Background: Appropriate long-term drinking of red wine is associated with a reduced risk of cardiovascular disease. Resveratrol, a well-known SIRT1 activator is considered to be one of the beneficial components contained in red wine, and also developed as a drug candidate. We previously demonstrated that resveratrol protects brain against ischemic stroke in mice through a PPARα-dependent mechanism. Here we report the different effects of the oligomers of resveratrol. Methods: We evaluated the activation of PPARs by ε-viniferin, a resveratrol dimer, and vaticanol C, a resveratrol tetramer, in cell-based reporter assays using bovine arterial endothelial cells, as well as the activation of SIRT1. Moreover, we tested the metabolic action by administering vaticanol C with the high fat diet to wild-type and PPARα-knockout male mice for eight weeks. Results: We show that vaticanol C activates PPARα and PPARβ/δ in cell-based reporter assays, but does not activate SIRT1. ε-Viniferin shows a similar radical scavenging activity as resveratrol, but neither effects on PPARs and SIRT-1. Eight-week intake of vaticanol C with a high fat diet upregulates hepatic expression of PPARα-responsive genes such as cyp4a10, cyp4a14 and FABP1, and skeletal muscle expression of PPARβ/δ-responsive genes, such as UCP3 and PDK4 (pyruvate dehydrogenase kinase, isoform 4), in wild-type, but not PPARα-knockout mice. Conclusion: Vaticanol C, a resveratrol tetramer, activated PPARα and PPARβ/δ in vitro and in vivo. These findings indicate that activation of PPARα and PPARβ/δ by vaticanol C may be a novel mechanism, affording beneficial effects against lifestyle-related diseases.

There are growing concerns that poor dietary behaviors at young ages will increase the future risk of chronic diseases in adulthood. We found that female college students who skipped breakfast had higher incidences of dysmenorrhea and irregular menstruation, suggesting that meal skipping affects ovarian and uterine functions. Since dysmenorrhea is more prevalent in those with a past history of dieting, we proposed a novel concept that inadequate dietary habits in adolescence become a trigger for the subsequent development of organic gynecologic diseases. Since inadequate feeding that was limited during the non-active phase impaired reproductive functions in post-adolescent female rats, we hypothesize that circadian rhythm disorders due to breakfast skipping disrupts the hypothalamic–pituitary–ovarian axis, impairs the reproductive rhythm, and leads to ovarian and uterine dysfunction. To explain how reproductive dysfunction is memorized from adolescence to adulthood, we hypothesize that the peripheral clock system also plays a critical role in the latent progression of reproductive diseases together with the central system, and propose naming this concept “adolescent dietary habit-induced obstetric and gynecologic disease (ADHOGD)”. This theory will contribute to analyzing the etiologies of and developing prophylaxes for female reproductive diseases from novel aspects. In this article, we describe the precise outline of the above hypotheses with the supporting evidence in the literature.

Background. Urinary collagen peptides, the breakdown products of endogenous collagen, have been used as biomarkers for various diseases. These non-invasive biomarkers are easily measured via mass spectrometry, aiding in diagnostics and therapy effectiveness. Objectives. The objective of this study was to investigate the effects of consuming collagen-containing meat on collagen peptide composition in human blood and urine. Methods. Ten collagen peptides in 24 h urine were quantified. Results. Prolyl-hydroxyproline (Pro-Hyp) was the most abundant peptide. Except for hydroxyprolyl-glycine (Hyp-Gly), levels of other minor collagen peptides showed high correlation coefficients with Pro-Hyp (r = 0.42 vs. r > 0.8). Notably, 24 h urinary Hyp-Gly showed a correlation coefficient of r = 0.72 with meat consumption, significantly higher than the coefficient for Pro-Hyp (r = 0.37). Additionally, the levels of Pro-Hyp and Hyp-Gly in the blood of seven young women participants increased similarly after consuming fish meat, while before ingestion, only negligible amounts of Hyp-Gly were present. To examine which peptides are generated by the degradation of endogenous collagen, mouse skin was cultured. The amount of Pro-Hyp released from the skin was approximately 1000-fold higher than that of Hyp-Gly. Following consumption of collagen-containing meat, both Pro-Hyp and Hyp-Gly are released in blood and excreted into urine, although Pro-Hyp is primarily generated from endogenous collagen even under physiological conditions. Conclusions. Therefore, in 24 h urine samples, the non-negligible fraction of Pro-Hyp is contributed by endogenous collagen, making 24 h urine Hyp-Gly level a potential biomarker for evaluating meat consumption on the day.

Currently, dieting and breakfast skipping is increasing among young women in Japan. We found that breakfast skipping among female students was accompanied by menstrual disorders, while students who had dieted in the past experienced deterioration in menstrual pains, warning that abnormal eating in young women may induce obstetric and gynecological disorders in the future. We named this concept adolescent dietary habit-induced obstetric and gynecologic disease (ADHOGD). A questionnaire survey showed that pregnant women who had menstrual pain in their youth were at high risk of hypertensive disorders during pregnancy. In rodents, ovulation was suppressed in young female rats whose feeding was limited to the non-active (light) phase. In female mice, feeding stimulation directly regulated the uterine clock gene rhythm. Furthermore, in conditional knockout mice of uterine Bmal1, the fetuses died before delivery, indicating that abnormal uterine clock function cannot maintain fetal development. These findings suggest a mechanism of ADHOGD, in which hunger stress due to inappropriate eating habits during adolescence and young adulthood affects uterine function via clock gene abnormalities, causing placental dysfunction and fetal growth failure during pregnancy. Thus, valid and appropriate rodent experiments are effective to analyze ADHOGD, especially from the aspect of circadian rhythms.

Underweight in pregnant women adversely affects the next generation. Although young female underweight has become an important issue even in developed countries, the precise mechanisms that induce an underweight status in young women remains unknown. To examine the influence of feeding timing in young women on the following underweight conditions, we examined the effects of chronic light–dark cycle-reversed feeding restriction on post-restriction dietary behaviors using adult and young adult female rats. Eight- and 24-week-aged female Wistar rats were classified into three groups: (1) the control group (without time or calorie restriction), (2) the night-time-fed group that was fed only during the active phase, and (3) the daytime-fed group that was fed only during the non-active phase. After a 4-week feeding restriction, all groups were additionally fed ad libitum for 7 weeks with daily food intake and weight gain measurements. After sacrifice, mRNA expressions of neuropeptide Y (NPY), agouti-related protein (AgRP), orexin-A, pro-opiomelanocortin (POMC), and thyrotropin-releasing hormone (TRH) in the hypothalamus and leptin in the fatty tissues were examined by real-time PCR. Daytime-fed groups decreased food intake during restriction. After stress relief, adult rats showed a rebound increase in food intake beyond the level of the control group, whereas young adult rats showed no significant rebound response. At the end of the non-restricted period, both adult and young adult rats in the daytime-fed group reduced NPY expression in the hypothalamus. These findings indicate that recovery responses in food intake against chronic light–dark cycle-reversed stress are different between adult and young adult rats. The lower response in young adult rats may provide clues to elucidating a new mechanism for underweight status in young females.