Objective:Dietary obesity is usually linked with hypothalamic leptin resistance, in which the primary impact is an interference in the homeostatic control of body weight and appetite. Notably, proanthocyanidins (PACs), which are the most abundant phenolic compounds present in human diet, modulate adiposity and food intake. The aim of this study was to assess whether PACs could re-establish appropriate leptin signalling in both the hypothalamus and peripheral tissues.Design:Male Wistar rats were fed either a standard chow diet (STD group, n=7) or a cafeteria diet (CD) for 13 weeks. The CD-fed rats were treated with either grape-seed PAC extract (GSPE) at 25 mg  per kg of body weight per day (CD+GSPE group, n=7) or with the vehicle (CD group, n=7) for the last 21 days of the study period. Specific markers for intracellular leptin signalling, inflammation and endoplasmic reticulum stress in the hypothalamus, liver, mesenteric white adipose tissue and skeletal muscle were analysed using immunoblotting and quantitative PCR.Results:GSPE treatment significantly reduced the food intake but did not reverse the hyperleptinemia and body wt gain assessed. However, the animals treated with GSPE exhibited greater hypothalamic activation of signal transducer and activator of transcription-3, which was associated with a rise in the Pomc mRNA levels compared with the CD group. In addition, this restoration of leptin responsiveness was accompanied by lower local inflammation and increased Sirt1 gene expression. The effects of the GSPE treatment in the peripheral tissues were not as evident as those in the hypothalamus, although the GSPE treatment significantly restored the mRNA levels of Socs3 and Ptp1b in the skeletal muscle.Conclusions:The use of GSPE reduces hyperphagia and improves the central and peripheral leptin resistance associated with diet-induced obesity. Our results suggest that GSPE could exert these effects partially by increasing Sirt1 expression and preventing hypothalamic inflammation.

Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD+) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD+ availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD+ levels.

Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound.

Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.

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.

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Further computational analysis shows how Ephedra's alkaloids could be used as promising lead molecules for designing more potent and selective DPP-IV inhibitors.

The interaction of leptin with its hepatic longest receptor (OBRb) promotes the phosphorylation of signal transducer and activator of transcription-3 (STAT3), protecting the liver from lipid accumulation. However, leptin signalling is disrupted in hepatic steatosis, causing leptin resistance. One promising strategy to combat this problem is the use of bioactive compounds such as polyphenols. Since resveratrol (RSV) is a modulator of lipid homeostasis in the liver, we investigated whether treatment with different doses of RSV restores appropriate leptin action and fat accumulation in palmitate-induced steatotic human hepatoma (HepG2) cells. Both RSV metabolism and the expression of molecules implicated in leptin signalling were analysed. RSV at a 10 μM concentration was entirely metabolized to resveratrol-3-sulfate after 24 and counteracted leptin resistance by increasing the protein levels of OBRb. In addition, RSV downregulated the expression of lipogenic genes including fatty acid synthase (Fas) and stearoyl-CoA desaturase-1 (Scd1) without any significant change in Sirtuin-1 (SIRT1) enzymatic activity. These results demonstrate that RSV restored leptin sensitivity in a cellular model of hepatic steatosis in a SIRT1-independent manner.