Visceral fat sympathectomy ameliorates systemic and local stress response related to chronic sleep restriction.

Disturbance of sleep homeostasis encompasses health issues, including metabolic disorders like obesity, diabetes, and augmented stress vulnerability. Sleep and stress interact bidirectionally to influence the central nervous system and metabolism. Murine models demonstrate that decreased sleep time is associated with an increased systemic stress response, characterized by endocrinal imbalance, including the elevated activity of hypothalamic-pituitary-adrenal axis, augmented insulin, and reduced adiponectin, affecting peripheral organs physiology, mainly the white adipose tissue (WAT). Within peripheral organs, a local stress response can also be activated by promoting the formation of corticosterone. This local amplifying glucocorticoid signaling is favored through the activation of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). In WAT, 11ß-HSD1 activity is upregulated by the sympathetic nervous system, suggesting a link between sleep loss, augmented stress response, and a potential WAT metabolic disturbance. To gain more understanding about this relationship, metabolic and stress responses of WAT-sympathectomized rats were analyzed to identify the contribution of the autonomic nervous system to stress response-related metabolic disorders during chronic sleep restriction. Male Wistar rats under sleep restriction were allowed just 6 h of daily sleep over eight weeks. Results showed that rats under sleep restriction presented higher serum corticosterone, increased adipose tissue 11ß-HSD1 activity, weight loss, decreased visceral fat, augmented adiponectin, lower leptin levels, glucose tolerance impairment, and mildly decreased daily body temperature. In contrast, sympathectomized rats under sleep restriction exhibited decreased stress response (lower serum corticosterone and 11ß-HSD1 activity). In addition, they maintained weight loss, explained by a reduced visceral fat pad, leptin, and adiponectin, improved glucose management, and persisting decline in body temperature. These results suggest autonomic nervous system is partially responsible for the WAT-exacerbated stress response and its metabolic and physiological disturbances.

Feeding during the resting phase causes gastrointestinal tract dysfunction and desynchronization of metabolic and neuronal rhythms in rats.

BACKGROUND: Disrupted circadian rhythms may result from a misalignment between the environmental cycles (due to shift work, sleep restriction, feeding at an unusual time of day) and endogenous rhythms or by physiological aging. Among the numerous adverse effects, disrupted rhythms affect the brain-gut axis, contributing to the pathogenesis of several diseases in the gastrointestinal tract, for example, abdominal pain, constipation, gastric dyspepsia, inflammatory bowel disease, irritable bowel syndrome, and others. METHODS: This study evaluated the rat gastric emptying, gastrointestinal motility, a clock gene, gut hormones, and the neuron activity on the nucleus of tractus solitarius (NTS), area postrema (AP), and the dorsal motor nucleus of the vagus (DMV) in rats with restricted food access to the rest phase for 4 weeks. KEY RESULTS: Our results show that food restricted to the rest light period disturbed the expression pattern of a series of transcripts, including metabolic and circadian regulation. Also, the secretion of gastrointestinal hormones, gastric emptying, intestinal motility, and NTS, AP, and DMV activity were altered. CONCLUSIONS & INFERENCES: These data indicate the importance of the time of the day food is ingested on the regulation of energy balance and the endocrine activity of the stomach and small intestine, emphasizing the importance of food as a powerful circadian synchronizer and an essential factor for the triggering of gastrointestinal diseases and metabolic problems. These findings offer a novel clue regarding the obesity-promoting effect attributed to feeding time and open the possibility of treating this and other intestinal disorders.

Morphological changes and Mitochondrial alterations on Cardiomyocytes exposed to Fluoride.

OBJECTIVE: To evaluate the morphological changes of cardiomyocytes exposed to different sodium fluoride (NaF) concentrations, as well as to evaluate the behavior of the mitochondria. METHODS: Rat H9c2 cardiomyocytes were exposed to NaF at concentrations of 0.5 to 5 mmol/L. The morphology and number of mitochondria in these cells were monitored, and the calcium ion (Ca2+) concentration was determined. RESULTS: Morphological changes were evident in the cells treated with different NaF concentrations, and both the number of mitochondria and the Ca2+ concentration decreased in a dose-dependent manner. CONCLUSION: Sodium fluoride induced morphological damage in cardiomyocytes, decreases the Ca2+ concentration and mitochondrial number.

Leptin and adiponectin regulate the activity of nuclei involved in sleep-wake cycle in male rats.

Epidemiological and experimental evidence recognize a relationship between sleep-wake cycles and adiposity levels, but the mechanisms that link both are not entirely understood. Adipose tissue secretes adiponectin and leptin hormones, mainly involved as indicators of adiposity levels and recently associated to sleep. To understand how two of the main adipose tissue hormones could influence sleep-wake regulation, we evaluated in male rats, the effect of direct administration of adiponectin or leptin in the ventrolateral preoptic nuclei (VLPO), a major area for sleep promotion. The presence of adiponectin (AdipoR1 and AdipoR2) and leptin receptors in VLPO were confirmed by immunohistochemistry. Adiponectin administration increased wakefulness during the rest phase, reduced delta power, and activated wake-promoting neurons, such as the locus coeruleus (LC), tuberomammillary nucleus (TMN) and hypocretin/orexin neurons (OX) within the lateral hypothalamus (LH) and perifornical area (PeF). Conversely, leptin promoted REM and NREM sleep, including increase of delta power during NREM sleep, and induced c-Fos expression in VLPO and melanin concentrating hormone expressing neurons (MCH). In addition, a reduction in wake-promoting neurons activity was found in the TMN, lateral hypothalamus (LH) and perifornical area (PeF), including in the OX neurons. Moreover, leptin administration reduced tyrosine hydroxylase (TH) immunoreactivity in the LC. Our data suggest that adiponectin and leptin act as hormonal mediators between the status of body energy and the regulation of the sleep-wake cycle.

Temporal dysregulation of hypothalamic integrative and metabolic nuclei in rats fed during the rest phase.

Temporal coordination of organisms according to the daytime allows a better performance of physiological processes. However, modern lifestyle habits, such as food intake during the rest phase, promote internal desynchronization and compromise homeostasis and health. The hypothalamic suprachiasmatic nucleus (SCN) synchronizes body physiology and behavior with the environmental light-dark cycle by transmitting time information to several integrative hypothalamic nuclei, such as the paraventricular nucleus (PVN), dorsomedial hypothalamic nucleus (DMH) and median preoptic area (MnPO). The SCN receives metabolic information mainly via Neuropeptide Y (NPY) inputs from the intergeniculate nucleus of the thalamus (IGL). Nowadays, there is no evidence of the response of the PVN, DMH and MnPO when the animals are subjected to internal desynchronization by restricting food access to the rest phase of the day. To explore this issue, we compared the circadian activity of the SCN, PVN, DMH and MnPO. In addition, we analyzed the daily activity of the satiety centers of the brainstem, the nucleus of the tractus solitarius (NTS) and area postrema (AP), which send metabolic information to the SCN, directly or via the thalamic intergeniculate leaflet (IGL). For that, male Wistar rats were assigned to three meal protocols: fed during the rest phase (Day Fed); fed during the active phase (Night Fed); free access to food (ad libitum). After 21 d, the daily activity patterns of these nuclei were analyzed by c-Fos immunohistochemistry, as well as NPY immunohistochemistry, in the SCN. The results show that eating during the rest period produces a phase advance in the activity of the SCN, changes the daily activity pattern in the MnPO, NTS and AP and flattens the c-Fos rhythm in the PVN and DMH. Altogether, these results validate previous observations of circadian dysregulation that occurs within the central nervous system when meals are consumed during the rest phase, a behavior that is involved in the metabolic alterations described in the literature.

Raman Spectroscopy for Adipose Tissue Assessment in Rat Models of Obesity and Type 1 Diabetes.

Adipose tissue presents structural and functional changes in obesity and type 1 diabetes mellitus (T1DM). In obesity, the size and number of adipocytes and adipokine secretion increases. In T1DM, a loss of adipose tissue suggests changes in the metabolic activity of this tissue. A significant challenge is to find alternative noninvasive methods to evaluate molecular changes in adipose tissue related to obesity and T1DM. Recently, Raman spectroscopy and chemometrics techniques have emerged as a tool for biological tissue analysis. In this work, we propose the use of Raman spectroscopy to characterize spectral differences in adipose tissue from different rat groups (control, obese, and T1DM). The Raman spectra were analyzed using direct band analysis, ratiometric analysis, and chemometric methods (principal component analysis (PCA) and support vector machines (SVMs)). We found that the Raman spectra of obese rats showed significant spectral differences compared to control and diabetic groups related to fatty acids Raman bands. Also, the obese group has a significant decrease in the degree of unsaturation of lipids. The PCA-SVM models showed classification performance ranging from 71.43% to 71.79% accuracy for brown and white adipose tissue samples, respectively. In conclusion, the results demonstrate that Raman spectroscopy can be used as a nondestructive method to assess adipose tissue according to a metabolic condition.

Nicotine smoking concentrations modulate GABAergic synaptic transmission in murine medial prefrontal cortex by activation of α7* and ß2* nicotinic receptors.

Nicotine is the major addictive component of cigarettes, reaching a brain concentration of ~300 nM during smoking of a single cigarette. The prefrontal cortex (PFC) mechanisms underlying temporary changes of working memory during smoking are incompletely understood. Here, we investigated whether 300 nM nicotine modulates γ-aminobutyric acid (GABA) ergic synaptic transmission from pyramidal neurons of the output layer (V) of the murine medial PFC. We used patch clamp in vitro recording from C57BL/6 mice in the whole-cell configuration to investigate the effect of nicotine on pharmacologically isolated GABAergic postsynaptic currents (IPSCs) in the absence or presence of methyllycaconitine (MLA) or dihydro-ß-erythroidine (DHßE), selective antagonists of α7- and ß2-containing (α7* and ß2*) nicotinic acetylcholine receptors (AChRs), respectively. Our results indicated that nicotine, alone or in the presence of MLA, decreases electrically evoked IPSC (eIPSC) amplitude, whereas in the presence of DHßE, nicotine elicited either an eIPSCs amplitude increase or a decrease. In the presence of DHßE, nicotine increased membrane conductance leaving the paired pulse ratio unchanged in all conditions, suggesting a non-ß2* mediated effect. In the presence of MLA, nicotine decreased the mean spontaneous IPSC (sIPSC) frequency but increased their rise time, suggesting a non-α7* AChR-mediated synaptic modulation. Also, in the presence of DHßE, nicotine decreased both eIPSC rise and decay times. No receptors other than α7* and ß2* appear to be involved in the nicotine effect. Our results indicate that nicotine smoking concentrations modulate GABAergic synaptic currents through mixed pre- and post-synaptic mechanisms by activation of α7* and ß2* AChRs.

Differential Recovery Speed of Activity and Metabolic Rhythms in Rats After an Experimental Protocol of Shift-Work.

The circadian system drives the temporal organization of body physiology in relation to the changing daily environment. Shift-work (SW) disrupts this temporal order and is associated with the loss of homeostasis and metabolic syndrome. In a rodent model of SW based on forced activity in the rest phase for 4 weeks, we describe the occurrence of circadian desynchrony, as well as metabolic and liver dysfunction. To provide better evidence for the impact of altered timing of activity, this study explored how long it takes to recover metabolic rhythms and behavior. Rats were submitted to experimental SW for 4 weeks and then were left to recover for one week. Daily locomotor activity, food intake patterns, serum glucose and triglycerides, and the expression levels of hepatic Pparα, Srebp-1c, Pepck, Bmal1 and Per2 were assessed during the recovery period and were compared with expected data according to a control condition. SW triggered the circadian desynchronization of all of the analyzed parameters. A difference in the time required for realignment was observed among parameters. Locomotor activity achieved the expected phase on day 2, whereas the nocturnal feeding pattern was restored on the sixth recovery day. Daily rhythms of plasma glucose and triglycerides and of Pparα, Pepck and Bmal1 expression in the liver resynchronized on the seventh day, whereas Srebp-1c and Per2 persisted arrhythmic for the entire recovery week. SW does not equally affect behavior and metabolic rhythms, leading to internal desynchrony during the recovery phase.

Arsenic Exposure Contributes to the Bioenergetic Damage in an Alzheimer's Disease Model.

Worldwide, every year there is an increase in the number of people exposed to inorganic arsenic (iAs) via drinking water. Human populations present impaired cognitive function as a result of prenatal and childhood iAs exposure, while studies in animal models demonstrate neurobehavioral deficits accompanied by neurotransmitter, protein, and enzyme alterations. Similar impairments have been observed in close association with Alzheimer's disease (AD). In order to determine whether iAs promotes the pathophysiological progress of AD, we used the 3xTgAD mouse model. Mice were exposed to iAs in drinking water from gestation until 6 months (As-3xTgAD group) and compared with control animals without arsenic (3xTgAD group). We investigated the behavior phenotype on a test battery (circadian rhythm, locomotor behavior, Morris water maze, and contextual fear conditioning). Adenosine triphosphate (ATP), reactive oxygen species, lipid peroxidation, and respiration rates of mitochondria were evaluated, antioxidant components were detected by immunoblots, and immunohistochemical studies were performed to reveal AD markers. As-3xTgAD displayed alterations in their circadian rhythm and exhibited longer freezing time and escape latencies compared to the control group. The bioenergetic profile revealed decreased ATP levels accompanied by the decline of complex I, and an oxidant state in the hippocampus. On the other hand, the cortex showed no changes of oxidant stress and complex I; however, the antioxidant response was increased. Higher immunopositivity to amyloid isoforms and to phosphorylated tau was observed in frontal cortex and hippocampus of exposed animals. In conclusion, mitochondrial dysfunction may be one of the triggering factors through which chronic iAs exposure exacerbates brain AD-like pathology.

Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism.

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.

Cholinergic signaling plasticity maintains viscerosensory responses during Aspiculuris tetraptera infection in mice small intestine.

Intestinal parasites alter gastrointestinal (GI) functions like the cholinergic function. Aspiculuris tetraptera is a pinworm frequently observed in laboratory facilities, which infests the mice cecum and proximal colon. However, little is known about the impact of this infection on the GI sensitivity. Here, we investigated possible changes in spontaneous mesenteric nerve activity and on the mechanosensitivity function of worm-free regions of naturally infected mice with A. tetraptera. Infection increased the basal firing of mesenteric afferent nerves in jejunum. Our findings indicate that nicotinic but not muscarinic receptors, similarly affect spontaneous nerve firing in control and infected animals; these axons are mainly vagal. No difference between groups was observed on spontaneous activity after nicotinic receptor inhibition. However, and contrary to the control group, during infection, the muscarinic signaling was shown to be elevated during mechanosensory experiments. In conclusion, we showed for the first time that alterations induced by infection of the basal afferent activity were independent of the cholinergic function but changes in mechanosensitivity were mediated by muscarinic, but not nicotinic, receptors and specifically by high threshold nerve fibers (activated above 20mmHg), known to play a role in nociception. These plastic changes within the muscarinic signaling would function as a compensatory mechanism to maintain a full mechanosensory response and the excitability of nociceptors during infection. These changes indicate that pinworm colonic infection can target other tissues away from the colon.

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.

Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented-in order of decreasing affinity for the catecholamine-by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and ß adrenoceptors (ßRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and ß-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing-in turn-a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large number of experimental and clinical findings, a major challenge will be to adapt this hypothesis to integrate the role of other neurotransmitters released during stress in a centralized fashion, like serotonin, acetylcholine, and histamine, as well as those released in a non-centralized fashion, like purines and cytokines.

Shift Work in Rats Results in Increased Inflammatory Response after Lipopolysaccharide Administration: A Role for Food Consumption.

The suprachiasmatic nucleus (SCN) drives circadian rhythms in behavioral and physiological variables, including the inflammatory response. Shift work is known to disturb circadian rhythms and is associated with increased susceptibility to develop disease. In rodents, circadian disruption due to shifted light schedules (jet lag) induced increased innate immune responses. To gain more insight into the influence of circadian disruption on the immune response, we characterized the inflammatory response in a model of rodent shift work and demonstrated that circadian disruption affected the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. Since food consumption is a main disturbing element in the shift work schedule, we also evaluated the inflammatory response to LPS in a group of rats that had no access to food during their working hours. Our results demonstrated that the shift work schedule decreased basal TNF-α levels in the liver but not in the circulation. Despite this, we observed that shift work induced increased cytokine response after LPS stimulation in comparison to control rats. Also, Kupffer cells (liver macrophages) isolated from shift work rats produced more TNF-α in response to in vitro LPS stimulation, suggesting important effects of circadian desynchronization on the functionality of this cell type. Importantly, the effects of shift work on the inflammatory response to LPS were prevented when food was not available during the working schedule. Together, these results show that dissociating behavior and food intake from the synchronizing drive of the SCN severely disturbs the immune response.

Activation of the anti-inflammatory reflex blocks lipopolysaccharide-induced decrease in synaptic inhibition in the temporal cortex of the rat.

Stress is a potential trigger for a number of neuropsychiatric conditions, including anxiety syndromes and schizophrenic psychoses. The temporal neocortex is a stress-sensitive area involved in the development of such conditions. We have recently shown that aseptic inflammation and mild electric shock shift the balance between synaptic excitation and synaptic inhibition in favor of the former in this brain area (Garcia-Oscos et al., 2012), as well as in the prefrontal cortex (Garcia-Oscos et al., 2014). Given the potential clinical importance of this phenomenon in the etiology of hyperexcitable neuropsychiatric illness, this study investigates whether inactivation of the peripheral immune system by the "anti-inflammatory reflex" would reduce the central response to aseptic inflammation. For a model of aseptic inflammation, this study used i.p. injections of the bacterial toxin lipopolysaccharide (LPS; 5 µM) and activated the anti-inflammatory reflex either pharmacologically by i.p. injections of the nicotinic α7 receptor agonist PHA543613 or physiologically through electrical stimulation of the left vagal nerve (VNS). Patch-clamp recording was used to monitor synaptic function. Recordings from LPS-injected Sprague Dawley rats show that activation of the anti-inflammatory reflex either pharmacologically or by VNS blocks or greatly reduces the LPS-induced decrease of the synaptic inhibitory-to-excitatory ratio and the saturation level of inhibitory current input-output curves. Given the ample variety of pharmacologically available α7 nicotinic receptor agonists as well as the relative safety of clinical VNS already approved by the FDA for the treatment of epilepsy and depression, our findings suggest a new therapeutic avenue in the treatment of stress-induced hyperexcitable conditions mediated by a decrease in synaptic inhibition in the temporal cortex.

Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex.

The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (single acute injections of lipopolysaccharide, LPS, 10mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-signaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic α7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or - in wild-type animals - upon application sgp130Fc. Similar results were obtained by activating the "anti-inflammatory reflex" - a neural circuit regulating peripheral immune response - by stimulation of the vagal nerve or through peripheral administration of the α7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-signaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depression.

Food entrains clock genes but not metabolic genes in the liver of suprachiasmatic nucleus lesioned rats.

Hepatic circadian transcription, considered to be driven by the liver clock, is largely influenced by food even uncoupling it from the suprachiasmatic nucleus (SCN). In SCN lesioned rats (SCNx) we determined the influence of a physiological feeding schedule on the entrainment of clock and clock-controlled (CCG) genes in the liver. We show that clock genes and the CCG Rev-erbα and peroxisome proliferator-activated receptor alpha (PPARα) in food-scheduled intact and SCNx have a robust diurnal differential expression persisting after a 24h fast. However, hepatic nicotinamide phosphoribosyl transferase (Nampt) shows time dependent changes that are lost in intact animals under fasting; moreover, it is unresponsive to the nutrient status in SCNx, indicating a poor reliance on liver clock genes and highlighting the relevance of SCN-derived signals for its metabolic status-related expression.

Reciprocal interaction between the suprachiasmatic nucleus and the immune system tunes down the inflammatory response to lipopolysaccharide.

Several studies have shown circadian variations in the response of the immune system suggesting a role of the suprachiasmatic nucleus (SCN). Here we show that lipopolysaccharide (LPS) administration in the beginning of the active period induced more severe responses in temperature and cytokines than LPS given in the rest period. Moreover night administered LPS increased SCN basal neuronal activity indicating a direct influence of inflammation on the SCN. Bilateral lesions of the SCN resulted in an increased inflammatory response to LPS demonstrating that an interaction between the SCN and the immune system modulates the intensity of the inflammatory response.

Simulated shift work in rats perturbs multiscale regulation of locomotor activity.

Motor activity possesses a multiscale regulation that is characterized by fractal activity fluctuations with similar structure across a wide range of timescales spanning minutes to hours. Fractal activity patterns are disturbed in animals after ablating the master circadian pacemaker (suprachiasmatic nucleus, SCN) and in humans with SCN dysfunction as occurs with aging and in dementia, suggesting the crucial role of the circadian system in the multiscale activity regulation. We hypothesized that the normal synchronization between behavioural cycles and the SCN-generated circadian rhythms is required for multiscale activity regulation. To test the hypothesis, we studied activity fluctuations of rats in a simulated shift work protocol that was designed to force animals to be active during the habitual resting phase of the circadian/daily cycle. We found that these animals had gradually decreased mean activity level and reduced 24-h activity rhythm amplitude, indicating disturbed circadian and behavioural cycles. Moreover, these animals had disrupted fractal activity patterns as characterized by more random activity fluctuations at multiple timescales from 4 to 12 h. Intriguingly, these activity disturbances exacerbated when the shift work schedule lasted longer and persisted even in the normal days (without forced activity) following the shift work. The disrupted circadian and fractal patterns resemble those of SCN-lesioned animals and of human patients with dementia, suggesting a detrimental impact of shift work on multiscale activity regulation.

La mala calidad de sueño es factor promotor de obesidad / Poor quality sleep is a contributing factor to obesity

La presente revisión tiene como objetivos presentar a la comunidad académica evidencias recientes que proponen una relación entre la mala calidad y cantidad de sueño y la propensión al sobrepeso y obesidad. Se presentan en este escrito evidencias obtenidas en estudios clínicos controlados y de investigación básica experimental que demuestran que una cantidad o calidad deficiente de sueño lleva a corto plazo a alteraciones de tipo metabólico y conductual conducentes a la sobre ingestión de alimentos y al sobrepeso. También se discuten los posibles mecanismos que pudieran subyacer a este fenómeno, a nivel cerebral, metabólico y celular. El objetivo de esta revisión es presentar a las horas de sueño como un factor poco considerado en los estudios epidemiológicos y experimentales y posible desencadenante de alteraciones metabólicas. Con este escrito esperamos poder interesar a otros profesionistas involucrados en el estudio de este fenómeno para incluir la calidad y cantidad de sueño entre sus variables de estudio y/o incluir la higiene del sueño entre sus propuestas de tratamiento y prevención.

The aim of this revisión is to highlight recent evidence that links low quality and quantity of sleep with an increased propensity to develop overweight or obesity. In this text we present evidence obtained with controlled clinical studies as well as with experimental models, both indicating that decreased hours of sleep lead to metabolic and behavioral changes that then induce overconsumption of food, which then results in weight gain. With this review we want to present sleep as an additional factor contributing to metabolic disease and we aim to raise interest in professional involved in the study of overweight and obesity in order to include this factor as an additional variable in their research and strategies of intervention.