Grape seed proanthocyanidin supplementation reduces adipocyte size and increases adipocyte number in obese rats.

OBJECTIVES: White adipose tissue (WAT) expands through hypertrophy (increased adipocyte size) and/or hyperplasia (increased adipocyte number). Hypertrophy has been associated with insulin resistance and dyslipidemia independently of body composition and fat distribution. In contrast, hyperplasia protects against metabolic alterations. Proanthocyanidins, which are the most abundant flavonoids in the human diet, improve metabolic disturbances associated with diet-induced obesity without reducing body weight or adiposity. The aim of this study was to determine whether grape seed proanthocyanidin extract (GSPE) can modulate WAT expandability. Because GSPE also contains gallic acid, we also studied the capacity of gallic acid to remodel WAT. DESIGN: Male Wistar rats were fed a standard chow diet (n=6) or a cafeteria diet (CAF) for 11 weeks. After 8 weeks, the CAF-fed animals were supplemented with 25 mg GSPE/kg body weight (n=6), 7 mg gallic acid/kg body weight (n=6) or the vehicle (n=6) for 3 weeks. Histological analyses were performed in the retroperitoneal (rWAT) and inguinal (iWAT) WAT to determine adipocyte size and number. Specific markers for adipogenesis and WAT functionality were analysed in rWAT using quantitative RT-PCR. RESULTS: GSPE or gallic acid supplementation did not reduce weight gain or reverse and adiposity. However, GSPE reduced adipocyte size significantly in rWAT and moderately in iWAT and tripled the adipocyte number in rWAT. Gallic acid slightly reduced adipocyte size in rWAT and iWAT and doubled the adipocyte number in both WATs. In accordance with this adipogenic activity, Pref-1 and PPARγ tended to be overexpressed in rWAT of rats supplemented with GSPE. Moreover, GSPE supplementation increased Plin1 and Fabp4 expression and restored adiponectin expression completely, indicating a better functionality of visceral WAT. CONCLUSIONS: GSPE supplementation has anti-hypertrophic and hyperplasic activities in rats with established obesity, mainly in visceral WAT inducing a healthier expansion of WAT to match the surplus energy provided by the cafeteria diet.

Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats.

Circadian rhythm plays an important role in maintaining homeostasis, and its disruption increases the risk of developing metabolic syndrome. Circadian rhythm is maintained by a central clock in the hypothalamus that is entrained by light, but circadian clocks are also present in peripheral tissues. These peripheral clocks are trained by other cues, such as diet. The aim of this study was to determine whether proanthocyanidins, the most abundant polyphenols in the human diet, modulate the expression of clock and clock-controlled genes in the liver, gut and mesenteric white adipose tissue (mWAT) in healthy and obese rats. Grape seed proanthocyanidin extracts (GSPEs) were administered for 21 days at 5, 25 or 50 mg GSPE/kg body weight in healthy rats and 25 mg GSPE/kg body weight in rats with diet-induced obesity. In healthy animals, GSPE administration led to the overexpression of core clock genes in a positive dose-dependent manner. Moreover, the acetylated BMAL1 protein ratio increased with the same pattern in the liver and mWAT. With regards to clock-controlled genes, Per2 was also overexpressed, whereas Rev-erbα and RORα were repressed in a negative dose-dependent manner. Diet-induced obesity always resulted in the overexpression of some core clock and clock-related genes, although the particular gene affected was tissue specific. GSPE administration counteracted disturbances in the clock genes in the liver and gut but was less effective in normalizing the clock gene disruption in WAT. In conclusion, proanthocyanidins have the capacity to modulate peripheral molecular clocks in both healthy and obese states.

Grape seed procyanidin supplementation to rats fed a high-fat diet during pregnancy and lactation increases the body fat content and modulates the inflammatory response and the adipose tissue metabolism of the male offspring in youth.

OBJECTIVE: Procyanidins are polyphenolic bioactive compounds that exert beneficial effects against obesity and its related diseases. The aim of this study was to evaluate whether supplementation with low doses of a grape seed procyanidin extract (GSPE) to rats during pre- and postnatal periods provides biological effects to their offspring in youth. DESIGN: The metabolic programming effect of GSPE was evaluated in the 30-day-old male offspring of four groups of rats that were fed either a standard diet (STD) or a high-fat diet (HFD) and that were supplemented with either GSPE (25 mg kg(-1) of body weight per day) or vehicle during pregnancy and lactation. RESULTS: Significant increases in the adiposity index and in the weights of all the white adipose tissue depots studied (retroperitoneal, mesenteric, epididymal (EWAT) and inguinal) were observed in the offspring of rats that were fed a HFD and that were treated with GSPE (HFD-GSPE group) compared with the offspring of rats that were fed the same diet but that did not receive the procyanidins (HFD group). The HFD-GSPE animals also exhibited a higher number of cells in the EWAT, a sharp decrease in the circulating levels of monocyte chemoattractant protein-1 (MCP-1) and a moderate decrease in the plasma glycerol levels. The transcriptomic analysis performed in the EWAT showed 238 genes that were differentially expressed between the HFD and the HFD-GSPE animals, most of which were associated with the immune function and the inflammatory response, in addition to genes associated with adipose tissue remodeling and function, lipid and glucose homeostasis and the metabolism of methyl groups. CONCLUSION: The GSPE treatment in rats that were fed an HFD during pregnancy and lactation induced a clear metabolic programming effect in the offspring, increasing adiposity, decreasing the circulating levels of MCP-1 and changing the gene expression in the EWAT toward a better inflammatory profile.

Effect of low molecular grape seed proanthocyanidins on blood pressure and lipid homeostasis in cafeteria diet-fed rats.

Cardiovascular disease (CVD) and related pathologies are the leading cause of death worldwide. Fruits and vegetables are known to improve CVD, an effect that has been associated with flavonoid intake. The aim of this study was to simultaneously evaluate the acute effect of a low molecular grape seed proanthocyanidin extract (LM-GSPE) on two of the main risk factors of CVD, high blood pressure (BP) and dyslipidaemia, using high-fat diet-fed rats. Therefore, male Wistar rats that were cafeteria diet fed for 10 weeks were administered with 375 mg/kg of body weight of LM-GSPE, and the BP as well as plasmatic and hepatic parameters were determined at 6 h post-administration. The BP and plasmatic and hepatic lipid were decreased 6 h after the LM-GSPE administration. Moreover, the liver lipid peroxidation products decreased after the LM-GSPE treatment, indicating a reduction in oxidative stress. However, hepatic-reduced glutathione or plasma angiotensin converting enzyme activity was not altered by the LM-GSPE. In conclusion, grape proanthocyanidins is able to simultaneously reduce more than one risk factor for CVD by decreasing the BP and improving hypertriglyceridaemia at least in part due to an improvement in oxidative stress. These results open up the possibility of using grape proanthocyanidins in functional foods for CVD improvement.

Acute administration of grape seed proanthocyanidin extract modulates energetic metabolism in skeletal muscle and BAT mitochondria.

Proanthocyanidin consumption might reduce the risk of developing several pathologies, such as inflammation, oxidative stress and cardiovascular diseases. The beneficial effects of proanthocyanidins are attributed to their antioxidant properties, although they also can modulate gene expression at the transcriptional level. Little is known about the effect of proanthocyanidins on mitochondrial function and energy metabolism. In this context, the objective of this study was to determine the effect of an acute administration of grape seed proanthocyanidin extract (GSPE) on mitochondrial function and energy metabolism. To examine this effect, male Wistar rats fasted for fourteen hours, and then they were orally administered lard oil containing GSPE or were administered lard oil only. Liver, muscle and brown adipose tissue (BAT) were used to study enzymatic activity and gene expression of proteins related to energetic metabolism. Moreover, the gastrocnemius muscle and BAT mitochondria were used to perform high-resolution respirometry. The results showed that, after 5 h, the GSPE administration significantly lowers plasma triglycerides, free fatty acids, glycerol and urea concentrations. In skeletal muscle, GSPE lowers FATP1 mRNA levels and increases mitochondrial oxygen consumption, using pyruvate as the substrate, suggesting a promotion of glycosidic metabolism. Furthermore, GSPE increased the genetic expression of key genes in energy metabolism such as peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α), and modulated the enzyme activity of proteins, which are involved in the citric acid cycle and electron transport chain (ETC) in BAT. In conclusion, GSPE affects mainly the skeletal muscle and BAT mitochondria, increasing their oxidative capacity rapidly after acute supplementation.