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

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.

Resveratrol Treatment Enhances the Cellular Response to Leptin by Increasing OBRb Content in Palmitate-Induced Steatotic HepG2 Cells

“…However, in the present study, despite this improvement of leptin signalling, cells treated with RSV did not display a significant decrease in markers of inflammation and ER stress, indicating that RSV at the dosage used in this experiment was not sufficient to completely reverse these cellular alterations. These data are consistent with previous results obtained in cafeteria Wistar rats supplemented with different doses of RSV (25, 100, and 200 mg/kg body weight) in which we did not find significant differences in hepatic inflammatory and ER stress markers [7]. Instead, in this previous study [7], SIRT1 activity was highlighted as a mediator of leptin action in this tissue.…”

“…These data are consistent with previous results obtained in cafeteria Wistar rats supplemented with different doses of RSV (25, 100, and 200 mg/kg body weight) in which we did not find significant differences in hepatic inflammatory and ER stress markers [7]. Instead, in this previous study [7], SIRT1 activity was highlighted as a mediator of leptin action in this tissue.…”

“…In the present study, we found that RSV increased the cellular response to leptin by increasing the OBRb content in steatotic HepG2 cells and reduced the intracellular lipid content without any significant change in SIRT1 activity, inflammatory status, or ER stress markers. Previous studies have already shown the relevance of leptin receptor/STAT3-dependent signals in the regulation of lipid homeostasis [18], as well as the effect of RSV on hyperleptinaemia by increasing pSTAT3 content in the hypothalamus of adult offspring from high-fat-obese rats [19] and in the metabolic tissues of cafeteria-obese rats [7]. However, to the best of our knowledge, this article provides the first instances of evidence regarding the molecular mechanisms by which these beneficial effects of RSV are achieved in hepatic cells.…”

“…Finally, we evaluated whether RSV treatment could enhance SIRT1 activity, which is an additional mechanism involved in the regulation of leptin signalling in hepatic cells [7]. However, the deacetylase activity of SIRT1 was not significantly affected after 24 h of treatment with RSV at any dose ( Figure 5A).…”

“…Within this context, we have previously reported that a polyphenol-rich extract from grape seeds protects against hepatic fat accumulation by increasing the availability of cellular nicotinamide adenine dinucleotide (NAD + ) and the functionality of sirtuin 1 (SIRT1) [4]. In addition, resveratrol (3,5,4'-trihydroxystilbene, RSV), a dietary non-flavonoid polyphenol found in grapes (0.002-0.008 mg/g) and red wine (1.98-7.13 mg/L) has also been found to protect the liver against lipid metabolic disorders in various rodent models of hepatic steatosis, possibly via regulating SIRT1 activity and endoplasmic reticulum (ER) stress [5][6][7]. In fact, RSV has been indicated to have a wide range of biological effects, including cardioprotective, anticancer, anti-inflammatory, and antioxidant properties [8,9].…”