INTRODUCTION: Mesenchymal stem cells (MSCs) possess endogenous reparative properties and may serve as an exogenous therapeutic intervention in patients with chronic kidney disease. Cardiovascular risk factors clustering in the metabolic syndrome (MetS) might adversely affect cellular properties. To test the hypothesis that Mets interferes with MSC characteristics, we performed comprehensive comparison of the mRNA, microRNA, and protein content of MSCs isolated from Lean and MetS pigs. METHODS: Domestic pigs were fed a 16-week Lean or MetS diet (n = 4 each). Expression profiles of co-existing microRNAs, mRNAs, and proteins were obtained by high-throughput sequencing and liquid chromatography-mass spectrometry. TargetScan and ComiR were used to predict target genes of differentially expressed microRNAs, and DAVID 6.7 for functional annotation analysis to rank primary gene ontology categories for the microRNA target genes, mRNAs, and proteins. RESULTS: Differential expression analysis revealed 12 microRNAs upregulated in MetS-MSCs compared to Lean-MSCs (fold change>1.4, p < .05), which target 7728 genes, whereas 33 mRNAs and 78 proteins were downregulated (fold change<0.7, p < .05). Integrated analysis showed that targets of those microRNAs upregulated in MetS-MSCs overlap with at least half of mRNAs and proteins dysregulated in those cells. Functional analysis of overlapping mRNAs and proteins suggest that they are primarily involved in mitochondria, inflammation and transcription. MetS-MSCs also exhibited increased nuclear translocation of nuclear factor kappa-B, associated with increased SA-β-Galactosidase and decreased cytochrome-c oxidase-IV activity. CONCLUSION: MetS alters the transcriptome and proteome of swine adipose tissue-derived MSCs particularly genes involved in mitochondria, inflammation and transcription regulation. These alterations might limit the reparative function of endogenous MSC and their use as an exogenous regenerative therapy.