Estrogen Receptor α Participates to the Beneficial Effect of Red Wine Polyphenols in a Mouse Model of Obesity-Related Disorders.

Daniela Leonetti,Luisa Vergori,Catherine Dourguia,Lucie Duluc,Nicolas Clere,Maria C Martínez,Ramaroson Andriantsitohaina,Caroline Jacques,Raffaella Soleti

doi:10.3389/fphar.2016.00529

Abstract

Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders associated with obesity. Previously, we demonstrated that the alpha isoform of estrogen receptor (ERα) triggers the vascular protection of polyphenols. Here, we investigated the contribution of ERα on the effects of polyphenols on cardiovascular and metabolic alterations associated with obesity. We used ovariectomized wild type or ERα-deficient mice receiving standard (SD) or western (WD) diets, or SD and WD containing polyphenols (SD+polyphenols and WD+polyphenols, respectively) over a 12-week period. Body weight was measured during treatment. Echocardiography examination was performed before sacrifice. Blood and tissues were sampled for biochemical and functional analysis with respect to nitric oxide (NO•) and oxidative stress. Vascular reactivity and liver mitochondrial complexes were analyzed. In WD-fed mice, polyphenols reduced adiposity, plasma triglycerides and oxidative stress in aorta, heart, adipose and liver tissues and enhanced NO• production in aorta and liver. ERα deletion prevented or reduced the beneficial effects of polyphenols, especially visceral adiposity, aortic and liver oxidative stresses and NO• bioavailability. ERα deletion, however, had no effect on polyphenol’s ability to decrease the fat accumulation and oxidative stress of subcutaneous adipose tissue. Also, ERα deletion did not modify the decrease of ROS levels induced by polyphenols treatment in the visceral adipose tissue and heart from WD-fed mice. Dietary supplementation of polyphenols remarkably attenuates features of metabolic syndrome; these effects are partially mediated by ERα-dependent mechanisms. This study demonstrates the therapeutic potential of this extract in metabolic and cardiovascular alterations linked to excessive energy intake.

Highlights

Obesity is defined as abnormal or excessive fat accumulation associated with an increased risk of premature death due to an increased incidence of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease and coronary heart disease
Polyphenols did not modify body weight of wild type (WT) mice fed with standard diet (SD) (Table 1) and it did not significantly reduce the body weight gain induced by western diet (WD) compared to control
In WT mice fed with WD, the increase of body weight was associated with higher visceral and subcutaneous adiposity compared to WT SD mice (P = 0.0002 and P = 0.0045, FIGURE 1 | The evolution of (A,B) body weight gain of estrogen receptor alpha (ERα) WT (A) and Knock Out (KO) (B) mice receiving normal diet (SD), western diet (WD), or SD and WD containing polyphenols (SD + polyphenols and WD + polyphenols, respectively) during 12 weeks

Summary

Introduction

Obesity is defined as abnormal or excessive fat accumulation associated with an increased risk of premature death due to an increased incidence of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease and coronary heart disease. Based on epidemiological studies reporting a greater reduction in cardiovascular risk and metabolic disorders associated with polyphenol-rich diet, several dietary and pharmacological approaches have been proposed to manage or prevent obesity and obesity-related diseases. Polyphenols are bioactive food compounds primarily present in fruits and vegetables and exert health benefits protecting against metabolic and cardiovascular disturbances (Andriantsitohaina et al, 2012). Polyphenols, in particular those derived from red wine, possess anti-aggregatory platelet activity, antioxidant and free radical scavenging properties (Curin et al, 2006; Pechanova et al, 2006), as well as lipidand lipoprotein-lowering effects (Curin et al, 2006). In a context of obesity, polyphenols ameliorate glucose and lipid metabolism, cardiac function, decrease peripheral resistance and improve endothelium-dependent relaxation by enhancing NO bioavailability (Agouni et al, 2009)

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