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Increased adiposity is related to oxidative stress, inflammation and metabolic disorders. Our group has shown that melatonin totally or partially prevents the alterations that obesity causes in some neuroendocrine and inflammatory parameters indicative of oxidative stress. This study analyzes the effects of HFD on the relative gene expression of several redox balance enzymes on adult male Wistar rats subcutaneous (SAT) and perirenal adipose tissue (PRAT) and the possible preventive role of melatonin. Three experimental groups were established: control, high fat diet (HFD) and HFD plus 25 μg/mL melatonin in tap water. After 11 weeks, animals were sacrificed at 09:00 a.m. and 01:00 a.m. and PRAT and SAT were collected for selected redox enzymes qRT-PCR. Differential expression of redox enzyme genes, except for SODMn, GPx and catalase, was observed in the control group as a function of fat depot. HFD causes the disappearance of the temporal changes in the expression of the genes studied in the two fat depots analyzed. PRAT seems to be more sensitive than SAT to increased oxidative stress induced by obesity. Melatonin combined with a HFD intake, partially prevents the effects of the HFD on the gene expression of the redox enzymes. According to our results, melatonin selectively prevents changes in the relative gene expression of redox enzymes in PRAT and SAT of animals fed an HFD.

Background: Epicardial adipose tissue (EAT) is a visceral fat depot with unique anatomic, biomolecular and genetic features. Due to its proximity to the coronary arteries and myocardium, dysfunctional EAT may contribute to the development and progression of cardiovascular and metabolic-related adiposity-based chronic diseases. The aim of this work was to describe, by morphological techniques, the early origin of EAT. Methods: EAT adipogenesis was studied in 41 embryos from 32 gestational days (GD) to 8 gestational weeks (GW) and in 23 fetuses until full term (from 9 to 36 GW). Results: This process comprises five stages. Stage 1 appears as mesenchyme at 33–35 GD. Stage 2 is characterized by angiogenesis at 42–45 GD. Stage 3 covers up to 34 GW with the appearance of small fibers in the extracellular matrix. Stage 4 is visible around the coronary arteries, as multilocular adipocytes in primitive fat lobules, and Stage 5 is present with unilocular adipocytes in the definitive fat lobules. EAT precursor tissue appears as early as the end of the first gestational month in the atrioventricular grooves. Unilocular adipocytes appear at the eighth gestational month. Conclusions: Due to its early origin, plasticity and clinical implications, factors such as maternal health and nutrition might influence EAT early development in consequence.

Aims To study the effect of adjunctive systemic administration of melatonin to standard mechanical periodontal therapy in obese rats with experimental periodontitis. Materials and methods In 42 Wistar rats with an initial body weight of 180 g., half (n=21) were fed with a high‐fat diet to induce obesity. In both obese and normal‐weight groups, experimental periodontitis was subsequently induced through oral gavages with a combination of Porphyromona gingivalis and Fusobacterium nucleatum. Both groups were randomly allocated to either, no treatment or periodontal treatment consisting on standard mechanical debridement, with either adjunctive chlorhexidine or melatonin. Outcomes were evaluated by the changes in clinical parameters (probing depth modified gingival index, plaque dental index and bleeding on probing), in bone resorption and in the levels of biomarkers in plasma and in gingival tissue (inflammatory cytokines, insulin, leptin, osteocalcin, osteopontin, plasminogen activator inhibitor‐1, intercellular adhesion molecule 1, E‐selectin and lipids). Results In the obese‐periodontitis group, adjunctive melatonin administration resulted in reduced gingival inflammation and bleeding on probing, with significant reductions in probing depth and enhanced bone repair demonstrated by Micro‐CT (15% reduction in alveolar bone destruction) when compared with the same group treated with adjunctive CHX or the normal‐weight rats with either melatonin or CHX. In this melatonin‐treated obese‐periodontitis group, a significant impact on biochemical biomarkers was also demonstrated in both gingival and plasma samples, when compared with the other groups, with significant reductions in pro‐inflammatory cytokines. Conclusions Adjunctive melatonin therapy significantly reduced alveolar bone loss and exerted a protective anti‐inflammatory effect mainly in those experimental animals affected by the co‐morbidity of periodontitis and obesity.

Background and Objective: Melatonin deficiency has been associated with obesity and systemic inflammation. This study aims to evaluate whether melatonin could interfere with the mechanisms of co‐morbidity linking obesity and periodontitis. Material and Methods: Twenty‐eight male Wistar rats were randomly divided in 4 groups: control group (Con) (fed with standard diet); high‐fat diet group (HFD) (fed with a diet containing 35.2% fat); Con group with induced periodontitis (Con‐Perio) and HFD group with induced periodontitis (HFD‐Perio). To induce periodontitis, the method of oral gavages with Porphyromonas gingivalis ATCC W83K1 and Fusobacterium nucleatum DMSZ 20482 was used. Circulating melatonin levels were analyzed by multiplex immunoassays. Periodontitis was assessed by alveolar bone loss (micro‐computed tomography and histology) and by surrogate inflammatory outcomes (periodontal pocket depth, modified gingival index and plaque dental index). Results: Plasma melatonin levels were significantly decreased (P < .05) in the obese rats with periodontitis when compared with controls or with either obese or periodontitis rats. Alveolar bone loss increased 27.71% (2.28 µm) in HFD‐Perio group compared with the Con group. The histological analysis showed marked periodontal tissue destruction with osteoclast activity, particularly in the HFD‐Perio group. A significant negative correlation (P < .05) was found between periodontal pocket depth, modified gingival index and circulating melatonin levels. Conclusion: Obese and periodontitis demonstrated significantly lower melatonin concentrations when compared with controls, but in obese rats with periodontitis these concentrations were even significantly lower when compared with either periodontitis or obese rats. These results may indicate that melatonin deficiency could be a key mechanism explaining the co‐morbidity effect in the association between obesity and periodontitis. © 2018 Wiley

The present work analyses the possible influence of the colon in weight gain of obese animals. Subtotal colectomy was performed in rats fed with standard chow or high-fat diets. The results, suggested that subtotal colectomy did not exert any effect on the % of weight gain in rats administered a high-fat diet during the whole experiment as compared to controls. Animals submitted to a high-fat diet during the pre-surgery period and to a standard diet during the post-surgery period gained a lesser % of weight gain as compared to control or high-fat fed rats, together with a decrease in this parameter in colectomized animals. These changes did not agree with average food intake in rats fed with standard or high-fat diets. Surprisingly, the increase in body weight of sham-operated or subtotal colectomized rats fed with high- fat diet cannot be explained by a diminished food intake when compared to controls. Moreover, the change in food intake after surgery showed a correlation with body weight in sham-operated animals, although this correlation disappeared in colectomized rats. Mortality only appeared in colectomized rats administered a high-fat diet. However, stool was normalized and presented normal characteristics when animals returned to be fed with their respective diet after surgery. The results of this study support the concept that the maintenance of a high fat diet may originate a decrease of the intake, overall in subtotal colectomized rats, possibly through neuroendocrine mechanisms related to gut hormones or to adaptive mechanism along the gastrointestinal tract.

Virtually all neuroendocrine and immunological variables investigated in animals and humans display biological periodicity. Circadian rhythmicity is revealed for every hormone in circulation as well as for circulating immune cells, lymphocyte metabolism and transformability, cytokines, receptors, and adhesion molecules. Clock genes, notably the three Period (Per1/Per2/Per3) genes and two Cryptochrome (Cry1/Cry2) genes, are present in immune and endocrine cells and are expressed in a circadian manner in human cells. This review discusses the circadian disruption of hormone release and immune-related mechanisms in several animal models in which circulating cytokines are modified including rat adjuvant arthritis, social isolation in rats and rabbits and alcoholism, the aging process and calorie restriction in rats. In every case the experimental manipulation used perturbed the temporal organization by affecting the shape and amplitude of a rhythm or by modifying the intrinsic oscillatory mechanism itself.

This study analyzes the effect of chronic ethanol feeding on 24-h variation of hypothalamic-pituitary mechanisms involved in prolactin regulation in growing male Wistar rats. Animals were maintained under a 12:12 h light/dark photoperiod (lights off at 2000 h), and they received a liquid diet for 4 wk, starting on d 35 of life. The ethanol-fed group received a similar diet to controls except that maltose was isocalorically replaced by ethanol. Ethanol replacement provided 36% of the total caloric content of the diet. Rats were killed at six time intervals every 4 h, beginning at 0900 h. Mean concentration of serum prolactin in ethanol-fed rats was 58.7% higher than in controls. Peak circulating prolactin levels occurred at the early phase of the activity span in both groups of rats, whereas a second peak was found late in the resting phase in ethanol-fed rats only. In control rats, median eminence dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), and taurine levels exhibited two maxima, the major one preceding prolactin release and a second one during the first part of the resting phase. Median eminence DA and 5-HT turnover (as measured by 3,4-dihydroxyphenylacetic acid, DOPAC/DA, and 5-hydroxyindoleacetic acid, 5-HIAA/5-HT ratio) showed a single maximum preceding prolactin, at 0100 h. Ethanol treatment did not affect median eminence DA or 5-HT levels but it decreased significantly their turnover rate. The midday peak in DA and 5-HT levels (at 1300 h) was abolished and the night peak (at 0100 h) became spread and blunted in the ethanol-fed rats. This was accompanied with the disappearance of the 0100 h peak in DA and 5-HT turnover and the occurrence of a peak in 5-HT turnover at 1700 h. Ethanol intake suppressed the night peak in median eminence GABA and taurine (at 0100 h) as well as the midday peak of GABA. Ethanol augmented pituitary levels of DOPAC and 5-HIAA. The results indicate that chronic ethanol administration affects the mechanisms that modulate the circadian variation of prolactin release in growing male rats.

The objective of this study was to evaluate the efficacy of melatonin to affect mild inflammation in the metabolic syndrome (MS) induced by a high-fat diet in rats. Adult Wistar male rats were divided into four groups (n = 16/group): (i) control diet (3% fat); (ii) high-fat (35%) diet; (iii) high-fat diet + melatonin; and (iv) melatonin. Rats had free access to high-fat or control chow and one of the following drinking solutions for 10 wk: (a) tap water; (b) 25 μg/mL of melatonin. Plasma interleukin (IL)-1β, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and C-reactive protein (CRP) were measured at two time intervals, that is, the middle of daylight period and the middle of the scotophase. In addition, a number of somatic and metabolic components employed clinically to monitor the MS were measured. Melatonin decreased the augmented circulating levels of IL-1β, IL-6, TNF-α, IFN-γ, and CRP seen in obese rats and restored the depressed levels of IL-4 and IL-10. Rats fed with the high-fat diet showed significantly higher body weights and augmented systolic blood pressure from the third and fourth week onwards, respectively, melatonin effectively preventing these changes. In high-fat-fed rats, circulating low-density lipoprotein-cholesterol, total cholesterol, and triglyceride concentration augmented significantly, melatonin being effective to counteract these changes. Melatonin-treated rats showed a decreased insulin resistance, the highest values of plasma high-density lipoprotein-cholesterol, and the lowest values of plasma uric acid. The results indicate that melatonin is able to normalize the altered biochemical pro-inflammatory profile seen in rats fed with a high-fat diet. Fil: Cano Barquilla, Pilar. Universidad Complutense de Madrid; España Fil: Pagano, Eleonora Samanta. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Jiménez Ortega, Vanesa. Universidad Complutense de Madrid; España Fil: Fernández Mateos, Pilar. Universidad Complutense de Madrid; España Fil: Esquifino, Ana I.. Universidad Complutense de Madrid; España Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina

Fil: Jiménez Ortega, Vanesa. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Cano Barquilla, Pilar. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Fernández Mateos, Pilar. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Fernández Mateos, Pilar. Universidad Complutense. Facultad de Medicina. Departamento de Biología Celular; España Fil: Cardinali, Daniel P. Pontificia Universidad Católica Argentina. Facultad de Medicina. Departamento de Docencia e Investigación; Argentina Fil: Cardinali, Daniel P. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Esquifino, Ana I. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Abstract: To examine the effect a low dose of Cd as an endocrine disruptor, male Wistar rats received CdCl2 (5 ppm Cd) in drinking water or drinking water alone. After 1 month, rats were euthanized at one of six time intervals around the clock and the 24-h pattern of adenohypophysial PRL synthesis and release, lipid peroxidation and redox enzyme and metallothionein (MT) gene expression was examined. Cd suppressed 24-h rhythmicity in expression of PRL gene and in circulating PRL by increasing them at early photophase only, in correlation with an augmented pituitary lipid peroxidation and redox enzyme expression. CdCl2 treatment effectively disrupted the 24-h variation in expression of every pituitary parameter tested except for MT-3. In a second experiment the effect of melatonin (3 μg/mL drinking water) was assessed at early photophase, the time of maximal endocrine disrupting effect of Cd. Melatonin treatment blunted the effect of Cd on PRL synthesis and release, decreased Cd-induced lipid peroxidation and counteracted the effect of Cd on expression of most redox enzymes. A third experiment was performed to examine whether melatonin could counteract Cd-induced changes in the 24-h pattern of pituitary circadian clock gene expression and plasma PRL, LH, TSH and corticosterone levels. Rats receiving CdCl2 exhibited a suppressed daily rhythm of Clock expression and a significant disruption in daily rhythms of pituitary Bmal1, Per1, Per2, Cry1 and Cry2. The co-administration of melatonin restored rhythmicity in Clock and Bmal1 expression but shifted the maxima in pituitary Per1, Cry1 and Cry2 expression to the scotophase. Melatonin also counteracted the effect of Cd on 24-h rhythmicity of circulating PRL, LH, TSH and corticosterone. The results underline the occurrence of a significant endocrine disruptor effect of a low dose of Cd. Generally melatonin counteracted the effects of Cd and ameliorated partly the circadian disruption caused by the pollutant.

Fil: Jiménez Ortega, Vanesa. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Cano Barquilla, Pilar. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Pagano, Eleonora S. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina Fil: Fernández Mateos, Ana. Universidad Complutense. Facultad de Medicina. Departamento de Biología Celuar; España Fil: Esquifino, Ana I. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular III; España Fil: Cardinali, Daniel P. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina Fil: Cardinali, Daniel P. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Abstract: In the laboratory rat a number of physiological parameters display seasonal changes even under constant conditions of temperature, lighting and food availability. Since there is evidence that prolactin (PRL) is, among the endocrine signals, a major mediator of seasonal adaptations, we aimed to examine whether melatonin administration in drinking water resembling in length the exposure to a winter photoperiod could affect accordingly the 24-h pattern of PRL synthesis and release and some of their pituitary redox state- and circadian clock modulatory mechanisms. Melatonin (3 μg/mL drinking water) or vehicle was given for a month and rats were eutanized at 6 time intervals during a 24-h cycle. High concentrations of melatonin (more than 2000 pg/mL) were detected in melatonin-treated rats from the beginning of scotophase (at 21:00 h) to early photophase (at 09:00 h) as compared to a considerably narrower high melatonin phase observed in controls. In a cosinor analysis, melatonin-treated rats had significantly decreased mesor values of pituitary PRL gene expression and circulating PRL levels with acrophases at middle of scotophase as in the control group. Melatonin treatment disrupted the 24-h pattern in anterior pituitary gene expression of nitric oxide synthase (NOS)-1 and -2, heme oxygenase-1 and -2, glutathione peroxidase, glutathione reductase, Cu/Zn- and Mnsuperoxide dismutases and catalase by shifting their acrophases to early/middle scotophase or by amplifying the maxima found. Only the inhibitory effect of melatonin on pituitary NOS-2 gene expression correlated temporally with the inhibition of PRL production. Gene expression of metallothionein-1 and -3 showed maxima at early/middle photophase after melatonin treatment. 24-Hour pattern of pituitary lipid peroxidation did not vary after treatment. In vehicle-treated rats, Clock and Bmal1 expression peaked at mid scotophase while that of Per1 and Per2, and of Cry1 and Cry2, peaked at mid and late photophase, respectively. Treatment with melatonin decreased mean expression of Per1 and raised that of Per2, Cry1 and Cry2. Melatonin significantly phase-delayed expression of Per1, Per2 and Cry1. Melatonin also phasedelayed plasma corticosterone rhythm and increased the amplitude of plasma corticosterone and TSH rhythms. The results indicate that under a prolonged duration of a daily melatonin signal, rat pituitary PRL synthesis and release are depressed together with significant changes in the redox and circadian mechanisms controlling them

Fil: Fernández Mateos, María P. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular; España Fil: Fernández Mateos, María P. Universidad Complutense. Facultad de Medicina. Departamento de Biología Celular; España Fil: Jiménez Ortega, Vanesa. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular; España Fil: Cano Barquilla, Pilar. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular; España Fil: Cardinali, Daniel P. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina Fil: Cardinali, Daniel P. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Esquifino, Ana I. Universidad Complutense. Facultad de Medicina. Departamento de Bioquímica y Biología Molecular; España Abstract: Aims. Discontinuous (weekend) consumption of alcohol is common in adolescents and young adults. This study therefore assesses, in peripubertal male rats, the effect of discontinuous as compared to chronic feeding of ethanol or control liquid diet. Methods. Animals received an ethanol liquid diet (6.2 % wt/vol) starting on day 35 of life. Every week for 5 weeks, the discontinuous ethanol group received the ethanol diet for 3 consecutive days and the control liquid diet for 4 days. At the 5th week, 24 h after the last ethanol administration to the discontinuous ethanol treated animals, rats were killed at 4 h intervals beginning at 0900 h. Chronically administered rats received the ethanol diet until immediately before study. Results. Disrupted 24-h rhythmicity together with a significant nocturnal increase in plasma luteinizing hormone (LH), testosterone and prolactin (PRL) occurred in the discontinuous ethanol group. Plasma ethanol levels were undetectable at 24 h after the last ethanol treatment. In contrast, after chronic ethanol administration, plasma PRL was increased late in scotophase while LH and testosterone decreased; blood ethanol levels were 2-fold greater than those in discontinuously ethanoladministered rats killed immediately after ethanol withdrawal. Circulating testosterone positively correlated with LH levels in control rats only. Chronic administration of ethanol significantly augmented mean expression of pituitary nitric oxide synthase (NOS)-2, heme oxygenase (HO)-1, Per1 and Per2 genes and disrupted their diurnal rhythmicity. Decreased NOS-1 and NOS-2 expression during scotophase, together with suppression of the rhythm in Per1 and Per2 expression, were found in the discontinuous ethanol group. Conclusions. Abstinence after discontinuous drinking of alcohol in rats, as compared to chronic administration of ethanol, is accompanied by increases of plasma LH and testosterone, a greater PRL response and a less pronounced oxidative damage of the anterior pituitary.

The presence of dopamine (DA) within the cochlea has been previously reported, indicating that its turnover increases under noise stimulation. In the present report, piribedil, a dopaminergic D2 agonist, was used in order to provide evidence of the activity of D2 receptors in the turnover of DA under noise stimulation. Long-Evans rats were intraperitoneally injected with distilled water or with a solution of piribedil one hour previously to either noise or silence exposure. Noise stimulation was performed in an anechoic chamber at 70, 90 or 110 dB SPL for one hour. The animals were then sacrificed and the cochlear contents of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were quantified by HPLC with electrochemical detection. The administration of piribedil to animals kept in silence did not modify the cochlear DA, DOPAC and HVA content. Noise stimulation resulted in a decrease of the cochlear DA content and an increase of the cochlear DOPAC and HVA contents in vehicle treated animals. The administration of piribedil resulted in a blockade of this noise induced cochlear DA turnover. These results suggest that piribedil stimulates cochlear D2 receptors controlling the cochlear DA release. Piribedil action on D2 receptors could explain the improvement observed in some cochleo-vestibular diseases signs after piribedil treatment.

Dopamine (DA) appears to be one of the putative neurotransmitters of the lateral efferent olivocochlear fibers. However, its role in the cochlear physiology remains unknown. In this study, animals were exposed for 1 h to white noise at 70, 90 or 110 dB SPL or were kept in silence conditions. Afterwards, the cochlear content of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were analyzed using HPLC coupled to electrochemical detection. Cochlear DA concentration decreased with the noise intensity, while cochlear DOPAC and HVA concentrations increased. Males presented higher cochlear DOPAC contents and lower HVA contents than females. This sexual dimorphism could be related to the link between DA and gonadal steroids. Present results show that DA, as other lateral efferent neurotransmitters, is released and metabolized in relationship with the noise stimulation, and suggest that DA could be involved in the modulation of the type I afferent fiber activity.