Obesity is a multifactorial disorder involving an abnormal or excessive amount of body fat. Obese people have a very high probability of developing metabolic syndrome, a condition in which cholesterol, lipid, and glucose levels rise, causing diabetes and heart disease. From the point of view of energy balance, the main contributors to obesity are excessive energy intake, inadequate energy expenditure and metabolic malfunctions. For this reason, health organisations are working to implement policies and plans to promote healthy eating and active living. However, these measures have not yet proven sufficient to combat this worldwide epidemic; therefore, drugs and bioactive compounds are being investigated to complement the existing strategies. In the present review, we discuss the available data regarding the modulation of obesity by proanthocyanidin rich extracts. Because studies with human subjects are very scarce, we focus on studies using laboratory animals. The results of in vitro studies are included because, although they cannot be directly extrapolated to the biological effects of proanthocyanidin, they can reveal some mechanisms of action.

Modulation of miR-33 and miR-122 has been proposed to be a promising strategy to treat dyslipidemia and insulin resistance associated with obesity and metabolic syndrome. Interestingly, specific polyphenols reduce the levels of these mi(cro)RNAs. The aim of this study was to elucidate the effect of polyphenols of different chemical structure on miR-33a and miR-122 expression and to determine whether direct binding of the polyphenol to the mature microRNAs (miRNAs) is a plausible mechanism of modulation. The effect of two grape proanthocyanidin extracts, their fractions and pure polyphenol compounds on miRNA expression was evaluated using hepatic cell lines. Results demonstrated that the effect on miRNA expression depended on the polyphenol chemical structure. Moreover, miR-33a was repressed independently of its host-gene SREBP2. Therefore, the ability of resveratrol and epigallocatechin gallate to bind miR-33a and miR-122 was measured using 1H NMR spectroscopy. Both compounds bound miR-33a and miR-122 and differently. Interestingly, the nature of the binding of these compounds to the miRNAs was consistent with their effects on cell miRNA levels. Therefore, the specific and direct binding of polyphenols to miRNAs emerges as a new posttranscriptional mechanism by which polyphenols could modulate metabolism.

These results suggest that proanthocyanidin treatment increased hepatic cholesterol efflux to produce new HDL particles by repressing miR-33, and it reduced lipogenesis by repressing miR-122. These results highlight a new mechanism by which grape seed proanthocyanidins produce hypolipidemia through their effects on miRNA modulators of lipid metabolism.

miR-33 and miR-122 are major regulators of lipid metabolism in the liver, and their deregulation has been linked to the development of metabolic diseases such as obesity and metabolic syndrome. However, the biological importance of these miRNAs has been defined using genetic models. The aim of this study was to evaluate whether the levels of miR-122 and miR-33a in rat liver correlate with lipemia in nutritional models. For this purpose, we analyzed the levels of miRNA-33a and miR-122 in the livers of dyslipidemic cafeteria diet-fed rats and of cafeteria diet-fed rats supplemented with proanthocyanidins and/or ω-3 PUFAs because these two dietary components are well-known to counteract dyslipidemia. The results showed that the dyslipidemia induced in rats that were fed a cafeteria diet resulted in the upregulation of miR-33a and miR-122 in the liver, whereas the presence of proanthocyanidins and/or ω-3 PUFAs counteracted the increase of these two miRNAs. However, srebp2, the host gene of miR-33a, was significantly repressed by ω-3 PUFAs but not by proanthocyanidins. Liver mRNA levels of the miR-122 and miR-33a target genes, fas and pparβ/δ, cpt1a and abca1, respectively, were consistent with the expression of these two miRNAs under each condition. Moreover, the miR-33a and abca1 levels were also analyzed in PBMCs. Interestingly, the miR-33a levels evaluated in PBMCs under each condition were similar to the liver levels but enhanced. This demonstrates that miR-33a is expressed in PBMCs and that these cells can be used as a non-invasive way to reflect the expression of this miRNA in the liver. These findings cast new light on the regulation of miR-33a and miR-122 in a dyslipidemic model of obese rats and the way these miRNAs are modulated by dietary components in the liver and in PBMCs.

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Metabolism follows circadian rhythms, which are driven by peripheral clocks. Clock genes in the liver are entrained by daytime meals and food components. Proanthocyanidins (PAs), the most abundant flavonoids in the human diet, modulate lipid and glucose metabolism. The aim of this study was to determine whether PAs could adjust the clock system in the liver. Male Wistar rats were orally gavaged with 250 mg grape seed proanthocyanidin extract (GSPE)/kg body weight at zeitgeber time (ZT) 0 (light turned on), at ZT12 (light turned off), or before a 6 hour jet-lag and sacrificed at different times. The 24 hour rhythm of clock-core and clock-controlled gene expression indicated that nicotinamide phosphoribosyltransferase (Nampt) was the most sensitive gene to GSPE. However, Nampt was repressed or overexpressed after GSPE administration at ZT0 or ZT12, respectively. NAD levels, which are controlled by Nampt and also exhibit circadian rhythm, decreased or increased according to Nampt expression. Moreover, the ratio of acetylated Bmal1, that directly drives Nampt expression, only increased when GSPE was administered at ZT12. Therefore, GSPE modulated the clock system in the liver, suggesting that PAs can regulate lipid and glucose metabolism by adjusting the circadian rhythm in the liver.

Obesity is associated with the hypertrophy and hyperplasia of adipose tissue, affecting the healthy secretion profile of pro- and anti-inflammatory adipokines. Increased influx of fatty acids and inflammatory adipokines from adipose tissue can induce muscle oxidative stress and inflammation and negatively regulate myocyte metabolism. Muscle has emerged as an important mediator of homeostatic control through the consumption of energy substrates, as well as governing systemic signaling networks. In muscle, obesity is related to decreased glucose uptake, deregulation of lipid metabolism, and mitochondrial dysfunction. This review focuses on the effect of epigallocatechin-gallate (EGCG) on oxidative stress and inflammation, linked to the metabolic dysfunction of skeletal muscle in obesity and their underlying mechanisms. EGCG works by increasing the expression of antioxidant enzymes, by reversing the increase of reactive oxygen species (ROS) production in skeletal muscle and regulating mitochondria-involved autophagy. Moreover, EGCG increases muscle lipid oxidation and stimulates glucose uptake in insulin-resistant skeletal muscle. EGCG acts by modulating cell signaling including the NF-κB, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK) signaling pathways, and through epigenetic mechanisms such as DNA methylation and histone acetylation.

PAs could have chronobiological properties, although their activity depends largely on the time of administration.