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Ex vivo human peripheral blood mononuclear cell (PBMC) systems offer the possibility to test transcriptomic effects of food bioactive compounds with potential health effects. We investigated all-trans retinoic acid (ATRA) effect on mRNA expression of key lipid metabolism and inflammatory genes in PBMCs from normal-weight (NW) and overweight-obese (OW-OB) men with different metabolic syndrome-related features. PBMCs were incubated with 10 µM ATRA and mRNA levels of selected genes were analyzed using real-time RT-qPCR. Human ex vivo PBMCs responded to ATRA treatment, but the response for some genes was dependent on body mass index (BMI), with a lower response in PBMC from OW-OB than from NW donors. Moreover, gene expression response was affected by circulating high-density lipoprotein (HDL)-cholesterol levels. Particularly, the response to ATRA of CPT1A , previously reported as a sensitive metabolic risk predictive biomarker, was dependent on HDL levels and not on BMI, being impaired in those individuals with lower HDL levels, specifically in OW-OB. Thus, PBMCs' insensitivity to ATRA, which can be considered as indicative of impaired metabolism, was observed in individuals with higher metabolic risk (OW-OB with low HDL levels). In conclusion, an ex vivo human PBMC system indicates that ATRA response could be influenced by metabolic syndrome features. Moreover, our study reinforces the role of CPT1A as a marker of metabolic risk and points to plasmatic HDL-cholesterol levels as a parameter to take into consideration when the effects of nutritional factors and/or dietary interventions on humans are under study. Further studies including women are required to detect potential gender differences in the observed effects.

Impaired CPT1A Gene Expression Response to Retinoic Acid Treatment in Human PBMC as Predictor of Metabolic Risk