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Baicalin alleviates lipid accumulation in adipocytes via inducing metabolic reprogramming and targeting Adenosine A1 receptor

ABSTRACT: Excessive lipid accumulation can lead to obesity, metabolic-associated fatty liver disease, and type 2 diabetes. However, there are currently few drugs that could effectively and safely inhibit the accumulation of intracellular lipid. In this study, we observed that baicalin significantly altered cellular respiration by reducing mitochondrial oxygen consumption while enhancing glycolytic flux, accompanied by increased phosphorylation of AMPK and ACC, suggesting an adaptation to altered energy availability. Baicalin effectively reduced lipid droplet formation and intracellular triglyceride levels in adipocytes, as marked by downregulating genes and proteins associated with lipid storage, including Cd36, Fabp4, and FASN. Transcriptomic analysis identified 2,150 differentially expressed genes in baicalin-treated adipocytes, with significant enrichment in metabolic pathways such as glycolysis, gluconeogenesis, and lipid metabolism. Further analysis revealed that baicalin upregulated glycolytic and fatty acid β-oxidation (FAO) pathways while downregulating pyruvate dehydrogenase, inducing a shift toward glycolysis and FAO for energy production. Molecular docking analysis revealed that adenosine A1 receptor (ADORA1) was the target of baicalin, which inhibited the maturation of sterol regulatory element binding protein 1 (SREBP1) and finally alleviated lipid deposition. These results demonstrate that baicalin induces metabolic reprogramming of adipocytes by inhibiting glucose aerobic metabolism while enhancing anaerobic glycolysis and FAO. Meanwhile, baicalin targets ADORA1, which subsequently influences the processing of SREBP1 and downregulates lipid biosynthesis, positioning baicalin as a potential therapeutic agent against obesity and related metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE285116 | GEO | 2024/12/25

REPOSITORIES: GEO

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Project description:Human monocyte-derived dendritic cells (moDCs) have been used as an in vitro model for studying tolerance and immunity. However, the underlying metabolic states of tolerogenic (dexamethasone and vitamin D3-treated), immature and immunogenic (mature, LPS-treated) moDCs have not been completely characterized. Through transcriptomic analyses, we determined that tolerogenic moDCs exhibit augmented catabolic pathways with respect to oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis. Functionally, tolerogenic moDCs showed the highest mitochondrial membrane potential, production of reactive oxygen species and superoxide, and increased mitochondrial spare respiratory capacity. Tolerogenic and mature moDCs manifested differential FAO gene expression with FAO activity being significantly higher in tolerogenic and immature moDCs than in mature. In addition, tolerogenic and mature moDCs demonstrated similar levels of glycolytic rate, but not glycolytic capacity and reserve, which were more pronounced in tolerogenic and immature moDCs. Finally, tolerogenic and immature moDCs, but not mature moDCs, showed high plasticity to compensate the intracellular ATP content after inhibition of different energetic metabolic pathways. Overall, tolerogenic moDCs exhibit a metabolic signature of increased, stable OXPHOS programing and high plasticity for metabolic adaptation. These findings provide a framework for future research of metabolic properties of human DCs. Total RNA of sixteen samples from four moDC types (tolerogenic, LPS-tolerogenic, immature and mature) were extracted by Trizol (Invitrogen) followed by a clean-up procedure using RNeasy Micro Kit (Qiagen). All RNA samples had an integrity number ≥9.6 assessed by Agilent Bioanalyzer. Total RNA samples were amplified using TargetAmp™ and the biotinilated cRNA was prepared by Nano-g™ Biotin-aRNA Labeling Kit for the Illumina® System (Epicentre). After the hybridization to the Illumina Human HT-12 v4 Beadchips for 17 h at 58°C, the arrays were washed, stained (Illumina Wash Protocol) and then scanned using BeadArray Scanner 500GX. Array data were extracted at the probe level without background correction using Illumina GenomeStudio software. These raw data were quantile normalized and log2 transformed. Technical replicates were obtained from the hybridization in duplicate of three samples. Pearson correlation analysis showed high correlation between the technical replicates (r>0.99). Differentially expressed genes (DEGs) were identified using Limma16 with Benjamini-Hochberg multiple testing correction (p<0.05). DEGs were further clustered into different groups according to the patterns of expression change among the different moDC types using STEM software17. The analysis was performed in R v.2.12.2 (http://www.R-project.org) with Bioconductor 2.12 (http://www.bioconductor.org) and enabled by Pipeline Pilot (www.accelrys.com).

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Baicalin alleviates lipid accumulation in adipocytes via inducing metabolic reprogramming and targeting Adenosine A1 receptor

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