Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity (original) (raw)
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The FASEB Journal, 2019
Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice. Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload.
Antioxidants
Long-term high-fat diet (HFD) consumption can cause weight gain and obesity, two conditions often associated with hepatic non-alcoholic fatty liver and oxidative stress. Oleoylethanolamide (OEA), a lipid compound produced by the intestine from oleic acid, has been associated with different beneficial effects in diet-induced obesity and hepatic steatosis. However, the role of OEA on hepatic oxidative stress has not been fully elucidated. In this study, we used a model of diet-induced obesity to study the possible antioxidant effect of OEA in the liver. In this model rats with free access to an HFD for 77 days developed obesity, steatosis, and hepatic oxidative stress, as compared to rats consuming a low-fat diet for the same period. Several parameters associated with oxidative stress were then measured after two weeks of OEA administration to diet-induced obese rats. We showed that OEA reduced, compared to HFD-fed rats, obesity, steatosis, and the plasma level of triacylglycerols and...
Neuropharmacology, 2005
The fatty-acid ethanolamide, oleoylethanolamide (OEA), is a naturally occurring lipid that regulates feeding and body weight [2003. Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-a. Nature 425, 90e93], a ligand-activated transcription factor that regulates several aspects of lipid metabolism [Desvergne, B., Wahli, W., 1999. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20, 649e688]). OEA reduces food intake in wild-type mice, but not in mice deficient in PPAR-a (PPAR-a ÿ/ÿ ), an effect that is also observed with the PPAR-a agonists . The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527e550]. By contrast, specific agonists of PPARd/b (GW501516) or PPAR-g (ciglitazone) have no such effect. In obese Zucker rats, which lack functional leptin receptors, OEA reduces food intake and lowers body-weight gain along with plasma lipid levels. Similar effects are seen in diet-induced obese rats and mice. In the present study, we report that subchronic OEA treatment (5 mg kg ÿ1 , intraperitoneally, i.p., once daily for two weeks) in Zucker rats initiates transcription of PPAR-a and other PPAR-a target genes, including fatty-acid translocase (FAT/ CD36), liver fatty-acid binding protein (L-FABP), and uncoupling protein-2 (UCP-2). Moreover, OEA decreases neutral lipid content in hepatocytes, as assessed by Oil red O staining, as well as serum cholesterol and triglyceride levels. The results suggest that OEA regulates lipid metabolism and that this effect may contribute to its anti-obesity properties.
Biology, 2020
The aim of this study was to compare the effect of palmitic acid (PA), a long-chain fatty acid, and lauric acid (LA), a medium-chain fatty acid, on obesity-related metabolic disorders. We used a mouse model of diet-induced obesity and fed them a modified high fat diet supplemented with 3% PA or LA for 12 wk. An LA diet led to an increase in visceral fat mass with a reduction in inflammation compared to the PA diet. We also noted that PA significantly increased systemic insulin resistance whereas LA showed only a trend towards an increase compared to lean control mice. The expression of a protein involved in muscle glucose uptake was higher in LA-treated mice compared to the PA-treated group, indicating improved muscle glucose uptake in LA-fed mice. Analysis of liver samples showed that hepatic steatosis was higher in both PA and LA-fed mice compared to lean controls. Markers of liver inflammation were not altered significantly in mice receiving PA or LA. Our data suggest that compared to PA, LA exerts less adverse effects on metabolic disorders and this could be due to the differential effects of these fatty acids in fat and muscle.
Nutrients
Oleoylethanolamide (OEA) is a naturally occurring bioactive lipid belonging to the family of N-acylethanolamides. A variety of beneficial effects have been attributed to OEA, although the greater interest is due to its potential role in the treatment of obesity, fatty liver, and eating-related disorders. To better clarify the mechanism of the antiadipogenic effect of OEA in the liver, using a lipidomic study performed by 1H-NMR, LC-MS/MS and thin-layer chromatography analyses we evaluated the whole lipid composition of rat liver, following a two-week daily treatment of OEA (10 mg kg−1 i.p.). We found that OEA induced a significant reduction in hepatic triacylglycerol (TAG) content and significant changes in sphingolipid composition and ceramidase activity. We associated the antiadipogenic effect of OEA to decreased activity and expression of key enzymes involved in fatty acid and TAG syntheses, such as acetyl-CoA carboxylase, fatty acid synthase, diacylglycerol acyltransferase, and ...
2020
α ligand with a well-known anti-inflammatory and analgesic properties (Mattace Raso et al. 2014). Recently, a cohort study investigated the effect of dysmetabolism on PEA and other congener circulating levels, whose concentration and ratio were profoundly altered in obese patients (Fanelli et al. 2018). Moreover, experimental findings demonstrate that PEA was able to manage energy balance in a rat model of mild obesity and in diabetic rats (Izzo et al. 2010, Mattace Raso et al. 2014), highlighting the metabolic features of PEA and its pharmacological potential in metabolic diseases.
Anti-inflammatory Effect of Palmitoylethanolamide on Human Adipocytes
Obesity, 2009
Obesity leads to the appearance of an inflammatory process, which can be initiated even with a moderate weight gain. Palmitoylethanolamide (PEA) is an endogenous lipid, secreted by human adipocytes, that possesses numerous anti-inflammatory properties. The main purpose of this study was to investigate the anti-inflammatory effect of PEA on human adipocytes, as well as in a murine model. The production of tumor necrosis factor-α (TNF-α) by lipopolysaccharide (LPS)-treated human subcutaneous adipocytes in primary culture and CF-1 mice was investigated by enzyme-linked immunosorbent assay. The effects of PEA on adipocyte TNF-α secretion were explored as well as some suspected PEA anti-inflammatory pathways: nuclear factor-κB (NF-κB) pathway, peroxisome proliferatoractivated receptor-α (PPAR-α) gene expression, and TNF-α-converting enzyme (TACE) activity. The effects of PEA on the TNF-α serum concentration in intraperitoneally LPS-treated mice were also studied. We demonstrate that the LPS induced secretion of TNF-α by human adipocytes is inhibited by PEA. This action is neither linked to a reduction in TNF-α gene transcription nor to the inhibition of TACE activity. Moreover, PPAR-α is not implicated in this anti-inflammatory activity. Lastly, PEA exhibits a wide-reaching anti-inflammatory action as the molecule is able to completely inhibit the strong increase in TNF-α levels in the serum of mice treated with high doses of LPS. In view of its virtual lack of toxicity, PEA might become a potentially interesting candidate molecule in the prevention of obesity-associated insulin resistance.
Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice
Biochimie, 2018
Obesity, triggered by high-fat diet (HFD), is associated to altered gustatory perception of dietary lipids. Oleanolic acid (OLA), a triterpene, has been reported to exert anti-obesity effects in animal models. Hence, we investigated the role of OLA in the modulation of oro-sensory perception of lipids in control and HFD-induced obese mice. As expected, OLA-treated obese mice exhibited a decrease in body, liver, and visceral adipose tissue weights. OLA treatment improved glucose tolerance, insulin level, plasma lipopolysaccharide (LPS), and hepatic cholesterol and triglyceride concentrations. OLA-treated obese mice exhibited higher fat preference compared to untreated obese mice, probably due to the increase in mRNA encoding CD36, a fat taste receptor, in mouse taste bud cells (mTBC). This phenomenon was associated with fatty-acid induced increases in free intracellular calcium concentrations, [Ca]i, induced in mTBC from OLA-treated obese mice. OLA also influenced the expression of m...