Cimmino, Fabiano Effects of N-acylethanolamines on glucose and lipid metabolism in a murine model of diet-induced obesity: modulation of mitochondrial function. [Tesi di dottorato]

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Abstract

Metabolic flexibility represents the ability to efficiently adapt the oxidation of energy substrates to the availability of nutrients by managing the sensing, uptake, transport, storage and utilization of nutrients. Mitochondria are key players in managing metabolic flexibility, regulating the capacity and efficiency of ATP production in response to the cell's energy demands to ensure metabolic homeostasis. Reduced metabolic flexibility has been associated with obesity and type 2 diabetes, but it is not yet known whether this altered condition is the cause or the consequence of these diseases. N-acylethanolamines (NAEs) are lipid mediators that are members of the fatty acid ethanolamines family. Palmitoylethanolamide (PEA), oleoylethanolamide (OEA) and stearoylethanolamide (SEA) are examples of these molecules. They are also called “endocannabinoid-like molecules” as they are structurally similar to endocannabinoids but do not bind to their CB1 and CB2 receptors. For this reason, they are part of the complex world of the endocannabinoidome (eCBome). These molecules bind to peroxisome proliferator-activated receptors (PPARs), intracellular lipid sensors capable of modulating metabolic pathways in response to substrate availability and involved in controlling the expression of a wide range of metabolic and inflammatory genes. Other targets of NAEs are transient receptor potential vanilloid type 1 (TRPV1), and G-protein-coupled receptors GPR55 and GPR119, implying an involvement of these molecules in the regulation of energy homeostasis, appetite, pain sensation, inflammation, immunity, obesity and dysmetabolism. Furthermore, the gut microbiome, which is altered in obese individuals, and the eCBome may communicate and influence each other as they play their role in nutrient processing. The aim of the research included the study, in animal models of diet-induced obesity, of the NAEs effects on glucose and lipid metabolism, in the modulation of mitochondrial function and consequently in the ability of these organelles to manage metabolic flexibility. The results obtained contribute to clarify the involvement of NAEs in inflammation and metabolic flexibility, demonstrating for the first time a link between NAEs levels and mitochondrial function.

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