Proanthocyanidins Restore the Metabolic Diurnal Rhythm of Subcutaneous White Adipose Tissue According to Time-Of-Day Consumption.

Consumption of grape seed proanthocyanidin extract (GSPE) has beneficial effects on the functionality of white adipose tissue (WAT). However, although WAT metabolism shows a clear diurnal rhythm, whether GSPE consumption could affect WAT rhythmicity in a time-dependent manner has not been studied. Ninety-six male Fischer rats were fed standard (STD, two groups) or cafeteria (CAF, four groups) diet for 9 weeks (n = 16 each group). From week 6 on, CAF diet animals were supplemented with vehicle or 25 mg GSPE/kg of body weight either at the beginning of the light/rest phase (ZT0) or at the beginning of the dark/active phase (ZT12). The two STD groups were also supplemented with vehicle at ZT0 or ZT12. In week 9, animals were sacrificed at 6 h intervals (n = 4) to analyze the diurnal rhythms of subcutaneous WAT metabolites by nuclear magnetic resonance spectrometry. A total of 45 metabolites were detected, 19 of which presented diurnal rhythms in the STD groups. Although most metabolites became arrhythmic under CAF diet, GSPE consumption at ZT12, but not at ZT0, restored the rhythmicity of 12 metabolites including compounds involved in alanine, aspartate, and glutamate metabolism. These results demonstrate that timed GSPE supplementation may restore, at least partially, the functional dynamics of WAT when it is consumed at the beginning of the active phase. This study opens an innovative strategy for time-dependent polyphenol treatment in obesity and metabolic diseases.

Time-of-day dependent effect of proanthocyanidins on adipose tissue metabolism in rats with diet-induced obesity.

BACKGROUND: Grape-seed proanthocyanidin extract (GSPE) improve white adipose tissue (WAT) expansion during diet-induced obesity. However, because adipose metabolism is synchronized by circadian rhythms, it is plausible to speculate that the bioactivity of dietary proanthocyanidins could be influenced by the time-of-day in which they are consumed. Therefore, the aim of the present study was to determine the interaction between zeitgeber time (ZT) and GSPE consumption on the functionality of WAT in rats with diet-induced obesity. METHODS: Male Wistar rats were fed a cafeteria diet for 9 weeks. After 5 weeks, the animals were supplemented with 25 mg GSPE/kg for 4 weeks at the beginning of the light/rest phase (ZT0) or of the dark/active phase (ZT12). Body fat content was determined by nuclear magnetic resonance and histological analyses were performed in the epididymal (EWAT) and inguinal (IWAT) fat depots to determine adipocyte size and number. In addition, the expression of genes related to adipose metabolism and circadian clock function were analyzed by qPCR. RESULTS: GSPE consumption at ZT0 was associated with a potential antidiabetic effect without affecting adiposity and energy intake and downregulating the gene expression of inflammatory markers in EWAT. In contrast, GSPE consumption at ZT12 improved adipose tissue expansion decreasing adipocyte size in IWAT. In accordance with this adipogenic activity, the expression of genes involved in fatty acid metabolism were downregulated at ZT12 in IWAT. In turn, GSPE consumption at ZT12, but not at ZT0, repressed the expression of the clock gene Cry1 in IWAT. CONCLUSIONS: The interaction between ZT and GSPE consumption influenced the metabolic response of WAT in a tissue-specific manner. Understanding the impact of circadian clock on adipose metabolism and how this is regulated by polyphenols will provide new insights for the management of obesity.

Time-of-Day Circadian Modulation of Grape-Seed Procyanidin Extract (GSPE) in Hepatic Mitochondrial Dynamics in Cafeteria-Diet-Induced Obese Rats.

Major susceptibility to alterations in liver function (e.g., hepatic steatosis) in a prone environment due to circadian misalignments represents a common consequence of recent sociobiological behavior (i.e., food excess and sleep deprivation). Natural compounds and, more concisely, polyphenols have been shown as an interesting tool for fighting against metabolic syndrome and related consequences. Furthermore, mitochondria have been identified as an important target for mediation of the health effects of these compounds. Additionally, mitochondrial function and dynamics are strongly regulated in a circadian way. Thus, we wondered whether some of the beneficial effects of grape-seed procyanidin extract (GSPE) on metabolic syndrome could be mediated by a circadian modulation of mitochondrial homeostasis. For this purpose, rats were subjected to "standard", "cafeteria" and "cafeteria diet + GSPE" treatments (n = 4/group) for 9 weeks (the last 4 weeks, GSPE/vehicle) of treatment, administering the extract/vehicle at diurnal or nocturnal times (ZT0 or ZT12). For circadian assessment, one hour after turning the light on (ZT1), animals were sacrificed every 6 h (ZT1, ZT7, ZT13 and ZT19). Interestingly, GSPE was able to restore the rhythm on clock hepatic genes (Bmal1, Per2, Cry1, Rorα), as this correction was more evident in nocturnal treatment. Additionally, during nocturnal treatment, an increase in hepatic fusion genes and a decrease in fission genes were observed. Regarding mitochondrial complex activity, there was a strong effect of cafeteria diet at nearly all ZTs, and GSPE was able to restore activity at discrete ZTs, mainly in the diurnal treatment (ZT0). Furthermore, a differential behavior was observed in tricarboxylic acid (TCA) metabolites between GSPE diurnal and nocturnal administration times. Therefore, GSPE may serve as a nutritional preventive strategy in the recovery of hepatic-related metabolic disease by modulating mitochondrial dynamics, which is concomitant to the restoration of the hepatic circadian machinery.