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Seasonal rhythms drive metabolic adaptations that influence body weight and adiposity. Adipose tissue is a key regulator of energy homeostasis in the organism, and its healthiness is needed to prevent the major consequences of overweight and obesity. In this context, supplementation with proanthocyanidins has been postulated as a potential strategy to prevent the alterations caused by obesity. Moreover, the effects of these (poly)phenols on metabolism are photoperiod dependent. In order to describe the impact of grape-seed proanthocyanidins extract (GSPE) on important markers of adipose tissue functionality under an obesogenic environment, we exposed Fischer 344 rats to three different photoperiods and fed them a cafeteria diet for five weeks. Afterwards, we supplemented them with 25 mg GSPE/kg/day for four weeks. Our results revealed that GSPE supplementation prevented excessive body weight gain under a long photoperiod, which could be explained by increased lipolysis in the adipose tissue. Moreover, cholesterol and non-esterified fatty acids (NEFAs) serum concentrations were restored by GSPE under standard photoperiod. GSPE consumption slightly helped combat the obesity-induced hypertrophy in adipocytes, and adiponectin mRNA levels were upregulated under all photoperiods. Overall, the administration of GSPE helped reduce the impact of obesity in the adipose tissue, depending on the photoperiod at which GSPE was consumed and on the type of adipose depots.

Tomatoes are widely consumed worldwide at any time of the year. However, depending on the variety, they have a characteristic season. We evaluated the consequences metabolic of consumption of Ekstasis tomatoes from different geographical origin and in different seasons in Fischer 344 rats. The hepatic gene expression of key enzymes in lipid metabolism was also evaluated. Animals were classified in three photoperiods (L6, L12, and L18) and in three treatments (vehicle: VH; local tomato: LT; and non-local tomato: nLT). We measured serum metabolic parameters and the gene expression of liver enzymes related to lipid metabolism (Acc1, Cpt1a, Had, Fas1, Srebp-1c, Fatp5, Cd36). LT consumption in season decreased cardiovascular risk 1 and coefficient atherogenic by 1.81 (p = 0.031) and in L6 decreased TAG and glucose (p = 0.046; p = 0.024). The L18-LT animals had decreased total cholesterol (p = 0.029) and gene expression of Srebp1-c (p = 0.022) but increased expression of Acc1 (p = 0.032). The treatments significantly affected the expression of Acc1 and Fas1 in the liver and the levels of serum TAG and glucose. A significant effect of photoperiod on serum concentration of glucose, insulin, HOMA index, and on the hepatic expression of Srep1-c, Fas1, and Acc1 was observed.

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.

Variations in the light/dark cycle and obesogenic diets trigger physiological and behavioral disorders. Proanthocyanidins, in addition to their healthy properties, have recently demonstrated a modulating effect on biological rhythms. Therefore, the aim of this study was to evaluate the administration of a grape seed proanthocyanidin-rich extract (GSPE) to mitigate the disruption caused by a sudden photoperiod change in healthy and cafeteria (CAF)-diet obese rats. For this, 48 photoperiod-sensitive Fischer 344 rats were fed standard or CAF diets for 6 weeks under a standard (12 h light/day, L12) conditions. Then, rats were switched to a long (18 h light/day, L18) or short (6 h light/day, L6) photoperiod and administered vehicle or GSPE (25 mg/kg) for 1 week. Body weight (BW) and food intake (FI) were recorded weekly. Animal activity and serum hormone concentrations were studied before and after the photoperiod change. Hormone levels were measured both at 3 h (ZT3) and 15 h (ZT15) after the onset of light. Results showed the impact of the CAF diet and photoperiod on the BW, FI, activity, and hormonal status of the animals. GSPE administration resulted in an attenuation of the changes produced by the photoperiod disruption. Specifically, GSPE in L6 CAF-fed rats reduced serum corticosterone concentration, restoring its circadian rhythm, increased the T3-to-T4 ratio, and increased light phase activity, while under L18, it decreased BW and testosterone concentration and increased the animal activity. These results suggest that GSPE may contribute to the adaptation to the new photoperiods. However, further studies are needed to elucidate the metabolic pathways and processes involved in these events.

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.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.

Circadian rhythms are ~24 h fluctuations of different biological processes that are regulated by the circadian clock system. They exert a major influence on most of the metabolism, such as the hepatic metabolism. This rhythmicity can be disrupted by obesogenic diets, fact that is considered to be a risk factor for the development of metabolic diseases. Nevertheless, obesogenic diets do not affect both genders in the same manner. We hypothesized that the circadian rhythms disruption of the hepatic metabolism, caused by obesogenic diets, is gender-dependent. Male and female Fischer 344 rats were fed either a standard diet or a cafeteria diet and sacrificed at two different moments, at zeitgeber 3 and 15. Only female rats maintained the circadian variations of the hepatic metabolism under a cafeteria diet. Most of those metabolites were related with the very low density lipoprotein (VLDL) synthesis, such as choline, betaine or phosphatidylcholine. Most of these metabolites were found to be increased at the beginning of the dark period. On the other hand, male animals did not show these time differences. These findings suggest that females might be more protected against the circadian disruption of the hepatic metabolism caused by a cafeteria diet through the increase of the VLDL synthesis at the beginning of the feeding time.

Conjugated linoleic acid (CLA) is a dietary supplement that has been shown to improve obesity. However, some authors have associated high doses of CLA supplementation with liver impairment and insulin resistance. The aim of this study was to assess whether the consumption of low doses of CLA maintained the beneficial effects on the main metabolic disturbances associated with metabolic syndrome (MetS) but prevented the occurrence of non-desirable outcomes associated with its consumption. Male Wistar rats, fed standard or cafeteria (CAF) diet for 12 weeks, were supplemented with three different low doses of CLA in the last three weeks. Both biochemical and H1 NMR-based metabolomics profiles were analysed in serum and liver. The consumption of 100 mg/kg CLA, but not doses of 200 and 300 mg/kg, ameliorated the increase in body weight gain as well as the serum concentrations of glucose, insulin, cholesterol, triglyceride, diglyceride, and total phospholipid induced by a CAF diet. In turn, CLA reverted the increase in lactate, alanine, and glucose concentrations in the liver of these animals, but enhanced hepatic cholesterol accumulation without any detrimental effect on liver function. In conclusion, a low dose of CLA corrected the adverse effects associated with MetS without compromising other metabolic parameters.

Biological rhythms can influence the activity of bioactive compounds, and at the same time, the intake of these compounds can modulate biological rhythms. In this context, chrononutrition has appeared as a research field centered on the study of the interactions among biological rhythms, nutrition, and metabolism. This review summarizes the role of phenolic compounds in the modulation of biological rhythms, focusing on their effects in the treatment or prevention of chronic diseases. Heterotrophs are able to sense chemical cues mediated by phytochemicals such as phenolic compounds, promoting their adaptation to environmental conditions. This is called xenohormesis. Hence, the consumption of fruits and vegetables rich in phenolic compounds exerts several health benefits, mainly attributed to the product of their metabolism. However, the profile of phenolic compounds present in plants differs among species and is highly variable depending on agricultural and technological factors. In this sense, the seasonal consumption of polyphenol-rich fruits could induce important changes in the regulation of physiology and metabolism due to the particular phenolic profile that the fruits contain. This fact highlights the need for studies that evaluate the impact of these specific phenolic profiles on health to establish more accurate dietary recommendations.

AVFQHNCQE is an antihypertensive nonapeptide obtained from a chicken foot protein hydrolysate. The present study aims to investigate the mechanisms involved in its blood pressure (BP)-lowering effect. Male (17⁻20 weeks old) spontaneously hypertensive rats (SHR) were used in this study. Rats were divided into two groups and orally administered water or 10 mg/kg body weight (bw) AVFQHNCQE. One hour post-administration, animals of both groups were intra-peritoneally treated with 1 mL of saline or with 1 mL of saline containing 30 mg/kg bw Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, or with 1 mL of saline containing 5 mg/kg bw indomethacin, which is an inhibitor of prostacyclin synthesis (n = 6 per group). Systolic BP was recorded before oral administration and six hours after oral administration. In an additional experiment, SHR were administered water or 10 mg/kg bw AVFQHNCQE (n = 6 per group) and sacrificed six hours post-administration to study the mechanisms underlying the peptide anti-hypertensive effect. Moreover, the relaxation caused by AVFQHNCQE in isolated aortic rings from Sprague-Dawley rats was evaluated. The BP-lowering effect of the peptide was not changed after indomethacin administration but was completely abolished by L-NAME, which demonstrates that its anti-hypertensive effect is mediated by changes in endothelium-derived NO availability. In addition, AVFQHNCQE administration downregulated aortic gene expression of the vasoconstrictor factor endothelin-1 and the endothelial major free radical producer NADPH. Moreover, while no changes in plasma ACE activity were observed after its administration, liver GSH levels were higher in the peptide-treated group than in the water group, which demonstrates that AVFQHNCQE presents antioxidant properties.

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.