tissue, i.e., the individual's BMI. Thus, ITIH5 has been proposed to be an inert marker of human obesity. However, when applied to adipose stem cells in vitro, recombinant (r)ITIH5 protein inhibited proliferation and adipogenesis, suggesting that ITIH5 negatively affects the development of fat mass. We now tested the role of ITIH5 in vivo and compared ITIH5+/+ wildtype with ITIH5-/- knockout mice.

Results: Genetic deletion of ITIH5 significantly increased adipose tissue mass relative to animal bodyweight (p < 0.05). Next, we characterized adipose stem cells (ASCs) from both genotypes in vitro. ITIH5-/- cells exhibited increased proliferation and adipogenic differentiation (p < 0.001), which could explain the increase in adipose tissue in vivo. Furthermore, ASCs from ITIH5-/- animals were more responsive to stimulation with inflammatory mediators, i.e., these cells released greater amounts of IL-6 and MCP-1 (p < 0.001). Importantly, the application of the rITIH5 protein reversed the observed knockout effects in ASCs.

Conclusions: Our data suggest that ITIH5 potently regulates adipose tissue development and homeostasis by modulating ASC biology in mice. In addition, the effect of the rITIH5 protein underscores its potential as a therapeutic agent to correct the adipose tissue dysregulation often associated with obesity and metabolic disorders.

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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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