Grape Seed Proanthocyanidin Extract Attenuates Cafeteria-Diet-Induced Liver Metabolic Disturbances in Rats: Influence of Photoperiod.

This study investigated the influence of photoperiod (day length) on the efficacy of grape seed proanthocyanidin extract (GSPE) in mitigating metabolic disorders in obese rats fed a cafeteria diet. Rats were exposed to standard (L12), long (L18), or short (L6) photoperiods and treated with GSPE or vehicle. In the standard photoperiod, GSPE reduced body weight gain (50.5%), total cholesterol (37%), and triglycerides (34.8%), while increasing the expression of hepatic metabolic genes. In the long photoperiod, GSPE tended to decrease body weight gain, increased testosterone levels (68.3%), decreased liver weight (12.4%), and decreased reverse serum amino acids. In the short photoperiod, GSPE reduced glycemia (~10%) and lowered triglyceride levels (38.5%), with effects modified by diet. The standard photoperiod showed the greatest efficacy against metabolic syndrome-associated diseases. The study showed how day length affects GSPE's benefits and underscores considering biological rhythms in metabolic disease therapies.

Molecular and Cellular Neurobiology of Circadian and Circannual Rhythms in Migraine: A Narrative Review.

Migraine-a primary headache-has circadian and circannual rhythms in the onset of attacks. The circadian and circannual rhythms involve the hypothalamus, which is strongly associated with pain processing in migraines. Moreover, the role of melatonin in circadian rhythms has been implied in the pathophysiology of migraines. However, the prophylactic effect of melatonin in migraines is controversial. Calcitonin gene-related peptide (CGRP) has recently attracted attention in the pathophysiology and treatment of migraines. Pituitary adenylate cyclase-activating peptide (PACAP)-a neuropeptide identical to CGRP-is a potential therapeutic target after CGRP. PACAP is involved in the regulation of circadian entrainment to light. This review provides an overview of circadian and circannual rhythms in the hypothalamus and describes the relationship between migraines and the molecular and cellular neurobiology of circadian and circannual rhythms. Furthermore, the potential clinical applications of PACAP are presented.

Clock-linked genes underlie seasonal migratory timing in a diurnal raptor.

Seasonal migration is a dynamic natural phenomenon that allows organisms to exploit favourable habitats across the annual cycle. While the morphological, physiological and behavioural changes associated with migratory behaviour are well characterized, the genetic basis of migration and its link to endogenous biological time-keeping pathways are poorly understood. Historically, genome-wide research has focused on genes of large effect, whereas many genes of small effect may work together to regulate complex traits like migratory behaviour. Here, we explicitly relax stringent outlier detection thresholds and, as a result, discover how multiple biological time-keeping genes are important to migratory timing in an iconic raptor species, the American kestrel (Falco sparverius). To validate the role of candidate loci in migratory timing, we genotyped kestrels captured across autumn migration and found significant associations between migratory timing and genetic variation in metabolic and light-input pathway genes that modulate biological clocks (top1, phlpp1, cpne4 and peak1). Further, we demonstrate that migrating individuals originated from a single panmictic source population, suggesting the existence of distinct early and late migratory genotypes (i.e. chronotypes). Overall, our results provide empirical support for the existence of a within-population-level polymorphism in genes underlying migratory timing in a diurnally migrating raptor.

Impact of Seasonal and Temperature-Dependent Variation in Root Defense Metabolites on Herbivore Preference in Taraxacum officinale.

Plants experience seasonal fluctuations in abiotic and biotic factors such as herbivore attack rates. If and how root defense expression co-varies with seasonal fluctuations in abiotic factors and root herbivore attack rates is not well understood. Here, we evaluated seasonal changes in defensive root latex chemistry of Taraxacum officinale plants in the field and correlated the changes with seasonal fluctuations in abiotic factors and damage potential by Melolontha melolontha, a major natural enemy of T. officinale. We then explored the causality and consequences of these relationships under controlled conditions. The concentration of the defensive sesquiterpene lactone taraxinic acid ß-D glucopyranosyl ester (TA-G) varied substantially over the year and was most strongly correlated to mean monthly temperature. Both temperature and TA-G levels were correlated with annual fluctuations in potential M. melolontha damage. Under controlled conditions, plants grown under high temperature produced more TA-G and were less attractive for M. melolontha. However, temperature-dependent M. melolontha feeding preferences were not significantly altered in TA-G deficient transgenic lines. Our results suggest that fluctuations in temperature leads to variation in the production of a root defensive metabolites that co-varies with expected attack of a major root herbivore. Temperature-dependent herbivore preference, however, is likely to be modulated by other phenotypic alterations.

Potential circadian and circannual rhythm contributions to the obesity epidemic in elementary school age children.

Children gain weight at an accelerated rate during summer, contributing to increases in the prevalence of overweight and obesity in elementary-school children (i.e., approximately 5 to 11 years old in the US). Int J Behav Nutr Phys Act 14:100, 2017 explained these changes with the "Structured Days Hypothesis" suggesting that environmental changes in structure between the school year and the summer months result in behavioral changes that ultimately lead to accelerated weight gain. The present article explores an alternative explanation, the circadian clock, including the effects of circannual changes and social demands (i.e., social timing resulting from societal demands such as school or work schedules), and implications for seasonal patterns of weight gain. We provide a model for understanding the role circadian and circannual rhythms may play in the development of child obesity, a framework for examining the intersection of behavioral and biological causes of obesity, and encouragement for future research into bio-behavioral causes of obesity in children.

Seasonal changes in plasma concentrations of the thyroid, glucocorticoid and reproductive hormones in the tegu lizard Salvator merianae.

The tegu lizard Salvator merianae is a large, widely distributed teiid lizard endemic to South America that exhibits annual cycles of high activity during the spring and summer, and hibernation during winter. This pattern of activity and hibernation is accompanied by profound seasonal changes in physiology and behavior, including endothermy during the austral spring. The unusual combination of seasonal endothermy, hibernation and oviparity, in a non-avian, non-mammalian species, makes S. merianae an interesting subject for study of comparative aspects of endocrine regulation of seasonal changes in physiology. In the present study, we first validated commercially available immunoassay kits for quantification of hormone concentrations of the reproductive (testosterone, estradiol and progesterone), adrenal (corticosterone), and thyroid [thyroxine (T4) and triiodothyronine (T3)] axes in plasma of an outdoor, captive adult male and female S. merianae in southeastern Brazil. All assays exhibited parallelism and accuracy with S. merianae plasma. We next assessed patterns of concentration of these hormones across the annual cycle of S. merianae. Testosterone in males and estradiol in females peaked in spring coincident with the peak in reproductive behavior. Progesterone in females was significantly elevated in October coincident with putative ovulation when gravid females build nests. Thyroid hormones, known for regulating energy metabolism, varied seasonally with some sex-dependent differences. T4 gradually increased from an annual nadir during pre-hibernation and hibernation to high concentrations during spring in both sexes. In contrast, T3 did not vary seasonally in males, but females showed a two-fold increase in T3 during the spring reproductive season. T3 may be involved in energy investment during the seasonal production of large clutches of eggs. Corticosterone was significantly elevated during the active season in both sexes, suggesting its involvement in mobilization of energy stores and modulation of behavior (territoriality) and physiology. Ours is the first investigation of concurrent changes in reproductive, thyroid and adrenal hormone concentrations in this endemic and physiologically unique South American lizard. Our findings set the stage for future investigations to determine the extent to which these hormones influence activity and thermoregulation in S. merianae.

The pars tuberalis: The site of the circannual clock in mammals?

Accurate timing and physiological adaptation to anticipate seasonal changes are an essential requirement for an organism's survival. In contrast to all other environmental cues, photoperiod offers a highly predictive signal that can be reliably used to activate a seasonal adaptive programme at the correct time of year. Coupled to photoperiod sensing, it is apparent that many organisms have evolved innate long-term timekeeping systems, allowing reliable anticipation of forthcoming environmental changes. The fundamental biological processes giving rise to innate long-term timing, with which the photoperiod-sensing pathway engages, are not known for any organism. There is growing evidence that the pars tuberalis (PT) of the pituitary, which acts as a primary transducer of photoperiodic input, may be the site of the innate long-term timer or "circannual clock". Current research has led to the proposition that the PT-specific thyrotroph may act as a seasonal calendar cell, driving both hypothalamic and pituitary endocrine circuits. Based on this research we propose that the mechanistic basis for the circannual rhythm appears to be deeply conserved, driven by a binary switching cell based accumulator, analogous to that proposed for development. We review the apparent conservation of function and pathways to suggest that these broad principles may apply across the vertebrate lineage and even share characteristics with processes driving seasonal adaptation in plants.

Circannual rhythms of acetylcholinesterase (AChE) activity in the freshwater fish Cnesterodon decemmaculatus.

The use of biomarkers as a tool to assess responses of organisms exposed to pollutants in toxicity bioassays, as well as in aquatic environmental risk assessment protocols, requires the understanding of the natural fluctuation of the particular biomarker. The aim of this study was to characterize the intrinsic variations of acetylcholinesterase (AChE) activity in tissues of a native freshwater teleost fish to be used as biomarker in toxicity tests, taking into account both seasonal influence and fish size. Specific AChE activity was measured by the method of Ellman et al. (1961) in homogenates of fish anterior section finding a seasonal variability. The highest activity was observed in summer, decreasing significantly below 40% in winter. The annual AChE activity cycle in the anterior section was fitted to a sinusoidal function with a period of 11.2 months. Moreover, an inverse relationship between enzymatic activity and the animal size was established. The results showed that both the fish length and seasonal variability affect AChE activity. AChE activity in fish posterior section showed a similar trend to that in the anterior section, while seasonal variations of the activity in midsection were observed but differences were not statistically significant. In addition, no relationship between AChE and total tissue protein was established in the anterior and posterior sections suggesting that the circannual rhythms observed are AChE-specific responses. Results highlight the importance of considering both the fish size and season variations to reach valid conclusions when AChE activity is employed as neurotoxicity biomarker.

Invited commentary: nighttime light exposure as a risk factor for obesity through disruption of circadian and circannual rhythms.

In this issue of the American Journal of Epidemiology, McFadden et al. (Am J Epidemiol. 2014;180(3):245-250) report findings on the relationship between light exposure at night and obesity from a cross-sectional study of United Kingdom women. Their research extends findings from a previous study with elderly participants by including a larger sample size of over 100,000 women and a broader age range of 16 years or older. The findings are consistent with animal studies showing that prolonged light exposure leads to weight gain. Humans' circadian, circannual, and metabolic regulatory systems evolved to be adaptive in environments that were quite different from those faced in modern industrial society. Technology has allowed exposures to levels and timing of light, nutrient intake, and physical activity never before possible. This commentary discusses how nighttime light exposure can increase the risk of obesity and the metabolic syndrome by disrupting circadian and circannual rhythms.

The Influence of Photoperiod, Intake of Polyunsaturated Fatty Acids, and Food Availability on Seasonal Acclimatization in Red Deer (Cervus elaphus).

Hypometabolism and hypothermia are common reactions of birds and mammals to cope with harsh winter conditions. In small mammals, the occurrence of hibernation and daily torpor is entrained by photoperiod, and the magnitude of hypometabolism and decrease of body temperature (Tb) is influenced by the dietary supply of essential polyunsaturated fatty acids. We investigated whether similar effects exist in a non-hibernating large mammal, the red deer (Cervus elaphus). We fed adult females with pellets enriched with either linoleic acid (LA) or α-linolenic acid (ALA) during alternating periods of ad libitum and restricted feeding in a cross-over experimental design. Further, we scrutinized the role of photoperiod for physiological and behavioral seasonal changes by manipulating the amount of circulating melatonin. The deer were equipped with data loggers recording heart rate, core and peripheral Tb, and locomotor activity. Further, we regularly weighed the animals and measured their daily intake of food pellets. All physiological and behavioral parameters measured varied seasonally, with amplitudes exacerbated by restricted feeding, but with only few and inconsistent effects of supplementation with LA or ALA. Administering melatonin around the summer solstice caused a change into the winter phenotype weeks ahead of time in all traits measured. We conclude that red deer reduce energy expenditure for thermoregulation upon short daylength, a reaction amplified by food restriction.

Diurnal and seasonal molecular rhythms in the human brain and their relation to Alzheimer disease.

Diurnal and seasonal rhythms influence many aspects of human physiology including brain function. Moreover, altered diurnal and seasonal behavioral and physiological rhythms have been linked to Alzheimer's disease and related dementias (ADRD). Understanding the molecular basis for these links may lead to identification of novel targets to mitigate the negative impact of normal and abnormal diurnal and seasonal rhythms on ADRD or to alleviate the adverse consequences of ADRD on normal diurnal and seasonal rhythms. Diurnally and seasonally rhythmic gene expression and epigenetic modification in the human neocortex may be a key mechanism underlying these links. This chapter will first review the observed epidemiological links between normal and abnormal diurnal and seasonal rhythmicity, cognitive impairment, and ADRD. Then it will review normal diurnal and seasonal rhythms of brain epigenetic modification and gene expression in model organisms. Finally, it will review evidence for diurnal and seasonal rhythms of epigenetic modification and gene expression the human brain in aging, Alzheimer's disease, and other brain disorders.

Physiological mechanisms underlying children's circannual growth patterns and their contributions to the obesity epidemic in elementary school age children.

Several studies since the 1990s have demonstrated that children increase their body mass index at a faster rate during summer months compared with the school year, leading some to conclude that the out-of-school summer environment is responsible. Other studies, however, have suggested that seasonality may play a role in children's height and weight changes across the year. This article reviews evidence for seasonal differences in the rate of children's height and weight gain and proposes potential physiological mechanisms that may explain these seasonal variations.

Exposure of Fischer 344 rats to distinct photoperiods influences the bioavailability of red grape polyphenols.

The consumption of grapes, rich in polyphenols, have several health effects. These effects are mainly attributed to the polyphenol metabolites generated after their ingestion. Several factors that affects host's physiology can modulate the bioavailability of grape polyphenols and, in turn, their effects. Mammals undergo physiological and metabolic changes due to the different day length (photoperiod) within a year. Thus, the aim of this study is to investigate if the bioavailability of phenolic compounds from the same red grapes with a different polyphenol profile (i.e. red grape produced organically (OG) or non-organically (conventional, CG)) differs with the photoperiod exposure. For this, the serum phenolic metabolites of Fischer 344 rats keep at different photoperiods (18, 12 or 6 h of light per day) and administered with OG or CG for 10-week were profiled by HPLC-MS/MS. Our results indicated that rats administered with OG reported a higher total serum metabolite concentration independent of the photoperiod exposure and CG-administered rats showed a more varied serum metabolite profile depending of the photoperiod exposure. Those rats exposed to 6 h of light per day, which emulates winter light conditions, presented a higher bioavailability of grape phenolics. Therefore, grape cultivar and animal photoperiod exposure condition grape phenolics' bioavailability.

Cherry consumption out of season alters lipid and glucose homeostasis in normoweight and cafeteria-fed obese Fischer 344 rats.

The xenohormesis theory postulates that animals, through the consumption of chemical cues, mainly polyphenols, synthetized by plants, are able to favorably adapt to changing environmental conditions. We hypothesized that the intake of fruits with a seasonally distinctive phenotype (in terms of bioactive compounds) produced a metabolic response that depends on mammals' circannual rhythms and that fruit intake out of season can lead to a disruption in characteristic seasonal metabolism. Fischer 344 rats were chronically exposed to short (L6, 6 h light/day) and long (L18, 18 h light/day) photoperiods in order to simulate autumn and spring seasons, respectively, and were fed either a standard diet (STD) or an obesogenic cafeteria diet (CAF) and orally treated with either vehicle or 100 mg kg-1 day-1 of lyophilized sweet cherry (Prunus avium L.), a fruit consumed during long-day seasons. Cherry consumption exerted a marked photoperiod-dependent effect, inducing more changes when it was consumed out of season, which was apparent in the following observations: (a) in L6 STD-fed rats, a down-regulation of the phosphorylated (p) levels of the downstream postreceptor target of insulin Akt2 in the soleus muscle and an enhancement of fatty acid transport and ß-oxidation-related pathways, which was evidenced by increased Had gene expression (soleus) and pAMPK levels (soleus and gastrocnemius) and (b) an increase in whole-body fat oxidation and circulating levels of glucose and insulin in L6-CAF-fed obese rats. Although the pathophysiological significance of these results requires further research, our findings could contribute to highlighting the importance of the consumption of seasonal fruits to maintain optimal health.

The Exposure to Different Photoperiods Strongly Modulates the Glucose and Lipid Metabolisms of Normoweight Fischer 344 Rats.

Seasonal variations in day length trigger clear changes in the behavior, growth, food intake, and reproductive status of photoperiod-sensitive animals, such as Fischer 344 rats. However, there is little information about the effects of seasonal fluctuations in day length on glucose and lipid metabolisms and their underlying mechanisms in this model. To gain knowledge on these issues, three groups of male Fischer 344 rats were fed with a standard diet and exposed to different photoperiods for 14 weeks: normal photoperiod (L12, 12 h light/day), long photoperiod (L18, 18 h light/day), and short photoperiod (L6, 6 h light/day). A multivariate analysis carried out with 239 biometric, serum, hepatic and skeletal muscle parameters revealed a clear separation among the three groups. Compared with L12 rats, L6 animals displayed a marked alteration of glucose homeostasis and fatty acid uptake and oxidation, which were evidenced by the following observations: (1) increased circulating levels of glucose and non-esterified fatty acids; (2) a sharp down-regulation of the phosphorylated Akt2 levels, a downstream post-receptor target of insulin, in both the soleus and gastrocnemius muscles; (3) decreased expression in the soleus muscle of the glucose metabolism-related microRNA-194 and lower mRNA levels of the genes involved in glucose metabolism (Irs1, soleus, and Glut2, liver), ß-oxidation (Had and Cpt1ß, soleus) and fatty acid transport (Cd36, soleus, and liver). L18 animals also displayed higher blood glucose levels than L12 rats and profound changes in other glucose and lipid metabolism-related parameters in the blood, liver, and skeletal muscles. However, the mechanisms that account for the observed effects were less evident than those reported in L6 animals. In conclusion, exposure to different photoperiods strongly modulated glucose and lipid metabolisms in normoweight rats. These findings emphasize the relevance of circannual rhythms in metabolic homeostasis regulation and suggest that Fischer 344 rats are a promising animal model with which to study glucose- and lipid-related pathologies that are influenced by seasonal variations, such as obesity, cardiovascular disease and seasonal affective disorder.

Intake of an Obesogenic Cafeteria Diet Affects Body Weight, Feeding Behavior, and Glucose and Lipid Metabolism in a Photoperiod-Dependent Manner in F344 Rats.

We previously demonstrated that chronic exposure to different photoperiods induced marked variations in several glucose and lipid metabolism-related parameters in normoweight Fischer 344 (F344) rats. Here, we examined the effects of the combination of an obesogenic cafeteria diet (CAF) and the chronic exposure to three different day lengths (L12, 12 h light/day; L18, 18 h light/day; and L6, 6 h light/day) in this rat strain. Although no changes were observed during the first 4 weeks of adaptation to the different photoperiods in which animals were fed a standard diet, the addition of the CAF for the subsequent 7 weeks triggered profound physiologic and metabolic alterations in a photoperiod-dependent manner. Compared with L12 rats, both L6 and L18 animals displayed lower body weight gain and cumulative food intake in addition to decreased energy expenditure and locomotor activity. These changes were accompanied by differences in food preferences and by a sharp upregulation of the orexigenic genes Npy and Ghsr in the hypothalamus, which could be understood as a homeostatic mechanism for increasing food consumption to restore body weight control. L18 rats also exhibited higher glycemia than the L6 group, which could be partly attributed to the decreased pAkt2 levels in the soleus muscle and the downregulation of Irs1 mRNA levels in the gastrocnemius muscle. Furthermore, L6 animals displayed lower whole-body lipid utilization than the L18 group, which could be related to the lower lipid intake and to the decreased mRNA levels of the fatty acid transporter gene Fatp1 observed in the soleus muscle. The profound differences observed between L6 and L18 rats could be related with hepatic and muscular changes in the expression of circadian rhythm-related genes Cry1, Bmal1, Per2, and Nr1d1. Although further research is needed to elucidate the pathophysiologic relevance of these findings, our study could contribute to emphasize the impact of the consumption of highly palatable and energy dense foods regularly consumed by humans on the physiological and metabolic adaptations that occur in response to seasonal variations of day length, especially in diseases associated with changes in food intake and preference such as obesity and seasonal affective disorder.

The full moon as a synchronizer of circa-monthly biological rhythms: Chronobiologic perspectives based on multidisciplinary naturalistic research.

Biological rhythmicity is presumed to be an advantageous genetic adaptation of fitness and survival value resulting from evolution of life forms in an environment that varies predictably-in-time during the 24 h, month, and year. The 24 h light/dark cycle is the prime synchronizer of circadian periodicities, and its modulation over the course of the year, in terms of daytime photoperiod length, is a prime synchronizer of circannual periodicities. Circadian and circannual rhythms have been the major research focus of most scientists. Circa-monthly rhythms triggered or synchronized by the 29.5 day lunar cycle of nighttime light intensity, or specifically the light of the full moon, although explored in waterborne and certain other species, have received far less study, perhaps because of associations with ancient mythology and/or an attitude naturalistic studies are of lesser merit than ones that entail molecular mechanisms. In this editorial, we cite our recent discovery through multidisciplinary naturalistic investigation of a highly integrated circadian, circa-monthly, and circannual time structure, synchronized by the natural ambient nyctohemeral, lunar, and annual light cycles, of the Peruvian apple cactus (C. peruvianus) flowering and reproductive processes that occur in close temporal coordination with like rhythms of the honey bee as its pollinator. This finding led us to explore the preservation of this integrated biological time structure, synchronized and/or triggered by environmental light cues and cycles, in the reproduction of other species, including Homo sapiens, and how the artificial light environment of today in which humans reside may be negatively affecting human reproduction efficiency.

Circannual variation of efficacy outcomes in patients with newly diagnosed metastatic colorectal cancer and treated with first-line chemotherapy.

Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.