Bioactive food ingredients of mediterranean diet that improve metabolic flexibility and mitochondrial function: a strategy to promote healthy and sustainable nutrition

Homeostasis is a key factor in human health and depends on metabolic flexibility, the ability to adapt fuel oxidation to changes in energy demand, and to efficiently respond to variable conditions or activity (Goodpaster et al., Cell Metab 2017). Mitochondria represent the functional core of metabolic flexibility (Obre and Rossignol, Int J Biochem Cell Biol 2015). Thus, the impact of diet on clinical endpoints, linked to altered homeostasis, must be sought in the changes occurring in mitochondrial metabolism (Javadov et al., Cells 2020). Several bioactive food components have been identified as a promising approach to modulate metabolic flexibility, acting on mitochondrial function and insulin sensitivity (Mollica ET AL., Diabetes 2017; Lama et al., Mol Nutr Food Res 2017; Trinchese et al., Cells 2020; Trinchese et al., J Nutr Biochem 2015). 
In this context, peripheral blood mononuclear cells (PBMCs) work as “sentinel” cells capable of revealing energy metabolism of tissues that are not easily accessible (muscle, liver or adipose tissue). Indeed, PBMCs are widely used as a biomarker in nutrition studies. Since PBMCs contain respiring mitochondria, they may work also as functional biomarkers in translational bioenergetics (O'Neill et al., Nat Rev Immunol 2016;  Costa et al., Sci Rep 2021).

The main aims of the project are to:
1. Assess the effects of bioactive food ingredients of Mediterranean diet in a murine model analyzing: energy balance; body composition; insulin sensitivity; mitochondrial bioenergetics in different tissues (liver, skeletal muscle and brain), and in PBMCs; cellular processes of energy transduction and regulatory mechanisms of ROS production.
2. Assess the effects of an adequate healthy dietary patterns during the first 1000 days window by analyzing the effects of the administration of the milk (gold standard for infant nutrition) in a murine model.
3. Investigate the impact of the nutritional status on the metabolic adaptations of PBMCs in individuals belonging to the PERMED cohort. In addition, the pathways that drive the metabolic flexibility and its interplay with insulin sensitivity, immune and inflammatory profile will be explored. 
Preclinical studies on animal model and analyses in humans are subjected to approval by the Ethics Committee.

This project will allow to shed light on the ability of metabolic and nutritional factors in modifying the metabolic flexibility. Our results may have a great relevance in shaping personalized strategies for promoting healthy and sustainable nutrition, and they will allow to identify bioactive food ingredients of Mediterranean Diet as modulators of the processes underlying metabolic flexibility such as mitochondrial function, lipid and glucose metabolism and insulin sensitivity.
Moreover, the investigation of the PBMCs mitochondrial metabolism represents an innovative approach to simultaneously monitor the metabolic panel and the immune functionality, which are continuously and physiologically changing during the lifetime.