High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Fat rather than sugar diet leads to binge-type eating, anticipation, effort behavior and activation of the corticolimbic system.

Objectives: One factor contributing to the development of obesity is overeating palatable food. The palatability of food is driven by specific energy yielding combinations and flavor profiles that may contribute to its overconsumption. In rodents, restricted access to palatable food (PF) is a strong stimulus to trigger binge-type eating behavior (BTE), food anticipatory activity (FAA), effort behaviors and withdrawal symptoms. This is accompanied by plastic changes in corticolimbic areas associated with motivation and reward responses. Palatable food contains mainly a mixture of fat and sugar, thus, the contribution of each macronutrient for the behavioral and neuronal changes is unclear.Methods: In this study, Wistar rats were exposed to restricted access to 50% fat rich diet (FRD) or 50% sugar rich diet (SRD) in order to compare the intensity of BTE, FAA, effort behaviors and withdrawal responses.Results: In corticolimbic areas, c-Fos activation and ΔFosB accumulation were evaluated. After an acute exposition, rats ate more SRD than FRD, but FDR stimulated higher c-Fos. After chronic administration, the FDR group exhibited higher levels of BTE and FAA; this was associated with higher c-Fos and accumulation of ΔFosB in the corticolimbic system. Similar effects in the FRD group were observed after one week of withdrawal.Discussion: Present data indicate that the fat rich diet is a stronger stimulus than the sugar rich diet for the development of wanting behavior for reward and the underlying plastic changes in the corticolimbic system. The differential effects may be due to the differing caloric density of the diets.

Addiction-like response in brain and behavior in a rat experimental model of night-eating syndrome.

STUDY OBJECTIVES: Individuals ailing from night eating syndrome (NES) consume more than 25% of their daily food intake during the normal sleep time, delaying their sleep or waking up in the middle of the night to eat. This study explored two experimental conditions resembling NES in Wistar rats by offering palatable food during the sleep phase, alone or combined with sleep delay. Also we explored their impact on addiction-like changes in the brain and behavior. METHODS: Experiment 1 explored the brain response after a first NES-like event; experiment 2 and 3 explored addiction-like behaviors c-Fos and FosB/ΔFosB in corticolimbic regions after 4 weeks exposition to NES-like conditions and after one week of withdrawal, respectively. For all 3 experiments 6 experimental groups were used: 1. Control; 2. Restricted access (1 h) to high-sugar diet (HSD) or to 3. high-fat diet (HFD); 4., Sleep delay for 4 h (SD) (from ZT0-ZT4, rats using slow rotating wheels); 5. SD + HSD; 6. SD + HFD. RESULTS: A first event of eating a palatable diet with or without SD was sufficient to stimulate c-Fos and ΔFosB. Along 4 weeks of exposure to the palatable diets rats exhibited escalation and binge eating, which was highest for the HFD. At this stage, SD did not influence behavioral changes nor the neuronal response. After one-week in withdrawal, rats exhibited craving and effort to obtain their palatable diet. The brains of rats previously exposed to sleep delay maintained high levels of FosB/ΔFosB in the accumbens shell and high c-Fos activation in the insular cortex. CONCLUSIONS: In our experimental models of NES-like a HFD in the sleep phase and SD are risk factors to develop binge eating and addiction-like behaviors.

Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model.

BACKGROUND: Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells. METHODS: Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet. RESULTS: We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions. CONCLUSIONS: Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.

Dim Light at Night Promotes Circadian Disruption in Female Rats, at the Metabolic, Reproductive, and Behavioral Level.

Inhabitants of urban areas are constantly exposed to light at night, which is an important environmental factor leading to circadian disruption. Streetlights filtering light through the windows and night dim light lamps are common sources of dim light at night (DLAN). The female population is susceptible to circadian disruption. The present study is aimed to determine the impact of DLAN on female Wistar rats circadian rhythms, metabolism, reproductive physiology, and behavior. After 5 weeks of DLAN exposure daily, oscillations in activity and body temperature of female rats are abolished. DLAN also decreases nocturnal food ingestion, which results in a diminishment in total food consumption. These alterations in the temporal organization of the body are associated with a significant decrease in melatonin plasmatic levels, reproductive disruptions, decreased exploration times, and marked anhedonia. This study highlights the importance of avoiding exposure to light at night, even at low intensities, to maintain the circadian organization of physiology, and denotes the great necessity of increasing the studies in females since the sexual dimorphism within the effects of desynchronizing protocols has been poorly studied.

Timed restricted feeding cycles drive daily rhythms in female rats maintained in constant light but only partially restore the estrous cycle.

Light at night is an emergent problem for modern society. Rodents exposed to light at night develop a loss of circadian rhythms, which leads to increased adiposity, altered immune response, and increased growth of tumors. In female rats, constant light (LL) eliminates the estrous cycle leading to a state of persistent estrus. The suprachiasmatic nucleus (SCN) drives circadian rhythms, and it interacts with the neuroendocrine network necessary for reproductive function. Timed restricted feeding (RF) exerts a powerful entraining influence on the circadian system, and it can influence the SCN activity and can restore rhythmicity or accelerate re-entrainment in experimental conditions of shift work or jet lag. The present study explored RF in female rats exposed to LL, with the hypothesis that this cyclic condition can rescue or prevent the loss of daily rhythms and benefit the expression of the estrous cycle. Two different feeding schedules were explored: 1. A 12-h food/12-h fasting schedule applied to arrhythmic rats after 3 weeks in LL, visualized as a rescue strategy (LL + RFR, 3 weeks), or applied simultaneously with the first day of LL as a preventive strategy (LL + RFP, 6 weeks). 2. A 12-h window of food intake with food given in four distributed pulses (every 3 h), applied after 3 weeks in LL, as a rescue strategy (LL + PR, 3 weeks) or applied simultaneously with the first day of LL as a preventive strategy (LL + PP, 6 weeks). Here, we present evidence that scheduled feeding can drive daily rhythms of activity and temperature in rats exposed to LL. However, the protocol of distributed feeding pulses was more efficient to restore the day-night activity and core temperature as well as the c-Fos day-night change in the SCN. Likewise, the distributed feeding partially restored the estrous cycle and the ovary morphology under LL condition. Data here provided indicate that the 12-h feeding/12-h fasting window determines the rest-activity cycle and can benefit directly the circadian and reproductive function. Moreover, this effect is stronger when food is distributed along the 12 h of subjective night.

Chocolate for breakfast prevents circadian desynchrony in experimental models of jet-lag and shift-work.

Night-workers, transcontinental travelers and individuals that regularly shift their sleep timing, suffer from circadian desynchrony and are at risk to develop metabolic disease, cancer, and mood disorders, among others. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental metabolic effects associated with circadian disruption. As an alternative, we hypothesized that a timed piece of chocolate scheduled to the onset of the activity phase may be sufficient stimulus to synchronize circadian rhythms under conditions of shift-work or jet-lag. In Wistar rats, a daily piece of chocolate coupled to the onset of the active phase (breakfast) accelerated re-entrainment in a jet-lag model by setting the activity of the suprachiasmatic nucleus (SCN) to the new cycle. Furthermore, in a rat model of shift-work, a piece of chocolate for breakfast prevented circadian desynchrony, by increasing the amplitude of the day-night c-Fos activation in the SCN. Contrasting, chocolate for dinner prevented re-entrainment in the jet-lag condition and favored circadian desynchrony in the shift-work models. Moreover, chocolate for breakfast resulted in low body weight gain while chocolate for dinner boosted up body weight. Present data evidence the relevance of the timing of a highly caloric and palatable meal for circadian synchrony and metabolic function.

Shift-work: is time of eating determining metabolic health? Evidence from animal models.

The circadian disruption in shift-workers is suggested to be a risk factor to develop overweight and metabolic dysfunction. The conflicting time signals given by shifted activity, shifted food intake and exposure to light at night occurring in the shift-worker are proposed to be the cause for the loss of internal synchrony and the consequent adverse effects on body weight and metabolism. Because food elicited signals have proven to be potent entraining signals for peripheral oscillations, here we review the findings from experimental models of shift-work and verify whether they provide evidence about the causal association between shifted feeding schedules, circadian disruption and altered metabolism. We found mainly four experimental models that mimic the conditions of shift-work: protocols of forced sleep deprivation, of forced activity during the normal rest phase, exposure to light at night and shifted food timing. A big variability in the intensity and duration of the protocols was observed, which led to a diversity of effects. A common result was the disruption of temporal patterns of activity; however, not all studies explored the temporal patterns of food intake. According to studies that evaluate time of food intake as an experimental model of shift-work and studies that evaluate shifted food consumption, time of food intake may be a determining factor for the loss of balance at the circadian and metabolic level.

Social jet-lag potentiates obesity and metabolic syndrome when combined with cafeteria diet in rats.

BACKGROUND/OBJECTIVES: Modern lifestyle promotes shifted sleep onset and shifted wake up time between weekdays and weekends, producing a condition termed "social-jet lag." Disrupted sleep promotes increased appetite for carbohydrate and fat-rich food, which in long term leads to overweight, obesity and metabolic syndrome. In order to mimic the human situation we produced an experimental model of social-jet lag (Sj-l). With this model, we explored the link between shifted sleep time with consumption of a cafeteria diet (CafD) and the development of obesity and metabolic syndrome. SUBJECTS/METHODS: The first experiment was designed to create and confirm the model of Sj-l. Rats (n=8-10/group) were exposed to a shifted sleep time protocol achieved by placing the rats in slow rotating wheels from Monday to Friday during the first 4h of the light period, while on weekends they were left undisturbed. The second experiment (n=8-12/group) explored the combined effect of Sj-l with the opportunity to ingest CafD. All protocols lasted 12weeks. We evaluated the development of overweight and indicators of metabolic syndrome. The statistical significance for all variables was set at P<0.05. RESULTS: Sj-l alone did not affect body weight gain but induced significant changes in cholesterol in metabolic variables representing a risk factor for metabolic syndrome. Daily restricted access to CafD in the day or night induced glucose intolerance and only CafD during the day led to overweight. Sj-l combined with CafD induced overconsumption of the diet, potentiated body weight gain (16%) and promoted 5 of the criteria for metabolic syndrome including high insulin and dislipidemia. CONCLUSION: Present data provide an experimental model of social-jet lag that combined with overconsumption of CafD, and maximized the development of obesity and metabolic syndrome. Importantly, access to CafD during the night did not lead to overweight nor metabolic syndrome.

La comida por la noche como factor inductor de obesidad / Food during the night is a factor leading to obesity

Resumen: Esta revisión tiene como objetivo presentar evidencias obtenidas mediante observaciones clínicas y modelos animales que señalan la relevancia que tiene el horario de alimentación sobre el metabolismo y el mantenimiento del peso corporal. Hallazgos recientes han puesto en evidencia que la misma cantidad de alimento ingerida durante el día o la noche afecta diferencialmente el metabolismo, lo que determina una diferencia significativa en el desarrollo del sobrepeso y la obesidad. Este conocimiento se fundamenta en el estudio del sistema circadiano, regido por el reloj biológico del hipotálamo anterior, que le transmite tiempos a todas las funciones del cuerpo, incluyendo aquellas para el gasto y el ahorro de energía. A pesar de que estos ciclos circadianos están normalmente regulados por los cambios de iluminación resultantes de la alternancia del día y la noche, los cambios metabólicos que resultan de una comida han mostrado también ser señales de tiempo que modifican el orden temporal de algunos sistemas y grupos celulares. De ello se desprende que para que el sistema circadiano funcione sincronizado, las horas de alimentación deben coincidir con los ciclos dictados por el reloj biológico. De tal manera, comer durante las horas normalmente asignadas al reposo lleva a la pérdida de coordinación de los ritmos circadianos metabólicos con respecto al reloj biológico. Esta desincronización sucede a diferentes niveles, tanto entre las células de los tejidos como en una misma célula a nivel molecular. En esta revisión se enfatizarán los efectos adversos de las comidas por la noche sobre el metabolismo energético, además se presentarán resultados recientes que describen los cambios circadianos y metabólicos a diversos niveles de regulación.

Abstract: The present review aims to present evidence obtained in clinical surveys and experimental studies that point out the relevance of meal schedules on metabolism and body weight. Recent findings indicate that in spite of ingesting equivalent amounts, food ingestion during the day or during the night can have completely different effects on metabolism determining bodyweight gain and propensity to obesity. Such findings find support in studies of the circadian rhythms, driven by a biological clock located in the anterior hypothalamus, which transmits temporal signals to the body including functions for energy balance. Circadian cycles are normally driven by the alternation of the day- night luminosity cycles, however metabolic changes resulting from food have proven to be powerful temporal signals capable of modifying de temporal order in tissues and cells. Considering the power of food elicited signals, the feeding schedule must coincide with the timing signals driven by the biological clock. Thus eating during the hours normally assigned for sleep and rest leads to a loss of coordination between metabolic rhythms and the biological clock. This circadian disruption occurs at different levels, among cells in a specific tissue as well as in the molecular processes in cells. The aim of this review is to emphasize the adverse effects that meals during the night can exhert on metabolism, we provide evidence about circadian and metabolic alterations at different regulatory levels.