Effects of Hesperidin Consumption on the Cardiovascular System in Pre- and Stage 1 Hypertensive Subjects: Targeted and Non-Targeted Metabolomic Approaches (CITRUS Study).

SCOPE: The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice (OJ) applying a non-targeted metabolomics approach validated by targeted metabolomics analyses of compliance biomarkers. METHODS AND RESULTS: Plasma/serum and urine targeted (HPLC-MS/MS) and untargeted (1 H-NMR) metabolomics signatures are explored in a subsample with pre- and stage-1 hypertension subjects of the CITRUS study (N = 159). Volunteers received 500 mL day-1 of control drink, OJ, or hesperidin-enriched OJ (EOJ) for 12-weeks. A 6-h postprandrial study is performed at baseline. Targeted analyses reveals plasma and urine hesperetin 7-O-ß-d-glucuronide as the only metabolite differing between OJ and EOJ groups after 12-weeks consumption, and in urine is correlated with a decreased systolic blood pressure level. The non-targeted approach shows that after single dose and 12-weeks consumption of OJ and EOJ change several metabolites related with an anti-inflammatory and antioxidant actions, lower blood pressure levels and uremic toxins. CONCLUSIONS: Hesperetin 7-O-ß-d-glucuronide can be a candidate marker for distinguishing between the consumption of different hesperidin doses at 12-weeks consumption as well as a potential agent mediating blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.

Alterations in gut microbiota associated with a cafeteria diet and the physiological consequences in the host.

OBJECTIVE: Gut microbiota have been described as key factors in the pathophysiology of obesity and different components of metabolic syndrome (MetS). The cafeteria diet (CAF)-fed rat is a preclinical model that reproduces most of the alterations found in human MetS by simulating a palatable human unbalanced diet. Our objective was to assess the effects of CAF on gut microbiota and their associations with different components of MetS in Wistar rats. METHODS: Animals were fed a standard diet or CAF for 12 weeks. A partial least square-based methodology was used to reveal associations between gut microbiota, characterized by 16S ribosomal DNA gene sequencing, and biochemical, nutritional and physiological parameters. RESULTS: CAF feeding resulted in obesity, dyslipidemia, insulin resistance and hepatic steatosis. These changes were accompanied by a significant decrease in gut bacterial diversity, decreased Firmicutes and an increase in Actinobacteria and Proteobacteria abundances, which were concomitant with increased endotoxemia. Associations of different genera with the intake of lipids and carbohydrates were opposed from those associated with the intake of fiber. Changes in gut microbiota were also associated with the different physiological effects of CAF, mainly increased adiposity and altered levels of plasma leptin and glycerol, consistent with altered adipose tissue metabolism. Also hepatic lipid accretion was associated with changes in microbiota, highlighting the relevance of gut microbiota homeostasis in the adipose-liver axis. CONCLUSIONS: Overall, our results suggest that CAF feeding has a profound impact on the gut microbiome and, in turn, that these changes may be associated with important features of MetS.

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.

Low doses of grape seed procyanidins reduce adiposity and improve the plasma lipid profile in hamsters.

OBJECTIVE: Procyanidins are polyphenolic compounds with beneficial effects on health in relation to cardiovascular disease and metabolic syndrome. In this study, we evaluated the potential beneficial effects of low doses of a grape seed procyanidin extract (GSPE) on body weight and fat deposition. DESIGN: Four groups of hamsters were fed either a standard diet (STD) or a high-fat diet (HFD) for 30 days and supplemented with either GSPE at 25 mg per kg of body weight per day (STD-GSPE and HFD-GSPE groups) or vehicle (STD and HFD groups) during the last 15 days of the study. RESULTS: A significant decrease in body weight gain was observed in both GSPE-treated animals at the end of the experiment. GSPE treatment significantly reduced the adiposity index and the weight of all the white adipose tissue depots studied (retroperitoneal (RWAT), mesenteric (MWAT), epididymal (EWAT) and inguinal (IWAT)) in both GSPE-treated groups. GSPE administration reversed the increase in plasma phospholipids induced by the HFD feeding. In the RWAT, GSPE treatment increased the mRNA expression of genes related to ß-oxidation and the glycerolipid/free fatty acid (GL/FFA) cycle, mainly in HFD-GSPE animals. In the MWAT, the effects of GSPE at the transcriptional level were not as evident as in the RWAT. Moreover, GSPE treatment induced heparin-releasable lipoprotein lipase activity in the RWAT and MWAT depots. The alterations in the lipid metabolic pathways induced by GSPE were accompanied by lower FFA levels in the plasma and decreased lipid and triglyceride accumulation in the MWAT. CONCLUSION: The use of GSPE at low doses protects against fat accumulation and improves the plasma lipid profile in hamsters. We suggest that GSPE exerts these effects in part through the activation of both ß-oxidation and the GL/FFA cycle, mainly in the RWAT.

Grape seed proanthocyanidins correct dyslipidemia associated with a high-fat diet in rats and repress genes controlling lipogenesis and VLDL assembling in liver.

OBJECTIVE: To determine whether proanthocyanidins can protect against dyslipidemia induced by a high-fat diet (HFD) and to address the mechanisms that underlie this hypolipidemic effect. DESIGN AND MEASUREMENTS: Female Wistar rats were fed on a HFD for 13 weeks. They were divided into two groups, one of which was treated with a grape seed proanthocyanidin extract (25 mg kg(-1) of body weight) for 10 days. Plasma and liver lipids were measured by colorimetric and gravimetric analysis. Liver, muscle and adipose tissue were used to study the expression of genes involved in the synthesis and oxidation of fatty acids and lipoprotein homeostasis by real-time RT-PCR. RESULTS: The administration of proanthocyanidins normalized plasma triglyceride and LDL-cholesterol (both parameters significantly increased with the HFD) but tended to decrease hypercholesterolemia and fatty liver. Gene expression analyses revealed that proanthocyanidins repressed both the expression of hepatic key regulators of lipogenesis and very low density lipoprotein (VLDL) assembling such as SREBP1, MTP and DGAT2, all of which were overexpressed by the HFD. CONCLUSION: These findings indicate that natural proanthocyanidins improve dyslipidemia associated with HFDs, mainly by repressing lipogenesis and VLDL assembly in the liver, and support the idea that they are powerful agents for preventing and treating lipid altered metabolic states.