[Hypothalamic inflammation and energy balance deregulations: focus on chemokines.] / Inflammation hypothalamique et dérégulations de la balance énergétique : focus sur les chimiokines.

The hypothalamus is a key brain region in the regulation of energy balance. It especially controls food intake and both energy storage and expenditure through integration of humoral, neural and nutrient-related signals and cues. Hypothalamic neurons and glial cells act jointly to orchestrate, both spatially and temporally, regulated metabolic functions of the hypothalamus. Thus, the existence of a causal link between hypothalamic inflammation and deregulations of feeding behavior, such as involuntary weight-loss or obesity, has been suggested. Among the inflammatory mediators that could induce deregulations of hypothalamic control of the energy balance, chemokines represent interesting candidates. Indeed, chemokines, primarily known for their chemoattractant role of immune cells to the inflamed site, have also been suggested capable of neuromodulation. Thus, chemokines could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators that are involved in the maintenance of energy balance. Here, we relate, on one hand, recent results showing the primary role of the central chemokinergic signaling CCL2/CCR2 for metabolic and behavioral adaptation to high-grade inflammation, especially loss of appetite and weight, through its activity on hypothalamic neurons producing the orexigenic peptide Melanin-Concentrating Hormone (MCH) and, on the other hand, results that suggest that chemokines could also deregulate hypothalamic neuropeptidergic circuits to induce an opposite phenotype and eventually participate in the onset/development of obesity. In more details, we will emphasize a study recently showing, in a model of high-grade acute inflammation of LPS injection in mice, that central CCL2/CCR2 signaling is of primary importance for several aspects explaining weight loss associated with inflammation: after LPS injection, animals lose weight, reduce their food intake, increase their fat oxidation (thus energy consumption from fat storage)...These inflammation-induced metabolic and behavioral changes are reduced when central CCR2 signaling is disrupted either pharmacologically (by a specific inhibitor of CCR2) or genetically (in mice deficient for CCR2). This underlines the importance of this signaling in inflammation-related weight loss. We further determined that the LPS-induced and CCR2-mediated weight loss depends on the direct effect of CCR2 activation on MCH neurons activity. Indeed, the MCH neurons express CCR2, and the application of CCL2 on brain slices revealed that activation of CCR2 actually depolarizes MCH neurons and induces delays and/or failures of action potential emission. Furthermore, CCL2 is able to reduce KCl-evoked MCH secretion from hypothalamic explants. Taken together, these results demonstrate the role of the central CCL2/CCR2 signaling in metabolic and behavioral adaptation to inflammation. On the other hand, this first description of how the chemokinergic system can actually modulate the activity of the hypothalamic regulation of energy balance, but also some less advanced studies and some unpublished data, suggest that some other chemokines, such as CCL5, could participate in the development of the opposite phenotype, that is to say obesity.

The gut microbiome as a target for regulatory T cell-based immunotherapy: induction of regulatory lymphocytes by oral administration of anti-LPS enriched colostrum alleviates immune mediated colitis.

BACKGROUND: Gut-derived bacterial endotoxin is an important cofactor in the pathogenesis of IBD. Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance and can prevent and alleviate IBD. To determine the immune modulatory effect of anti-LPS enriched hyperimmune colostrum, its ability to induce Tregs and alleviate immune mediated colitis. METHODS: Immune-mediated colitis was induced in mice by intra-colonic instillation of Trinitrobenzene Sulfonate (TNBS). Four groups of mice were orally administered with two dosages of IgG-enriched colostrum fractions. The fractions were harvested from cows immunized against LPS derived from intestinal Escherichia coli bacteria (Imm124E). Control mice received non-immunized colostrum or vehicle (PBS). Treatment was administered one day following sensitization and four additional days following the administration of TNBS. The following parameters in the mice were tracked: body weight, bowel histology, serum cytokine levels and regulatory T cells. RESULTS: Oral administration of Imm124E hyperimmune colostrum ameliorated immune-mediated colitis. Significant amelioration of weight reduction was noted in treated mice. Oral administration of Imm124E improved bowel histology. Both the extent of the disease, inflammation score, and colitis damage and regeneration scores decreased in Imm-124E treated animals. These effects were associated with an increase in serum IL10 anti inflammatory cytokine levels, and an increase in CD4 + CD25+ and CD4 + Foxp3+ Tregs. CONCLUSIONS: Oral administration of Imm124E promoted Tregs and alleviated bowel inflammation in immune mediated colitis. The present data suggests that the microbiome may serve as a target for Tregs-based immunotherapy.

Effects of auricular acupuncture on anthropometric, lipid profile, inflammatory, and immunologic markers: a randomized controlled trial study.

OBJECTIVES: A randomized controlled clinical trial was performed to examine the effectiveness of auricular acupuncture on body weight loss and its impact on lipid profile, and immunologic and inflammatory markers in obese subjects. METHODS: Participants (n=204) were randomized to therapeutic acupuncture and control groups. Subjects received authentic (cases) or sham (controls) acupuncture for 6 weeks (first period) in combination with a low-calorie diet. In the next 6 weeks (second period), the low-calorie diet was used on its own. Subjects were assessed at the beginning and 6 and 12 weeks later. In addition to anthropometric and lipid parameters, serum anti-heat shock protein (Hsp)-27, 60, 65, 70 and high sensitive C-reactive protein (hs-CRP) levels were assessed. RESULTS: In the first period, anthropometric parameters and hs-CRP changed significantly in both groups, while significant changes in anti-Hsp antibodies were only observed in case subjects. In the second period, which shows the sustainable effects of acupuncture, changes in anthropometric parameters were more prominent in controls, while significant reductions in the group receiving authentic acupuncture were maintained for anti-Hsp antibodies. A comparison between the first and second period in both groups showed that the changes for most of the parameters were more significant in the first period. Comparison between cases and controls showed that authentic acupuncture was more effective in reducing the levels of anthropometric factors and anti-Hsp antibodies but not hs-CRP. CONCLUSIONS: Auricular acupuncture in combination with diet restriction was effective for weight loss and dyslipidemia. Moreover, it was found that it has immunomodulatory but not anti-inflammatory effects on the immune system by regulation of the levels of anti-Hsp antibodies.

Influences of weight loss on monocytes and T-cell subpopulations in male judo athletes.

The purpose of this study was to examine weight loss effects on immune function in judo athletes. Six elite male Japanese judo athletes (20.3 ± 0.4 years) were enrolled in this study. They completed usual weight loss programs during 2 weeks preceding an actual competition. Subjects noted the appearance of upper-respiratory tract infection (URTI) symptoms during the study period. Blood samples were obtained at 40 (baseline period: BL) and 3 (weight loss period: WL) days before and 1 day after the competition (AC). The CD3, CD4, CD8, CD56CD3, CD28CD4, CD28CD8, and Toll-like-receptor-4 (TLR-4) CD14 cells were counted by using flow cytometer analysis. The 6 subjects reported 1 headache, 3 runny nose conditions, and 1 coughing instance during the WL. The CD3, CD4, CD8, and CD28CD4 cell counts were significantly lower at WL than at BL (p ≤ 0.05); they reverted to the baseline value at AC. The TLR-4CD14 cells were significantly fewer at WL (p ≤ 0.05); they remained fewer than they had been at BL, even at AC. These results suggest that 2 weeks of weight loss before a competition can impair cell-mediated immune function and induce high susceptibility to URTI in judo athletes. Coaches, support staff, and athletes should monitor athletes' weight loss, hydration status, appearance of URTI symptoms, and immunocompetence such as lymphocytes and monocytes to prevent the physical condition from becoming worse.

Changes of mucosal immunity and antioxidation activity in elite male Taiwanese taekwondo athletes associated with intensive training and rapid weight loss.

OBJECTIVE: The aim of this study was to investigate the cumulative effects of prolonged, intensive training and rapid weight loss on immunological parameters and antioxidation activity of elite male Taiwanese taekwondo athletes. DESIGN: 16 Elite male taekwondo athletes (mean age, 21.6 (1.3) years; mean height, 173.7 (5.5) cm) volunteered to participate in this study. Beginning at 30 days before a national competition, saliva samples were obtained during a 7-week training, the competition and the postcompetition period. Levels of salivary IgA, cortisol, lactoferrin and free-radical scavenging activity were measured at 30-, 14-, 7- and 1-day precompetition and 1-, 7- and 19-day postcompetition. Body weight and body fat were also recorded. RESULTS: The mean body weight was notably decreased during the week immediately before the competition. Results reveal that the levels of salivary IgA were differentially regulated during the training, competition and recovery period, while the salivary cortisol and lactoferrin concentrations and free-radical scavenging activity were not appreciably affected during the training and the competition period. Furthermore, the results of an upper respiratory tract infection incidence indicate that following the decreases of mucosal immunity, the risk of acquiring infection was significantly increased. CONCLUSIONS: Our results demonstrated that mucosal immunity in elite male taekwondo athletes is modulated by exercise and rapid weight reduction during the training, competition and recovery period. Cumulative effects of prolonged intensive training and rapid weight reduction suppressed mucosal immunity. Furthermore, because of the "open window" of impaired immunity during the precompetition period, the incidence of upper respiratory tract infection was significantly increased after the competition.

Weight reduction, but not a moderate intake of fish oil, lowers concentrations of inflammatory markers and PAI-1 antigen in obese men during the fasting and postprandial state.

BACKGROUND: In obese subjects, chronic low-grade inflammation contributes to an increased risk of metabolic abnormalities, which are reversed by weight loss. Sustained weight loss, however, is difficult to achieve and more insight into dietary approaches on anti-inflammatory responses in obese subjects is needed. In this respect, fish oil deserves attention. MATERIAL AND METHODS: Eleven obese men (BMI: 30-35 kg m(-2)) received daily fish oil (1.35 g n-3 fatty acids) or placebo capsules in random order for 6 weeks. Eight subjects continued with a weight reduction study that lasted 8 weeks. Mean weight loss was 9.4 kg. At the end of each experimental period a postprandial study was performed. RESULTS: Relative to fasting concentrations, interleukin-6 (IL-6) levels increased by 75% 2 h and by 118% 4 h after the meal (P < 0.001), when subjects consumed the control capsules. In contrast, C-reactive protein (C-RP) concentrations decreased slightly by 0.7% and 6.6% (P = 0.046), and those of plasminogen activator inhibitor-1 (PAI-1) antigen by, respectively, 26% and 53% (P < 0.001). Tumour necrosis factor-alpha (TNF-alpha; P = 0.330) and soluble TNF-receptor concentrations (sTNF-R55 and sTNF-R75; P = 0.451 and P = 0.108, respectively) did not change. Changes relative to fasting concentrations were not significantly affected by either fish oil or weight reduction. Absolute IL-6, C-RP, sTNF-R55, sTNF-R75, and PAI-1 antigen concentrations, however, were consistently lower after weight reduction, but not after fish oil consumption. CONCLUSION: For slightly obese subjects a moderate intake of fish oil does not have the same favourable effects on markers for a low-grade inflammatory state as weight reduction.

Carbohydrate supplementation during intense exercise and the immune response of cyclists.

OBJECTIVE: To evaluate the effect of carbohydrate supplementation upon some aspects of the immune function in athletes during intense indoor cycling. METHODS: Twelve male athletes cycled for 20 min at a velocity corresponding to 90% of that obtained at the anaerobic threshold and rested for 20 min. This protocol was repeated six times. The athletes received, during the trial, water ad libitum, or a solution of carbohydrate (95% glucose polymers and 5% fructose) at 10% (w/v), 1 g kg h every 20 min, starting at the 10th minute of the first exercise period, plus extra water ad libitum. RESULTS: Exercise induced a reduction in peripheral blood mononuclear cell proliferation (37%) as well as in the production of cytokines by cultured cells (interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), by 37%, 35%, 26% and 16%, respectively). All of these changes were prevented by the ingestion of a carbohydrate drink by the athletes, except that in IFN-gamma production, which was equally decreased (17%) after the second trial. The concentration of plasma glutamine, an important fuel for immune cells, was decreased in the placebo group but maintained in the group that received carbohydrate. CONCLUSION: Carbohydrate supplementation affects positively the immune response of cyclists by avoiding or minimizing changes in plasma glutamine concentration.

Depressed humoral immunity after weight reduction in competitive judoists.

We studied changes in serum opsonic activity (SOA) in male judoists who were engaged in active weight reduction. Serum immunoglobulins, complements and SOA, measured by neutrophil-associated chemiluminescence responses, were investigated 20 days, 7 days and 1 day before a competition and 5 days after the competition. In addition, muscle strength and anaerobic work capacity, as well as body composition, were also determined. A dietary survey was conducted daily during the observation period. Body weight decreased by 4.2 kg over 19 days. SOA significantly decreased 5 days after the competition, as well as the concentrations of serum immunoglobulins, complements and total proteins. These trends were noted in the marked weight reduction group (i.e. reduction weight of body fat/body fat weight before weight reduction > or = 25%) more than the slight reduction group (<25%). Depressed SOA was closely correlated with the decreased concentrations of immunoglobulins and complements. These results suggest that the decrease in immunoglobulins and complements following weight reduction is associated with reduced SOA, which might cause susceptibility to infections. This study demonstrated that such immunosuppression appeared in the recovery period after the competition rather than immediately before the competition.

Metástasis hepáticas secundarias a leiomiosarcoma de recto. Presentación de un caso / Liver metastases secondary to rectal leiomyosarcoma. A case report

Se presenta un caso de metástasis hepáticas en una paciente afectada por un leiomiosarcoma de localización rectal. Se incide en la rareza de este tipo de tumores, así como en su agresividad y posibilidades terapéuticas (AU)

Assessment of nutritional, clinical, and immunologic status of HIV-infected, inner-city patients with multiple risk factors.

OBJECTIVE: To evaluate the nutritional, clinical, and immunologic factors associated with human immunodeficiency virus (HIV)-infected, inner-city patients with multiple risk factors. DESIGN: Prospective cross-sectional nutrition evaluation of patients with HIV infection. SETTING: Patients were interviewed at the outpatient clinic at Mt Sinai Medical Center, New York City, NY. SUBJECTS: Our subjects were men and women older than 18 years of age and at all stages of HIV infection (n = 56). OUTCOME MEASURES: Anthropometric measurements, history of weight changes (maintenance of preillness body weight or decrease from preillness weight status), 3-day food records, and clinical laboratory tests. STATISTICAL ANALYSES: Tests were used to compare patients who were at a stable weight with patients who had lost weight with regard to the anthropometric, dietary, and clinical variables. Spearman's rank correlation coefficient and chi 2 tests were applied to examine correlations between pairs and differences in proportions, respectively. RESULTS: Patients were classified into groups according to whether they were at a stable weight (n = 25) or had lost weight (n = 31). All anthropometric measurements, CD4 lymphocytes, and CD8 lymphocytes were significantly lower in the patients who had lost weight. No differences were observed between the groups for absolute lymphocyte count or transferrin, hemoglobin, and albumin levels. The mean energy intake of the 56 patients was 74% of the Recommended Dietary Allowance (RDA). Forty-seven patients (84%) took vitamin and/or mineral supplements within a range of 2% to 50,000% of the RDA. No significant positive correlations were observed between nutrient intake, CD4 cells, and absolute lymphocyte count. CONCLUSIONS/APPLICATIONS: All anthropometric measurements, CD4 lymphocytes, and CD8 lymphocytes were notably lower in patients with weight loss. The mean energy intake of the subjects was only 74% of the RDA. Megadoses of vitamin supplements were taken by a large number of patients, but no significant positive effects were observed for absolute lymphocyte count and CD4 cells. Although supplementation of micronutrients may influence the progression of HIV infection, a balanced, nutritious diet may be more beneficial in maintaining or improving the physiologic status of the patients. However, members of a high-risk population may benefit less from HIV-related social services and food or nutrition resources. With the growing number of injection-drug users in the acquired immunodeficiency syndrome population, it will be essential to develop comprehensive strategies to address the interconnected needs for medical and nutrition care. Ensuring that patients have adequate meals during an extended course of treatment in the outpatient clinic or that dietitians have meals available in group settings or through home-delivery service may be the most appropriate nutrition intervention in these high-risk patients.

Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat.

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1.8 percent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, P < 0.05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2) versus 14.8(1.4) percent, P < 0.05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23.9(2.7) versus 9.4(2.1) percent, P < 0.05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.