Melini, Stefania (2025) INTERACTIONS AND SYNERGY BETWEEN N-ACYLETHANOLAMINES AND/OR POLYPHENOLIC COMPOUNDS IN THE CONTROL OF OBESITY AND RELATED DISORDERS. [Tesi di dottorato]

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Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD), obesity, and diabetes are closely interconnected, as changes in glucose and lipid metabolism play a vital role in the development of all these conditions. Lipid overnutrition and following positive energy balance contribute to the redistribution of fat within metabolic organs, causing the alteration of liver-adipose tissue axis, which plays a key role in maintaining lipid and glucose homeostasis. Due to the multi-variant metabolic features of the above-mentioned disorders, more than one drug or natural product may be required to achieve proper therapeutic effects. N-acylethanolamines (NAEs) are endogenous lipids involved in the control of inflammation and energy metabolism. On the other hand, classes of natural bioactive compounds, including polyphenols and flavonoids, provide strong protective effects against steatosis, oxidative stress, inflammation, and dysbiosis, which are linked to the progression of MAFLD and obesity. The potential pharmacological effects of combining NAEs with each other or with these bioactive compounds in managing inflammation-based metabolic disorders have not yet been explored. This PhD project aimed to investigate: i) the efficacy of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. ii) the metabolic effect of OLALIAMID® (OLA), an olive oil-derived NAE mixture containing oleoylethanolamide (OEA), palmitoylethanolamide (PEA), stearoylethanolamide (SEA), and linoleylethanolamide (LEA), in limiting liver and adipose tissue dysfunction of high-fat diet (HFD)-fed mice. iii) The possible capability of NAEs to modulate cellular responses induced by metabolic stress, including autophagy and senescence. We have demonstrated that these two NAE-based formulations are effective in alleviating the metabolic disturbances associated with obesity. Specifically, NORM3 was found to counteract insulin resistance and hepatic dysmetabolism related to 'diabesity,' while OLA improved the dysfunction of the adipose tissue and liver interplay induced by obesity. OLA, as well as NORM3, reduced body weight and fat mass of obese mice and decreased insulin resistance (IR), improving hepatic glucose and lipid metabolism, as shown by in vivo tolerance tests, homeostasis model assessment (HOMA) index, leptin/adiponectin ratio, and other ex vivo determinations (i.e Western blot, and real-time PCR). Moreover, both formulations improved serum lipid and hepatic profile and the immune/inflammatory pattern of metainflammation. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. At molecular level, NORM3 treatments counteracted glucose and lipid dysmetabolism induced by HFD, restoring insulin signaling, and regulating mRNAs of key markers of involved in lipid homeostasis, including the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation. Relevantly, NORM3 exhibited a profound antioxidant activity by reducing reactive oxygen species and increasing detoxifying factors and enzymes, in both liver of obese mice and hepatocytes in vitro. Otherwise, OLA treatment improved hepatic lipid and glucose metabolism altered by lipid overnutrition and stimulated adipose tissue reprogramming deeply altered by HFD inducing the thermogenesis of brown adipocytes (iBAT) and the beigeing of subcutaneous white adipose tissue (scWAT). Notably, the NAE mixture also reduced inflammation in iBAT and promoted M1-to-M2 macrophage shift in scWAT of obese mice. The systemic anti-inflammatory effects of OLA along with the increased expression of glucose transporter 4 in scWAT contributed to the improvement of gluco-lipid toxicity and insulin sensitivity. Finally, in in vitro models of metabolic damage we demonstrated the role of each NAEs constituting our formulations in improving cellular homeostasis. Not only increasing the protective activation of autophagy in response to metabolic stress, but also reducing cellular senescence and oxidative stress triggered by chronic lipid overnutrition. Summarizing, all these findings suggest that NAE-based formulations could offer a promising therapeutic strategy for controlling obesity and its metabolic co-morbidities. Indeed, this multitarget approach may help slow the progression of complex metabolic disorders associated with lipid overnutrition, such as diabesity and MAFLD, by correcting the imbalances in glucose and lipid metabolism and restoring the functionality of the adipose tissue–liver metabolic network.

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