Annunziata, Chiara (2020) Pharmacological effects of Palmitoylethanolamide, an endogenous N-acylethanolamines, in modulation of mitochondrial and metabolic function. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Pharmacological effects of Palmitoylethanolamide, an endogenous N-acylethanolamines, in modulation of mitochondrial and metabolic function
Date: 10 March 2020
Number of Pages: 103
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Dottorato: Scienza del farmaco
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
D'Auria, Maria
Date: 10 March 2020
Number of Pages: 103
Keywords: obesity, NAFLD, metabolic flexibility, mitochondrial dysfunction, lipid metabolism, brown adipose tissue
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/14 - Farmacologia
Date Deposited: 19 Mar 2020 11:25
Last Modified: 10 Nov 2021 11:33

Collection description

Liver and adipose tissue are closely related, and their mutual connection directly affects the whole-body energy homeostasis, being the key regulators of metabolic function. Not surprisingly, non-alcoholic fatty liver disease (NAFLD) and obesity usually arise in the same individual together with other metabolic abnormalities such as hypertension, atherosclerosis and hyperlipidemia and lead to the onset of a serious clinical condition known as metabolic syndrome. Palmitoylethanolamide (PEA) is an endogenous Autacoid Local Injury Antagonist amides (ALIAmide), biosynthesized on demand to maintain homeostasis in cell when it is insulted by stress-conditions. Pharmacological properties of PEA include analgesic, anti-inflammatory and neuroprotective effect. Over the years, PEA has been recognized as a potent agonist of peroxisome proliferator-activated receptor (PPAR)-α, whose activation mediates the anti-inflammatory and analgesic effects evoked by this lipid mediator. PPAR-α, as nuclear transcription factor, controls the complex network and pathways underlying cellular energy requirements and lipid and glucose metabolism. The aim of the study was focused on immunometabolic and pharmacological effects of PEA in a mouse model of obesity and correlated disease (i.e. non-alcoholic fatty liver disease, NAFLD) due to overnutrition induced by the assumption of a high fat diet (HFD). Long-term administration of PEA (30mg/kg/die) limited hepatic metabolic inflexibility in obese mice through the activation of 5' adenosine 5'monophosphate-activated protein kinase (AMPK) pathway, the signaling cascade that provides metabolic regulation of the cells according with nutrient status. PEA enhanced mitochondrial oxidative capacity and energy efficiency in hepatic isolated mitochondria. In vitro evidence addressed the direct involvement of AMPK in PEA-induced adaptative setting. PEA treatment ameliorated hepatocytes metabolism, improving mitochondrial bioenergetics and recovering mitochondrial dysfunction in insulin-resistant cells. In the latter part of the study, is described the effect of PEA on brown and white adipose tissue (BAT and WAT, respectively) activation and function. PEA promoted the recovery of BAT morphological features activation and allowed the adaptative thermogenesis in response to overfeeding. Furthermore, in subcutaneous W A T , this lipid mediator reverted adipose leptin resistance and induced tissue plasticity stimulating fat metabolism in obese mice. In light of the obtained data, PEA can be considered a therapeutic tool to improve metabolic flexibility impaired by obesity. PEA limits metabolic impairment, counteracting lipid accumulation in liver and adipose tissue, the main tissues involved in energy homeostasis and metabolism. The beneficial effects of PEA may be the result of multiple direct and indirect converging mechanisms: the improvement of mitochondrial efficiency, its well- known anti-inflammatory effects, and its new determined capability to modulate adipose tissue plasticity.


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