Potential Involvement of Peripheral Leptin/STAT3 Signaling in the Effects of Resveratrol and Its Metabolites on Reducing Body Fat Accumulation.

Andrea Ardid-Ruiz,Begoña Muguerza,Gerard Aragonès,Daniele Del Rio,Pedro Mena,Cinta Bladé,Manuel Suárez,Lluís Arola,Maria Ibars

doi:10.3390/nu10111757

Abstract

Bioactive compounds such as polyphenols have increased in importance in recent years, and among them, resveratrol (3,5,4′-trihydroxy-trans-stilbene) has generated great interest as an anti-obesity agent. Recent investigations have highlighted the importance of leptin signaling in lipid metabolism in peripheral organs. The aims of this study were (1) to investigate whether resveratrol can reduce fat accumulation in peripheral tissues by increasing their leptin sensitivity and (2) to identify which resveratrol-derived circulating metabolites are potentially involved in these metabolic effects. Serum leptin levels and the leptin signaling pathway were assessed in diet-induced obese rats. Moreover, serum metabolites of resveratrol were studied by ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MSn). The daily consumption of 200 mg/kg of resveratrol, but not doses of 50 and 100 mg/kg, reduced body weight and fat accumulation in obese rats and restored leptin sensitivity in the periphery. These effects were due to increases in sirtuin 1 activity in the liver, leptin receptors in muscle and protection against endoplasmic reticulum (ER)-stress in adipose tissue. In general, the resveratrol metabolites associated with these beneficial effects were derived from both phase II and microbiota metabolism, although only those derived from microbiota increased proportionally with the administered dose of resveratrol. In conclusion, resveratrol reversed leptin resistance caused by diet-induced obesity in peripheral organs using tissue-specific mechanisms.

Highlights

Obesity, defined by the World Health Organization (WHO) as excessive fat accumulation, has been increasing in recent decades and is reaching epidemic proportions [1]
The CAF diet for 12 weeks consistently resulted in obesity, as indicated by the significantly body weight gain (50.1% higher) and total body fat mass (124.3% higher, assessed by nuclear magnetic resonance (NMR) scanning) higher body weight gain (50.1% higher) and total body fat mass
Since the efficacy of orally administered RSV depends on its absorption and metabolism, we investigated whether RSV and its metabolites found in the bloodstream can account for the observed anti-obesity effects after the daily consumption of RSV for 22 days

Summary

Introduction

Obesity, defined by the World Health Organization (WHO) as excessive fat accumulation, has been increasing in recent decades and is reaching epidemic proportions [1]. Compliance with these treatments is frequently poor, especially in the long term, and they are less successful than expected [4] In this context, the scientific community is interested in naturally occurring bioactive compounds such as polyphenols that may be useful in body weight management [5]. The scientific community is interested in naturally occurring bioactive compounds such as polyphenols that may be useful in body weight management [5] Among these molecules, resveratrol (3,5,40 -trihydroxy-trans-stilbene, RSV), a 14-carbon skeleton stilbene consisting of two aromatic rings with hydroxyl groups in position 3, 5, and 40 , joined by a double styrene bond, has been found to provide a wide range of benefits for many metabolic diseases, including cardiovascular and neurological protective, thermogenic, antioxidant, anti-inflammatory, antiviral and anticancer activities [6,7,8,9,10,11]. RSV is a well-described activator of NAD+ -dependent deacetylase sirtuin 1

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