The circadian system: From clocks to physiology.

The circadian system, composed of the central autonomous clock, the suprachiasmatic nucleus (SCN), and systems of the body that follow the signals of the SCN, continuously change the homeostatic set points of the body over the day-night cycle. Changes in the body's physiological state that do not agree with the time of the day feedback to the hypothalamus, and provide input to the SCN to adjust the condition, thus reaching another set point required by the changed conditions. This allows the adjustment of the set points to another level when environmental conditions change, which is thought to promote adaptation and survival. In fasting, the body temperature drops to a lower level only at the beginning of the sleep phase. Stressful conditions raise blood pressure relatively more during the active period than during the rest phase. Extensive, mostly reciprocal SCN interactions, with hypothalamic networks, induce these physiological adjustments by hormonal and autonomic control of the body's organs. More importantly, in addition to SCN's hormonal and autonomic influences, SCN induced behavior, such as rhythmic food intake, induces the oscillation of many genes in all tissues, including the so-called clock genes, which have an essential role as a transcriptional driving force for numerous cellular processes. Consequently, the light-dark cycle, the rhythm of the SCN, and the resulting rhythm in behavior need to be perfectly synchronized, especially where it involves synchronizing food intake with the activity phase. If these rhythms are not synchronous for extended periods of times, such as during shift work, light exposure at night, or frequent night eating, disease may develop. As such, our circadian system is a perfect illustration of how hypothalamic-driven processes depend on and interact with each other and need to be in seamless synchrony with the body's physiology.

Feeding during the rest phase promotes circadian conflict in nuclei that control energy homeostasis and sleep-wake cycle in rats.

Food intake during the rest phase promotes circadian desynchrony, which has been associated with metabolic diseases. However, the link between circadian rhythm and metabolic alterations is not well understood. To investigate this issue, we explored the circadian rhythm of c-Fos immunoreactivity (IR) in rats fed during the day, during the night or with free access to food for 3 weeks. The analysis was focused on the hypothalamic nuclei, which are interconnected and involved in the control of energy homeostasis and/or arousal: lateral hypothalamus (LH), perifornical area, arcuate, ventrolateral pre-optic (VLPO) and tuberomammillary nuclei. The results show that food intake during the rest phase flattened the circadian c-Fos expression in the LH and perifornical area, and induced a phase shift in the VLPO area. In addition, c-Fos expression was analyzed in the orexin and melanin-concentrating hormone (MCH) neurons of the LH, which are involved in the control of food intake and arousal, and in α-melanin-stimulating hormone and neuropeptide Y (NPY) cells in the arcuate nucleus, all of which are involved in feeding-fasting cycles, energy homeostasis and sending projections to the LH. The results indicate that feeding during the rest phase decreased orexin neuron activation in the light in comparison with the other groups. Feeding during this phase also flattened the activity rhythm of MCH and α-melanin-stimulating hormone neurons and increased NPY IR when the light was turned on. This evidence indicates that mealtime differentially affected the hypothalamic nuclei under investigation leading to a circadian conflict that might account for metabolic impairment.

A light/dark cycle in the NICU accelerates body weight gain and shortens time to discharge in preterm infants.

BACKGROUND: Bright constant light levels in the NICU may have negative effects on the growth and development of preterm infants OBJECTIVE: The aim of this study is to evaluate the benefits of an alternating light/dark cycle in the NICU on weight gain and early discharge from the therapy in premature infants. PATIENTS AND METHODS: A randomized interventional study was designed comparing infants in the NICU of Hospital Juarez de México, exposed from birth either to an LD environment (LD, n=19) or to the traditional continuous light (LL, n=19). The LD condition was achieved by placing individual removable helmets over the infant's heads. Body weight gain was analyzed, as the main indicator of stability and the main criteria for discharge in preterm infants born at 31.73±0.31week gestational age. RESULTS: Infants maintained in an LD cycle gained weight faster than infants in LL and therefore attained a shorter hospital stay, (34.37±3.12 vs 51.11±5.29days; P>0.01). Also, LD infants exhibited improved oxygen saturation and developed a daily melatonin rhythm. CONCLUSIONS: These findings provide a convenient alternative for establishing an LD environment for preterm healthy newborns in the NICU and confirm the beneficial effects of an alternating LD cycle for growth and weight gain and for earlier discharge time. Here we provide an easy and practical alternative to implement light/dark conditions in the NICU.

The circadian system and the balance of the autonomic nervous system.

Our biological clock, the suprachiasmatic nucleus (SCN), sets the pace of our life: it provides a rhythmic function to our sleep-wake cycle. In order to do so properly the SCN synchronizes our physiology to behavioral patterns by directing the autonomic and hormonal output of the hypothalamus to the different organs of the body that require a different setting - activity or inactivity - during particular phases of the day or night. In this chapter we show that this delicate balance requires that the SCN should not only provide an output to these organs but also be informed about the physiological state of the organs in order to adapt its output. This occurs via a hypothalamic neuronal network that provides the necessary input to the SCN. We argue that the feedback that the SCN receives from its hypothalamic target structures is essential to maintain a balance in our physiological functions, which fluctuate during the sleep-wake cycle. We propose that this crucial role of the hypothalamus in the homeostatic response is the reason why, e.g., in aging or depression, changes in the functioning of the biological clock, the SCN, lead to the development of pathology. In addition, if this balance is not adequately organized, for example, if the signals of the biological clock are violated by being active and eating during the night, as in shift work, one will be more susceptible to diseases such as hypertension, obesity, diabetes, and metabolic syndrome.

[Alteration of biological rhythms causes metabolic diseases and obesity]. / La alteracion de los ritmos biologicos causa enfermedades metabolicas y obesidad.

The incidence of obesity worldwide has become a serious, constantly growing public health issue that reaches alarming proportions in some countries. To date none of the strategies developed to combat obesity have proved to be decisive, and hence there is an urgent need to address the problem with new approaches. Today, studies in the field of chronobiology have shown that our physiology continually adapts itself to the cyclical changes in the environment, regard-less of whether they are daily or seasonal. This is possible thanks to the existence of a biological clock in our hypothalamus which regulates the expression and/or activity of enzymes and hormones involved in regulating our metabolism, as well as all the homeostatic functions. It has been observed that this clock can be upset as a result of today's modern lifestyle, which involves a drop in physical activity during the day and the abundant ingestion of food during the night, among other factors, which together promote metabolic syndrome and obesity. Hence, the aim of this review is to summarise the recent findings that show the effect that altering the circadian rhythms has on the metabolism and how this can play a part in the development of metabolic diseases.

TITLE: La alteracion de los ritmos biologicos causa enfermedades metabolicas y obesidad.La incidencia de la obesidad a escala mundial se ha convertido en un grave y creciente problema de salud publica, que alcanza en algunos paises proporciones alarmantes, y hasta el momento ninguna de las estrategias desarrolladas para combatir la obesidad se ha demostrado resolutiva, por lo que es urgente abordar el problema con nuevos enfoques. Actualmente, en el estudio de la cronobiologia se ha demostrado que nuestra fisiologia se adapta continuamente a los cambios ciclicos del ambiente, sean estos diarios o estacionales, debido a la presencia de un reloj biologico en nuestro hipotalamo que regula la expresion y actividad de enzimas y hormonas implicadas en la regulacion del metabolismo, asi como de todas las funciones homeostaticas. Se ha observado que este reloj puede alterarse debido al estilo de vida moderno, que implica una baja actividad fisica durante el dia e ingesta abundante de comida durante la noche, entre otros factores, que promueven todos ellos el sindrome metabolico y la obesidad. Por lo tanto, el objetivo de esta revision es resumir los hallazgos recientes que demuestran el efecto de la alteracion circadiana sobre el metabolismo y como esta puede participar en el desarrollo de enfermedades metabolicas.

La alteración de los ritmos biológicos causa enfermedades metabólicas y obesidad / Alteration of biological rhythms causes metabolic diseases and obesity

.La incidencia de la obesidad a escala mundial se ha convertido en un grave y creciente problema de salud pú- blica, que alcanza en algunos países proporciones alarmantes, y hasta el momento ninguna de las estrategias desarrolladas para combatir la obesidad se ha demostrado resolutiva, por lo que es urgente abordar el problema con nuevos enfoques. Actualmente, en el estudio de la cronobiología se ha demostrado que nuestra fisiología se adapta continuamente a los cambios cíclicos del ambiente, sean estos diarios o estacionales, debido a la presencia de un reloj biológico en nuestro hipotálamo que regula la expresión y actividad de enzimas y hormonas implicadas en la regulación del metabolismo, así como de todas las funciones homeostáticas. Se ha observado que este reloj puede alterarse debido al estilo de vida moderno, que implica una baja actividad física durante el día e ingesta abundante de comida durante la noche, entre otros factores, que promueven todos ellos el síndrome metabólico y la obesidad. Por lo tanto, el objetivo de esta revisión es resumir los hallazgos recientes que demuestran el efecto de la alteración circadiana sobre el metabolismo y cómo ésta puede participar en el desarrollo de enfermedades metabólicas (AU)

The incidence of obesity worldwide has become a serious, constantly growing public health issue that reaches alarming proportions in some countries. To date none of the strategies developed to combat obesity have proved to be decisive, and hence there is an urgent need to address the problem with new approaches. Today, studies in the field of chronobiology have shown that our physiology continually adapts itself to the cyclical changes in the environment, regardless of whether they are daily or seasonal. This is possible thanks to the existence of a biological clock in our hypothalamus which regulates the expression and/or activity of enzymes and hormones involved in regulating our metabolism, as well as all the homeostatic functions. It has been observed that this clock can be upset as a result of today’s modern lifestyle, which involves a drop in physical activity during the day and the abundant ingestion of food during the night, among other factors, which together promote metabolic syndrome and obesity. Hence, the aim of this review is to summarise the recent findings that show the effect that altering the circadian rhythms has on the metabolism and how this can play a part in the development of metabolic diseases (AU)

Artificial feeding synchronizes behavioral, hormonal, metabolic and neural parameters in mother-deprived neonatal rabbit pups.

Nursing in the rabbit is under circadian control, and pups have a daily anticipatory behavioral arousal synchronized to this unique event, but it is not known which signal is the main entraining cue. In the present study, we hypothesized that food is the main entraining signal. Using mother-deprived pups, we tested the effects of artificial feeding on the synchronization of locomotor behavior, plasma glucose, corticosterone, c-Fos (FOS) and PERIOD1 (PER1) rhythms in suprachiasmatic, supraoptic, paraventricular and tuberomammillary nuclei. At postnatal day 1, an intragastric tube was placed by gastrostomy. The next day and for the rest of the experiment, pups were fed with a milk formula through the cannula at either 02:00 h or 10:00 h [feeding time = zeitgeber time (ZT)0]. At postnatal days 5-7, pups exhibited behavioral arousal, with a significant increase in locomotor behavior 60 min before feeding. Glucose levels increased after feeding, peaking at ZT4-ZT12 and then declining. Corticosterone levels were highest around the time of feeding, and then decreased to trough concentrations at ZT12-ZT16, increasing again in anticipation of the next feeding bout. In the brain, the suprachiasmatic nucleus had a rhythm of FOS and PER1 that was not significantly affected by the feeding schedule. Conversely, the supraoptic, paraventricular and tuberomammillary nuclei had rhythms of both FOS and PER1 induced by the time of scheduled feeding. We conclude that the nursing rabbit pup is a natural model of food entrainment, as food, in this case milk formula, is a strong synchronizing signal for behavioral, hormonal, metabolic and neural parameters.

Disruption of circadian rhythms: a crucial factor in the etiology of depression.

Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication) indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.

Early and post-weaning malnutrition impairs alpha-MSH expression in the hypothalamus: a possible link to long-term overweight.

The present study explored the effects of early and post-weaning malnutrition and nutritional rehabilitation on orexigenic (orexin (ORX) and neuropeptide Y (NPY)) and anorexigenic peptides (alpha-melanocyte stimulating hormone (alpha-MSH)) expressed in hypothalamic nuclei. Male Wistar rats were malnourished during gestation-lactation (MGL) or from weaning to post-natal day 55 (MPW; P55). Two groups of rats were rehabilitated with a balanced diet until P90 (MGL-R and MPW-R, respectively). After a glucose tolerance test (GTT) brains were processed for immunohistochemistry. Malnourished groups were hyperglycemic after GTT. ORX expression did not display any difference. Only MGL rats showed increased NPY immunoreactivity in ARC and PVN nuclei, and both malnourished groups showed low alpha-MSH expression in the PVN and DMH, as compared with their controls. After nutritional rehabilitation rats showed normal GTT, increased rate of body and adipose tissue weights and high proportion of food ingestion. Both rehabilitated groups maintained low alpha-MSH expression in the PVN, indicating a deleterious long-lasting effect.

In a rat model of night work, activity during the normal resting phase produces desynchrony in the hypothalamus.

Internal synchrony among external cycles and internal oscillators allows adaptation of physiology to cyclic demands for homeostasis. Night work and shift work lead to a disrupted phase relationship between external time cues and internal rhythms, also losing internal coherence among oscillations. This process results in internal desynchrony (ID) in which behavioral, hormonal, and metabolic variables cycle out of phase. It is still not clear whether ID originates at a peripheral or at a central level. In order to determine the possible role of hypothalamic oscillators in ID, we explored with a rat model of "night work" daily rhythms of activity and clock gene expression in the hypothalamus. This study provides evidence that wakefulness and activity during the normal resting phase lead to a shift in the diurnal rhythms of c-Fos and induce a rhythm of PER1 in the arcuate and dorsomedial nucleus of the hypothalamus, both associated with metabolism and regulation of the sleep/wake cycle. Moreover, the number of orexin (ORX)-positive neurons and c-Fos in the perifornical area increased during the working period, suggesting a relevant switch of activity in this brain region induced by the scheduled activity; however, the colocalization of c-Fos in ORX-positive cells was not increased. In contrast, the suprachiasmatic nucleus and the paraventricular nucleus remained locked to the light/dark cycle, resulting in ID in the hypothalamus. Present data suggest that ID occurs already at the level of the first output projections from the SCN, relaying nuclei that transmit temporal signals to other brain areas and to the periphery.

Altered Fos immunoreactivity in the hypothalamus after glucose administration in pre- and post-weaning malnourished rats.

The present study explored the effects of malnutrition and nutritional rehabilitation on the response to glucose in hypothalamic nuclei involved in metabolic homeostasis. Male Wistar rats were malnourished during gestation-lactation (MGL) or at weaning to 55 days (MPW). Two groups of rats were rehabilitated with a balanced diet until 90 days (MGL-R and MPW-R, respectively). After a glucose tolerance test (GTT), brains were processed for Fos immunoreactivity (Fos-IR). Both malnourished groups displayed hyperglycemia after GTT. MGL exhibited an increased number of Fos-IR neurons in the ventromedial hypothalamic nucleus (VMH), while MPW showed increased Fos-IR in the arcuate nucleus (ARC) and VMH and a decrease in the paraventricular nucleus (PVN), as compared with their controls. Nutritional rehabilitation normalized values of glucose after GTT in both groups, while low number of Fos-IR neurons remained in the ARC, PVN and VMH of MPW-R rats, indicating a deleterious, long-lasting effect after post-weaning malnutrition.

Unpredictable feeding schedules unmask a system for daily resetting of behavioural and metabolic food entrainment.

Restricted feeding schedules (RFS) are a potent Zeitgeber that uncouples daily metabolic and clock gene oscillations in peripheral tissues from the suprachiasmatic nucleus (SCN), which remains entrained to the light-dark cycle. Under RFS, animals develop food anticipatory activity (FAA), characterized by arousal and increased locomotion. Food availability in nature is not precise, which suggests that animals need to adjust their food-associated activity on a daily basis. This study explored the capacity of rats to adjust to variable and unpredictable feeding schedules. Rats were exposed either to RFS with fixed daily meal (RF) or to a variable meal time (VAR) during the light phase. RF and VAR rats exhibited daily metabolic oscillations driven by the last meal event; however, VAR rats were not able to show a robust adjustment in the anticipating corticosterone peak. VAR rats were unable to exhibit FAA but exhibited a daily activation pattern in phase with the previous meal. In both groups the dorsomedial nucleus of the hypothalamus and arcuate nucleus, involved in energy balance, exhibited increased c-Fos expression 24 h after the last meal, while only RF rats exhibited low c-Fos expression in the SCN. Data show that metabolic and behavioural food-entrained rhythms can be reset on a daily basis; the two conditions elicit a similar hypothalamic response, while only the SCN is inhibited in rats exhibiting anticipatory activity. The variable feeding strategy uncovered a rapid (24-h basis) resetting mechanism for metabolism and general behaviour.

c-Fos expression in hypothalamic nuclei of food-entrained rats.

The present study aimed to identify the hypothalamic nuclei involved with food entrainment by using c-Fos-like immunoreactivity (c-Fos-IR) as a marker of functional activation. We studied rats entrained 3 wk to restricted feeding schedules (RF), their ad libitum (AL) controls, and the persistence of c-Fos-IR temporal patterns in entrained-fasted rats. In addition, we included 22-h fasting and 22-h fasting-refeeding groups as controls of fasting and refeeding acute effects. Diurnal patterns of c-Fos-IR were observed in the tuberomammilar nucleus (TM) and suprachiasmatic nucleus (SCN) in AL rats. In all nuclei, except the SCN and ventromedial nucleus (VMH), restricted feeding schedules imposed a temporal pattern of increased c-Fos-IR around mealtime. An increase in c-Fos-IR before and after meal time was observed in dorsomedial nucleus (DMH), lateral nucleus (LH), perifornical area (PeF), and TM, and a marked increase was observed in the paraventricular nucleus (PVN) after feeding. Food-entrained c-Fos-IR patterns persisted after 3 days in fasting in DMH, LH, and PeF. Present data suggest that FEO might not rely on a single nucleus and rather may be a distributed system constituted of interacting nuclei in which the PVN is mainly involved with the response to signals elicited by food ingestion and, therefore, with the entraining pathway. We can suggest that the PeF and TM may be involved with the arousal state during food anticipation and the DMH and LH with the time-keeping mechanism of FEO or its output.