Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity

Rubén Tovar, Ana Luisa Gavito, Antonio Vargas, Laura Soverchia, Laura Hernandez-Folgado, Nadine Jagerovic, Elena Baixeras, Roberto Ciccocioppo, Fernando Rodríguez de Fonseca, Juan Decara, Rubén Tovar, Ana Luisa Gavito, Antonio Vargas, Laura Soverchia, Laura Hernandez-Folgado, Nadine Jagerovic, Elena Baixeras, Roberto Ciccocioppo, Fernando Rodríguez de Fonseca, Juan Decara

Abstract

Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague-Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans.

Keywords: N-acylethanolamine; cannabinoid receptors type 1; hypercaloric cafeteria diet; monounsaturated fatty acids; oleic acid; oleylethanolamide; palmitoleic acid; palmitoleylethanolamide; peroxisome proliferator receptor alpha.

Conflict of interest statement

The authors declare that there are no conflict of interest. This consent was obtained from all participants of the study.

Figures

Figure 1
Figure 1
Potential mechanisms of action of palmitoleylethanolamide (POEA). POEA is the N-acylethanolamine of palmitoleic acid (POA). Upon dietetic administration, POEA might act directly through peroxisome proliferator-activated receptor alpha (PPAR-α) receptors, promoting the inhibition of lipogenesis, reduction of appetite, increase in fatty acid oxidation, and reduction of inflammation. These actions are also mimicked by palmitoleic acid, its main degradation product. In addition, POEA has been found to activate the orphan G protein-coupled receptor 119 (GPR119), resulting in a reduction of appetite and improvement of insulin action. FAAH; fatty acid amide hydrolase.
Figure 2
Figure 2
Experimental design. Animals exposed to either regular standard diet chow (STD) or a hypercaloric cafeteria diet (HFD) for 13 weeks were subsequently treated for two weeks with either vehicle (VEH), N-oleylethanolamine (OEA) and N-palmitoleoylethanolamine (POEA).
Figure 3
Figure 3
Body weight gain (A) and cumulative kcal intake (B) in animals fed for 91 days (13 weeks) with either a standard diet chow (STD) or a hypercaloric cafeteria diet (HFD). Values are expressed as mean ± standard error of the mean (SEM) (n = 32 animals/group). Two-way ANOVA and Bonferroni post hoc test: (*) p < 0.05 and (***) p < 0.001 vs. STD group.
Figure 4
Figure 4
Effects of sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) (A,B) or palmitoleylethanolamide (POEA) (C,D) in animals fed with either a standard diet (STD) or hypercaloric cafeteria diet (HFD). Data are the evolution of cumulative body weight gain in male Sprague–Dawley rats. (Panels E,F) show the total weight gain variation after 15 days of treatment. Points or bars are means ± standard error of the mean (SEM) (n = 8 animals per group). Data were analyzed by two-way ANOVA (diet and time) and Bonferroni’s post hoc test. (**) p < 0.01, and (***) p < 0.001, significant differences compared with vehicle (VEH) STD group. (#) p < 0.05, (##) p < 0.01, and (###) p < 0.001 significant differences compared with VEH HFD group.
Figure 5
Figure 5
Effects of sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA) on food intake, which was measured as g/kg body weight (A,B) or cumulative kcal (C,D). Points or bars are means ± standard error of the mean (SEM) (n = 8 animals per group). Unpaired t-test: (#) p < 0.05 vs. vehicle (VEH) group.
Figure 6
Figure 6
Effects of sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA). on the plasma levels of insulin (A) and analyzed the Homeostatic Model Assessment for Insulin Resistance (HOMA IR) (B) in male Sprague–Dawley rats. Data are expressed as means ± standard error of the mean (SEM) (n = 8 animals/group) analyzed by two-way ANOVA (diet and treatment and Bonferroni post hoc test). (*) p < 0.05 and (**) p < 0.01 significant differences compared with standard diet (STD) vehicle (VEH) group; (#) p < 0.05, (##) p < 0.01, and (###) p < 0.001 significant differences compared with hypercaloric cafeteria diet (HFD) VEH group.
Figure 7
Figure 7
Effects of sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA) on the plasma levels of cytokines in male Sprague–Dawley rats: (A) Interleukin 6 (IL-6); and (B) tumor necrosis factor alpha (TNF-α), which were evaluated at the end of the treatment. Values are presented as means ± standard error of the mean (SEM) (n = 6–8 animals/group) analyzed by two-way ANOVA (diet and treatment and Bonferroni post hoc test). (*) p < 0.05 and (***) p < 0.001 significant differences compared with standard diet (STD) vehicle (VEH) group; (#) p < 0.05, (##) p < 0.01, and (###) p < 0.001 significant differences compared with hypercaloric cafeteria diet (HFD) VEH group.
Figure 8
Figure 8
Analysis of liver protein expression of lipogenic enzymes and N-acylethanolamines (NAEs) degrading enzyme after sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA) in standard diet (STD)-fed Sprague–Dawley rats. Fatty acid synthase (FAS) (A), stearoyl-CoA desaturase (SCD1) (B), and fatty acid amide hydrolase (FAAH) (C) were analyzed by imaging densitometry. The bars show the results from six independent samples for each treatment group. (D) Representative images of Western blot analysis of liver samples for each treatment. The corresponding expression of γ-adaptin is showed as a loading control per lane. All samples were derived at the same time and processed in parallel. The bars were determined the means and corrected for γ-adaptin protein as reference ± standard error of the mean (SEM) (n = 6 samples per group). Unpaired t-test: (*) p < 0.05 and (**) p < 0.01 vs. vehicle (VEH) group.
Figure 9
Figure 9
Analysis of protein expression after sub-chronic (15 days) administration of a 10 mg/kg dose of either N-acylethanolamines (NAEs) degrading enzyme after sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA) in liver in hypercaloric cafeteria diet (HFD)-fed Sprague–Dawley rats. Fatty acid synthase (FAS) (A), stearoyl-CoA desaturase (SCD1) (B), and fatty acid amide hydrolase (FAAH) (C) were analyzed by imaging densitometry. The bars show results from six independent samples from each treatment group. (D) Representative images of Western blot analysis of liver samples for each treatment. The corresponding expression of γ-adaptin is showed as a loading control per lane. All samples were derived at the same time and processed in parallel. The bars determined the means and corrected for γ-adaptin protein as reference ± standard error of the mean (SEM) (n = 6 samples per group). Unpaired t-test: (#) p < 0.05 and (##) p < 0.01 vs. vehicle (VEH) group.
Figure 10
Figure 10
Effect of sub-chronic (15 days) administration of a 10 mg/kg dose of either oleoylethanolamide (OEA) or palmitoleylethanolamide (POEA) in liver in hypercaloric cafeteria diet (HFD) male Sprague–Dawley rats on hepatic lipid content (A) in standard diet (STD) and HFD, and corresponding representative images of liver fat content with oil red O staining, taken under a microscope with 40× objective (B–G). (H) Measurement of the total fat content in liver. Bars are means ± standard error of the mean SEM per group (n = 6 samples per group) analyzed by two-way ANOVA (diet and treatment, with Bonferroni post-hoc test). (***) p < 0.001 significant differences compared with STD vehicle (VEH) group; (#) p < 0.05, (##) p < 0.01, and (###) p < 0.001 significant differences compared with HFD VEH group.

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