Abstract
Obesity is a persistent and continuously expanding social health concern. Excessive fat mass accumulation is associated with increased risk of chronic diseases including diabetes, atherosclerosis, non-alcoholic steatohepatitis, reproductive dysfunctions and certain types of cancer. Alchemilla monticola Opiz. is a perennial plant of the Rosaceae family traditionally used to treat inflammatory conditions and as a component of weight loss herbal mixtures. In the search for bioactive leads with potential anti-adipogenic effect from A. monticola extract (ALM), we have employed nuclear magnetic resonance (NMR) based metabolomics to obtain data for the phytochemical profile of the extract. Further, molecular docking simulation was performed against key adipogenic targets for selected pure compounds, present in the ALM extract. Evaluation of the biological activity was done in human adipocytes exposed to ALM (5, 10 and 25 μg/ml), pure astragalin (AST) or quercitrin (QUE) both at the concentrations of 5, 10 and 25 μM. Investigation of the molecular pathways involved was performed through real-time quantitative PCR and Western blot analyses. According to the docking predictions strong putative affinity was revealed for both AST and QUE towards peroxisome proliferator-activated receptor gamma (PPARγ) and phosphoinositide 3-kinase (PI3K). Assessment of the intracellular lipid accumulation revealed anti-adipogenic activity of ALM. Correspondingly, the expression of the adipogenic genes CCAAT/enhancer-binding protein alpha (CEBPA) and PPARG was downregulated upon ALM and AST treatment. The Western blotting results exposed protein kinase B (AKT), PI3K and PPARγ as targets for the inhibitory effect of ALM and AST on adipogenesis. Collectively, we provide a broader insight of the phytochemical composition of A. monticola. Additionally, we demonstrate the anti-adipogenic effect of ALM and its active compound AST in human adipocytes. Furthermore, PI3K/AKT signaling pathway is identified to mediate the ALM anti-adipogenic action. Hence, the ALM extract and its secondary metabolite AST are worth further exploration as potentially active agents in obesity management.
Highlights
Obesity and obesity-related metabolic syndromes represent a pandemic-scale health threat
The activation of AKT stimulates glucose transporter 4 (GLUT4) translocation, increase the glucose influx and the lipogenesis in adipocytes (Lee et al, 2017; Huang et al, 2018; Cignarelli et al, 2019; Liu et al, 2019; Huang et al, 2021). These stimulatory signals are processed by the key players CCAAT-enhancer-binding proteins (C/EBPs), peroxisome proliferator-activated receptors (PPARs), and sterolregulatory-element-binding protein (SERBP) and their downstream targets responsible for lipid biosynthesis such as fatty acid synthase (FASN) and acetyl-coA carboxylase (ACC) to transform the precursor cell into a mature adipocyte (Kim et al, 2018; Vasileva et al, 2018; Cignarelli et al, 2019; Mandl et al, 2019; Wang et al, 2021)
The phytochemical characterization of Alchemilla monticola Opiz. (ALM) extract was performed by 1H nuclear magnetic resonance (NMR) and heteronuclear single quantum coherence spectroscopy (HSQC) profiling
Summary
Obesity and obesity-related metabolic syndromes represent a pandemic-scale health threat. The activation of AKT stimulates glucose transporter 4 (GLUT4) translocation, increase the glucose influx and the lipogenesis in adipocytes (Lee et al, 2017; Huang et al, 2018; Cignarelli et al, 2019; Liu et al, 2019; Huang et al, 2021) These stimulatory signals are processed by the key players CCAAT-enhancer-binding proteins (C/EBPs), peroxisome proliferator-activated receptors (PPARs), and sterolregulatory-element-binding protein (SERBP) and their downstream targets responsible for lipid biosynthesis such as fatty acid synthase (FASN) and acetyl-coA carboxylase (ACC) to transform the precursor cell into a mature adipocyte (Kim et al, 2018; Vasileva et al, 2018; Cignarelli et al, 2019; Mandl et al, 2019; Wang et al, 2021)
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