Nutrient-sensing mechanisms in hypothalamic cell models: neuropeptide regulation and neuroinflammation in male- and female-derived cell lines.

The hypothalamus is responsible for the control of many of our physiological responses, including energy homeostasis. Of interest, there are a number of instances of sexual dimorphism documented with regard to metabolic processes. This review will discuss the necessity of utilizing both male and female models when studying the mechanisms underlying energy homeostasis, particularly those originating at the level of the hypothalamus. Because obesity often results in central neuroinflammation, we describe markers that could be used to study differences between male and female models, both the whole organism and also at the cellular level. Our laboratory has generated a wide array of immortalized hypothalamic cell models, originating from male and female rodents that we suggest could be beneficial for these types of studies. It is imperative that both sexes are considered before any recommendations for therapeutic interventions are considered.

Food Restriction Prolongs Murine Cardiac Grafts.

Overeating and obesity lead to cardiovascular disease, diabetes, and eventually premature death, whereas food or energy restriction reduces risk factors for cardiovascular disease and diabetes and expands the life span. The aim of this study was to investigate the effect of food restriction (FR) in a murine heart transplant model. CBA male recipients (H2(k)) that underwent transplantation of C57BL/6 (H2(b)) hearts were assigned to free access group or FR groups with food intake at 60% (40% FR), 50% (50% FR), or 40% (60% FR) of the average food intake for 1 week after transplantation, and each median survival time was measured. We also performed cell proliferation, cytokine production, and flow cytometry assessments. The 60% FR CBA recipients showed prolongation of allograft survival (median survival time, 24 days). Cell proliferation and interferon-γ were suppressed in the 60% FR CBA recipients. Flow cytometry studies showed a lower CD4(+)CD25(+)Foxp3(+) cell population in splenocytes from the 60% FR CBA recipients. In conclusion, the findings suggest that the prolongation of cardiac allograft resulted from not regulation of alloimmune responses, but partial impairment of alloimmune responses, linking energy restriction to low generation of splenic CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Leptina, péptido pleiotrópico: características y su relación con la enfermedad periodontal: revisión de la literatura / Leptin, pleiotropic peptide: general features and its relationship with periodontal disease: review of literature

La leptina es un péptido que inicialmente fue caracterizado como un factor regulador del apetito y se creía que era producido sólo por el tejido adiposo, sin embargo, actualmente se conoce que es sintetizado en diferentes tejidos y posee receptores a lo largo de toda la economía del organismo, mostrando así múltiples funciones, dentro de las que cabe destacar su participación en la regulación del metabolismo lipídico y de los carbohidratos, el crecimiento óseo y la respuesta inmunológica, siendo estos últimos, procesos involucrados en la génesis de la enfermedad periodontal. Por tal motivo, en la presente revisión, se esbozan las principales características tanto estructurales como funcionales de este péptido, y su participación en diferentes roles a nivel sistémico, haciendo énfasis en el moldeado óseo y la respuesta inmunológica, para luego adentrarse en diferentes hallazgos encontrados a nivel bucal, que pudiesen indicar su posible participación en la génesis y el desarrollo de la enfermedad periodontal

Leptin is a peptide that was initially characterized as an appetite regulatory factor and it was believed that it was only produced by adipose tissue, however, it ?s currently known that is synthesized in different tissues and posses receptors throughout the body economy, showing multiple functions, such as involvement in the regulation of lipid and carbohydrate metabolism, bone growth and immune response, being the latter processes, involved in the genesis of periodontal disease. Therefore, the present review outlines the main structural and functional characteristics of this peptide, and their participation in various capacities at the systemic level, with emphasis on bone shaping and the immune response, and then goes into different findings at the oral level that could indicate their possible role in the genesis and periodontal disease development

Fisiología de la leptina y su implicación en la regulación del apetito / Physiology of leptin and its involvement in appetite regulation

El estudio de la regulación del metabolismo energético supone un campo ampliamente estudiado desde tiempo atrás. Sin embrago no será hasta el descubrimiento de la leptina cuando se comience a investigar profundamente sobre la homeostasis energética. La leptina fue descubierta en el contexto de sus efectos sobre el control de la alimentación y del gasto energético, tratándose de una proteína de la familia de las citocinas, siendo su receptor, similar al de éstas. Dicha proteína participa en procesos tales como regulación del peso corporal, de la alimentación y del gasto energético, reproducción, función inmune, y probablemente en muchos otros procesos aún por determinar. El objetivo de este trabajo ha sido llevar a cabo una revisión profunda sobre la fisiología de la leptina, principales procesos orgánicos en los que interviene y su implicación en el desarrollo de cuadros como la obesidad (AU)

The study of the regulation of energy metabolism is a widely studied area for some time. Clutchless not until the discovery of leptin when they start to investigate deeply on energy homeostasis. Leptin was discovered in the context of their effects on the control of feeding and energy expenditure in the case of a protein family of cytokines, and its receptor, similar to these. This protein is involved in processes such as regulation of body weight, food and energy expenditure, reproduction, immune function, and probably many other processes to be determined. The aim of this study was to conduct a thorough review of the physiology of leptin, leading the organic processes involved and their involvement in the development of cadres such as obesity (AU)

Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats.

A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.

Food intake regulation by central complement system.

Complement C3a and C5a are released from C3 and C5, respectively, on activation of the complement system and play an important role in immune response. C3a, C5a and their receptors have been revealed to be present in the central nervous system (CNS) as well as the peripheral immune system. We found that centrally administered C3a suppresses food intake, while C5a stimulates food intake, and their food intake regulation may be associated with the prostaglandin system. We propose that complement C3a and C5a are regulators not only of the immune system but also of the CNS.

Emerging role of autoantibodies against appetite-regulating neuropeptides in eating disorders.

OBJECTIVE: Recent findings of autoantibodies directed against melanocortin peptides suggest that these autoantibodies may represent a source of variability in peptidergic signaling that can be responsible for altered appetite and emotion in eating disorders. However, it is still unknown if autoantibodies directed against some other appetite-regulating neuropeptides and peptide hormones exist in healthy human subjects and if these autoantibodies can regulate appetite and emotion. METHODS: We determined the presence of autoantibodies against some key appetite-regulating neuropeptides and peptide hormones in sera of human subjects and in rats, and used animal models to study the role of alpha-melanocyte-stimulating hormone autoantibodies in food intake and anxiety. RESULTS: Immunoglobulin G and A autoantibodies against alpha-melanocyte-stimulating hormone, neuropeptide Y, agouti-related protein, ghrelin, leptin, and some other neuropeptides or peptide hormones involved in appetite control were present in healthy humans and rats. Animal models including active and passive transfer showed that alpha-melanocyte-stimulating hormone autoantibodies are involved in the regulation of feeding and anxiety. Sequence homology was found between neuropeptides and proteins from some members of intestinal microflora, whereas germ-free rats showed altered levels of autoantibodies directed against several neuropeptides. CONCLUSION: Autoantibodies directed against appetite-regulating neuropeptides and peptide hormones are emerging as important participants in the peptidergic mechanisms controlling motivated behavior. Furthermore, these autoantibodies could provide a link in the gut-brain axis and may represent new biological targets for the diagnosis and treatment of eating disorders.

The putative role of neuropeptide autoantibodies in anorexia nervosa.

PURPOSE OF REVIEW: Anorexia nervosa remains a disease of unknown etiology. This situation explains the failure to develop effective therapy and emphasizes the fact that the neurobiological mechanisms of appetite and emotion are still incompletely understood. The present review is the first summary of recent research assigning to the immune system a new role in energy and emotional regulation by the production of autoantibodies directed against neuropeptides. The results of this research are promising to shed light on the etiology of eating disorders and open new fields for biological diagnosis and follow-up as well as designing new therapeutic strategies. RECENT FINDINGS: Following the initial identification of autoantibodies against alpha-melanocyte-stimulating hormone, a key neuropeptide involved in the regulation of satiety and mood, in the plasma of patients with anorexia and bulimia nervosa, it has been further found that the serum levels of these autoantibodies correlated with psychopathological traits in individuals with eating disorders. Furthermore, recent findings show that autoantibodies against alpha-melanocyte-stimulating hormone and against some other appetite-regulating peptide hormones are normally present in the blood of humans and rats and their production may be influenced by stress and the gut microflora. SUMMARY: Novel data provide evidence that autoantibodies against neuropeptides can be involved in the regulation of appetite and emotion and that alteration in autoantibody-mediated signaling pathways may be responsible for the development of eating disorders.

Regulation of food intake by inflammatory cytokines in the brain.

A number of inflammatory cytokines are synthesized and released after activation of the immune system. In addition to other biological effects, these cytokines can potently inhibit food intake. Cytokine-mediated inhibition of food intake is of particular importance because excessive production of peripheral inflammatory cytokines is often associated with the cachexia-anorexia syndrome seen in some chronic diseases. The weight loss in cachexia is associated with an increase in morbidity and mortality. Understanding how cytokines regulate food intake may be crucial in enhancing quality of life and facilitating recovery in patients exhibiting cachexia. This review describes the main inflammatory cytokines that influence food intake and explores how peripheral cytokines communicate with hypothalamic nuclei to influence feeding.

Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs.

Ghrelin has been implicated in the control of food intake and in the long-term regulation of body weight. We theorize that preventing the ability of ghrelin to interact with its receptors, would eventually lead to decreased appetite and thereby decrease body weight gain. To test our hypothesis, pigs were actively immunized against ghrelin. Ghrelin((1-10)) was conjugated to BSA and emulsified in Freund's incomplete adjuvant and diethylaminoethyl-dextran. Primary immunization was given at 19 weeks of age (WOA), with booster immunizations given 20 and 40 days after primary immunization. Body weight (BW) and plasma samples were collected weekly beginning at 19 WOA, and feed intake was measured daily. Fourteen days after primary immunization, the percentage of bound (125)I-ghrelin in plasma from immunized pigs was increased compared with control animals (P<0.001). Voluntary feed intake was decreased more than 15% in animals that were actively immunized against ghrelin compared with controls. By the end of the experiment, immunized pigs weighed 10% less than control animals (P<0.1). Concentrations of GH were increased (P<0.05) in immunized pigs. Apoptosis was not observed in post-mortem samples obtained from the fundic region of the stomach. Our observations suggest that immunization against ghrelin induces mild anorexia. This procedure could potentially be used as a treatment to control caloric intake and obesity.

A putative role for cytokines in the impaired appetite in depression.

Impaired appetite and weight changes are commonly seen in patients with depression, but the pathophysiology behind this imbalance between energy intake and energy expenditure remains largely unknown. The aim of this paper is to review the literature regarding a possible role for cytokines in the regulation of appetite and body weight, with special emphasis on depression. There now exists a substantial amount of evidence that depressed patients show signs of immune activation including increased levels of proinflammatory cytokines. Cytokines, which by themselves have anorectic properties, stimulate the release of the cytokine-like anorexogenic peptide leptin. In addition to their anorectic properties, both proinflammatory cytokines and leptin interact with the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS) and the immune system. In turn, these systems regulate energy balance as well as they are dysfunctional in depression. Furthermore, both proinflammatory cytokines and leptin can induce anhedonia, one of the cardinal symptoms of depression. In view of the different effects on appetite and/or body weight observed in melancholic versus atypical depression, we suggest that cytokines are differentially altered in these subtypes of depression, and that this may explain some of the inconsistency in the reported findings of cytokine as well as leptin levels in depressed patients. Finally, we propose that the immune system uses the interoceptive pathway projecting to the insular cortex, a brain region where cytokine-induced changes in appetite could be partly mediated, and that this pathway is activated in depression.

Reduced ingestion of sweetened milk induced by interleukin-1 and lipopolysaccharide is associated with induction of cyclooxygenase-2 in brain endothelia.

UNLABELLED: Previous studies have shown that interleukin-1 (IL-1) and lipopolysaccharide (LPS) administration to animals induces behavioral changes, including a reduction in feeding. These effects of IL-1 and LPS have been shown to be sensitive to inhibitors of cyclooxygenase (COX). OBJECTIVES: To determine the relationships between induction of COX-2 in the brain with IL-1beta- and LPS-induced changes in body temperature, plasma corticosterone and feeding. METHODS: Mice were injected with intraperitoneal doses of IL-1beta and LPS that decreased feeding. The induction of COX-2 was studied immunocytochemically in the brain, in parallel with core body temperature, the drinking of sweetened milk, and plasma concentrations of corticosterone. RESULTS: COX-2 immunoreactivity (ir) was sparse in the brains of the untreated mice, but IL-1beta and LPS both increased its expression. This COX-2 induction appeared to be confined to blood vessels, and was not markedly region specific. Induction was evident 30 min after IL-1 or LPS, and was greater at 90 than at 30 min. COX-2-ir in the parenchyma did not change significantly. Thus induction of COX-2 occurred in brain endothelia in parallel with the reduction in feeding. This is consistent with the previously determined sensitivity of IL-1-induced changes in feeding to selective COX-2 inhibitors, and the responses to IL-1 in COX-2-deficient mice. The time courses of the IL-1- and LPS-induced increases in plasma corticosterone paralleled those in the reduction in milk drinking, however, the changes in body temperature appeared later. CONCLUSIONS: Endothelial COX-2 may be involved in IL-1- and LPS-induced decreases in milk drinking, and possibly in the HPA axis activation. The decreased milk drinking may occur when IL-1 and LPS bind to receptors on brain endothelial cells subsequently inducing COX-2 and the production of prostanoids which elicit the reductions in milk drinking. Thus the behavioral effects of peripherally administered IL-1 and LPS appear to be mediated by multiple mechanisms, including endothelial COX-2, and vagal afferents.

RANTES, MDC and SDF-1alpha, prevent the HIVgp120-induced food and water intake decrease in rats.

Human immunodeficiency virus (HIV)-wasting syndrome might be facilitated by the HIVgp120 affecting the immunological system. We studied the effect (subchronic administration: 5 days) of HIVgp120, and a few immune-response mediators: regulated upon activation normal T-cell expressed and presumably secreted (RANTES), stromal derived factor-1alpha (SDF-1alpha), macrophage-derived chemokine (MDC), and their combination, on food and water intake in rats, motor control and pain perception. Eighty male adult Wistar rats received an intracerebroventricular (icv) administration of: vehicle 5 microl/day or 0.92 nmol daily of HIVgp120IIIB, RANTES, SDF-1alpha, or MDC, and the combination of RANTES+HIVgp120IIIB, SDF-1alpha+HIVgp120IIIB, or MDC+HIVgp120IIIB. Food and water intake was measured every day during administration, and 24 and 48 h after the last administration. Rats were also weighed the first and the last day of experiment in order to detect the impact of these treatments in the body weight. HIVgp120IIIB significantly decreased food and water intake. These rats gain less weight than the control (vehicle) and chemokines-treated subjects with exception of those treated with SDF-1alpha that also gain less weight. In addition, HIVgp120 deteriorated motor control. HIVgp120IIIB effects on food and water intake, and motor control were prevented by these chemokines. HIVgp120+RANTES, HIVgp120+SDF-1alpha, and SDF-1alpha alone induced hyperalgesia. Results suggest an interaction between HIVgp120 and the chemokine system to generate the HIV-wasting syndrome, the motor abnormalities and changes in pain perception.

Chronic mild stress in mice decreases peripheral cytokine and increases central cytokine expression independently of IL-10 regulation of the cytokine network.

OBJECTIVES: Accumulating evidence indicates that stress leads to an increased expression of pro-inflammatory cytokines such as interleukin (IL)-6. The production and action of pro-inflammatory cytokines are down-regulated by anti-inflammatory cytokines such as IL-10. This makes IL-10-deficient mice a potentially useful model to assess the effects of stress on cytokine production. METHODS: In the present study, IL-10-deficient mice were compared to wild-type mice in their behavioural and cytokine response to a chronic mild stress procedure. RESULTS: The 3-week chronic mild stress decreased body weight gain and sucrose consumption. It also resulted in a decreased expression of peripheral IL-1beta and IL-6 and an increased expression of brain IL-6. This last change in IL-6 was correlated to body weight loss in stressed mice. However, IL-10-deficient mice did not differ from wild-type mice in their response to the chronic mild stress procedure, despite substantial differences in functioning of the cytokine network. CONCLUSION: These results are interpreted in the context of the relationship between cytokines and behaviour.