Sacubitril/valsartan promotes white adipose tissue browning in rats with metabolic syndrome through activation of mTORC1

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2024-01-29 DOI:10.1002/biof.2040
Marina Nikolic, Nevena Jeremic, Nevena Lazarevic, Aleksandra Stojanovic, Andjela Milojevic Samanovic, Jovana Novakovic, Vladimir Zivkovic, Milos Nikolic, Nikola Nedeljkovic, Slobodanka Mitrovic, Vladimir Jakovljevic
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Abstract

In addition to their usual use in the treatment of cardiovascular disease, weak evidence is available for the potential of combined use of neprilysin inhibitor (sacubitril) and AT1 receptor antagonist (valsartan) to promote browning of white adipose tissue (WAT) in rats with metabolic syndrome (MetS). This study involved 32 male Wistar albino rats divided into four groups: CTRL—healthy control rats; ENT—healthy rats treated with sacubitril/valsartan; MS—rats with MetS; MS + ENT—rats with MetS treated with sacubitril/valsartan. After finishing the experimental protocol, different WAT depots were isolated for further analysis of molecular pathways. Molecular docking and molecular dynamics studies were used for in silico assessment of the binding affinity of sacubitril and valsartan towards subunits of mechanistic target of rapamycin complex 1 (mTORC1). Sacubitril/valsartan treatment markedly diminished morphological changes in adipose tissue, resulting in smaller lipid size and multilocular lipid droplet structure in WAT. We showed significantly higher protein expression of uncoupling protein-1 (UCP-1) and mTORC1 in WAT of MS + ENT rats, correlating with increased relative gene expression of browning-related markers in tissue of rats treated with sacubitril/valsartan compared with MS group of rats. In silico analysis showed that sacubitrilat and valsartan exhibited the highest binding affinity against mTOR and mLST8, forming stable complexes with these mTORC1 subunits. The observed results confirmed strong potential of combined sacubitril/valsartan treatment to increase browning markers expression in different WAT depots in MetS condition and to form permanent complexes with mTOR and mLST8 subunits over the time.

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萨库比特利/缬沙坦通过激活 mTORC1 促进代谢综合征大鼠白色脂肪组织褐变
除了通常用于治疗心血管疾病外,有微弱证据表明,联合使用肾素酶抑制剂(sacubitril)和AT1受体拮抗剂(缬沙坦)可促进代谢综合征(MetS)大鼠白色脂肪组织(WAT)的棕色化。这项研究涉及 32 只雄性 Wistar 白化大鼠,分为四组:CTRL-健康对照组;用沙库比特利/缬沙坦治疗的ENT-健康大鼠;MS-代谢综合征大鼠;用沙库比特利/缬沙坦治疗的MS + ENT-代谢综合征大鼠。完成实验方案后,分离出不同的 WAT 储库,以进一步分析分子通路。通过分子对接和分子动力学研究,对萨库比特利和缬沙坦与雷帕霉素机理靶点复合物 1(mTORC1)亚基的结合亲和力进行了硅学评估。萨库比特利/缬沙坦治疗明显减轻了脂肪组织的形态学变化,使脂肪组织中的脂质体积变小,脂滴结构呈多孔状。我们发现,与MS组大鼠相比,MS + ENT组大鼠WAT中解偶联蛋白-1(UCP-1)和mTORC1的蛋白表达明显升高,这与使用沙库比特利/缬沙坦治疗的大鼠组织中褐变相关标志物的相对基因表达增加有关。硅学分析表明,sacubitrilat 和缬沙坦对 mTOR 和 mLST8 具有最高的结合亲和力,能与这些 mTORC1 亚基形成稳定的复合物。观察结果证实,沙库比特利/缬沙坦联合治疗具有很强的潜力,可增加 MetS 状态下不同脂肪贮备中褐变标志物的表达,并与 mTOR 和 mLST8 亚基长期形成永久复合物。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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