Oxidative stress and immunosenescence in spleen of obese mice can be reversed by 2-hydroxyoleic acid.

We aimed to investigate the effects of obesity on oxidative stress and leukocyte function in spleen of mice, and to assess whether supplementation with 2-hydroxyoleic acid (2-OHOA) or n-3 polyunsaturated fatty acids (PUFA) could reverse those effects. Female ICR/CD1 mice (8 weeks old, n = 24) received an obesogenic diet (22% fat for 4 weeks and 60% fat for 14 weeks). After 6 weeks, mice were split in three groups (n = 8/group): no supplementation, 2-OHOA supplementation (1500 mg kg(-1) ) and n-3 PUFA supplementation (EPA + DHA, 3000 mg kg(-1) diet). Eight mice were fed standard diet for the whole duration of the study (control group). At the end of the experiment, the following variables were assessed in spleens: levels of reduced (GSH) and oxidized (GSSG) glutathione, GSH/GSSG, xanthine oxidase (XO) activity, lipid peroxidation, lymphocyte chemotaxis, natural killer (NK) activity and mitogen (ConA and LPS)-induced lymphocyte proliferation. Obese animals presented higher GSSG levels (P = 0.003), GSSG/GSH ratio (P = 0.013), lipid peroxidation (P = 0.004), XO activity (P = 0.015) and lymphocyte chemotaxis (P < 0.001), and lower NK activity (P = 0.003) and proliferation in response to ConA (P < 0.001) than controls. 2-OHOA reversed totally or partially most of the changes (body weight, fat content, GSSG levels, GSH/GSSG, lipid peroxidation, chemotaxis and proliferation, all P < 0.05), while n-3 PUFA reversed the increase in XO activity (P = 0.032). In conclusion, 2-OHOA, and to a lesser extent n-3 PUFA, could ameliorate the oxidative stress and alteration of leukocyte function in spleen of obese mice. Our findings support a link between obesity and immunosenescence and suggest a potential therapeutic tool for obesity-related immune dysfunction. This article is protected by copyright. All rights reserved

Cambios con el envejecimiento en la función y estado redox de leucocitos peritoneales de ratones sometidos a un shock endotóxico: efectos de intervenciones horméticas y nutricionales

El shock endotóxico constituye, debido a su elevada tasa de mortalidad, uno de los retos más importantes para la medicina actual, especialmente la ejercida en las unidades de cuidados intensivos. Aunque muchas infecciones pueden cursar con shock séptico son los bacilos Gram-negativos los principales responsables de esta situación clínica al ser capaces de liberar ciertos lipopolisacáridos (LPS) de su membrana celular, los cuales adquieren características de endotoxinas. Su instauración y progresión involucra varios procesos integrados y antagónicos, que implican una respuesta inflamatoria exacerbada que viene acompañada por una respuesta de supresión inmunitaria que busca contrarrestar la respuesta inicial, y que son definidas como fase hiperdinámica e hipodinámica, respectivamente. Se asume que es esa respuesta inmunitaria a la infección, en la que se liberan una gran cantidad de compuestos oxidantes e inflamatorios para defenderse de lo patógenos, la que, si no está bien regulada, causa el fallo multiorgánico que lleva a la muerte del individuo. Al avanzar la edad aumenta la susceptibilidad a padecer infecciones, y parece ser menor la cantidad de agente infeccioso que se requiere para desencadenar un shock séptico letal. Este hecho podría relacionarse con los cambios que al envejecer experimenta el sistema inmunitario, la denominada inmunosenescencia, en la que tiene lugar un mayor y mal regulado estrés oxidativo e inflamatorio..

Impaired Immune Response in Old Mice Suffering from Obesity and Premature Immunosenescence in Adulthood

Obesity and aging share an impaired immune system and oxidative and inflammatory stress. Therefore, the hypothesis of obesity as a possible model of premature immunosenescence has been proposed. In this study, we investigated whether adult obese mice, as a consequence of being fed with a fat-rich diet during their adolescence, showed premature immunosenescence and if this was aggravated with aging. Peritoneal cell suspensions were obtained when ICR/CD1 obese female mice were adults (28 weeks) and old (72 weeks), and several functions and antioxidant defenses were evaluated. The results showed that the chemotaxis of both macrophages and lymphocytes, phagocytosis of macrophages, activity of natural killer cells, proliferative response of lymphocytes, interleukin-1β, tumor necrosis factor-alpha, interleukin-6, interleukin-2, and interleukin-10 released in leukocyte cultures, as well as antioxidant and oxidant capacity were significantly impaired in adult obese mice with respect to adult nonobese mice, with values similar to those in chronologically old mice. When these obese animals grew older, although having been fed with a standard diet, they showed a higher deterioration of their immune functions in comparison with the old control group. In conclusion, these results demonstrate that a high fat intake during adolescence can produce an obesity state in adult age associated with a premature immunosenescence, which is aggravated through aging

Immune dysfunction and increased oxidative stress state in diet-induced obese mice are reverted by nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids

[Purpose]:Obesity is associated with impaired immune defences and chronic low levels of inflammation and oxidation. In addition, this condition may lead to premature aging. The aim of the study was to evaluate the effects of a nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids on several functions and oxidative stress parameters in peritoneal immune cells of obese mice, as well as on the life span of these animals. [Methods]:Obesity was induced in adult female ICR/CD1 by the administration of a high-fat diet (HFD) for 14 weeks. During the last 6 weeks of HFD feeding, one group of obese mice received the same HFD, supplemented with 1500 mg of 2-hydroxyoleic acid (2-OHOA) and another with 3000 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Several functions and oxidative stress parameters of peritoneal leukocytes were evaluated. [Results]:The groups of obese mice treated with 2-OHOA or with EPA and DHA showed a significant improvement in several functions such as chemotaxis, phagocytosis, digestion capacity, Natural killer activity and lymphoproliferation in response to mitogens. All of these functions, which were decreased in obese mice, increased reaching similar levels to those found in non-obese controls. Both treatments also improved oxidative stress parameters such as xanthine oxidase activity, which decreased, catalase activity and glutathione levels, which increased. [Conclusion]:These data suggest that dietary supplementation with monounsaturated and n-3 polyunsaturated fatty acids could be an effective nutritional intervention to restore the immune response and oxidative stress state, which are impaired in obese mice.This work was supported by grants from Ministry of Science and Innovation (BFU2011-30336), the Research Group of Madrid Complutense University (910379ENEROINN), Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF RD12/0043/0018) and FIS (PI15/01787) of Institute de Salud Carlos III—Fondo Europeo de Desarrollo Regional (ISCIII-FEDER), the PRONAOS study and BTSA-Applied Biotechnologies S.L. Caroline Hunsche is the recipient of a PhD fellowship from CNP-q-Brazil.Peer Reviewe

The postnatal leptin surge supports immune cell function in rats

Background: Leptin plays an important role in the regulation of the immune response. There is a physiological surge of leptin in rodents during the neonatal period, which has mainly been studied in the context of brain development. However, little is known about the effects of this neonatal leptin surge on immunity. Therefore, we investigated whether blocking this leptin surge could affect several immune functions. Methods: Male and female rats were injected subcutaneously with 5 mg/Kg/day of rat pegylated super leptin antagonist during the neonatal period (PND5-9). On the peripubertal period, relevant functions as well as cytokine release by spleen leukocytes were studied in these animals. Results: The results showed that the animals significantly display an impaired anti-tumor NK activity and chemotactic and proliferation capacity of lymphocytes in response to mitogens. In addition, several cytokine concentrations, released under mitogen-stimulated conditions, were also altered. Conclusion: In conclusion, the neonatal leptin surge seems to be involved in the establishment of an adequate immune response and cytokine profile, which are crucial for the maintenance of a healthy lif

Immune dysfunction and increased oxidative stress state in diet-induced obese mice are reverted by nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids

Purpose: Obesity is associated with impaired immune defences and chronic low levels of inflammation and oxidation. In addition, this condition may lead to premature aging. The aim of the study was to evaluate the effects of a nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids on several functions and oxidative stress parameters in peritoneal immune cells of obese mice, as well as on the life span of these animals. Methods: Obesity was induced in adult female ICR/CD1 by the administration of a high-fat diet (HFD) for 14 weeks. During the last 6 weeks of HFD feeding, one group of obese mice received the same HFD, supplemented with 1500 mg of 2-hydroxyoleic acid (2-OHOA) and another with 3000 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Several functions and oxidative stress parameters of peritoneal leukocytes were evaluated. Results: The groups of obese mice treated with 2-OHOA or with EPA and DHA showed a significant improvement in several functions such as chemotaxis, phagocytosis, digestion capacity, Natural killer activity and lymphoproliferation in response to mitogens. All of these functions, which were decreased in obese mice, increased reaching similar levels to those found in non-obese controls. Both treatments also improved oxidative stress parameters such as xanthine oxidase activity, which decreased, catalase activity and glutathione levels, which increased. Conclusion: These data suggest that dietary supplementation with monounsaturated and n-3 polyunsaturated fatty acids could be an effective nutritional intervention to restore the immune response and oxidative stress state, which are impaired in obesemice

Administration of a leptin antagonist during the neonatal leptin surge induces alterations in the redox and inflammatory state in peripubertal /adolescent rats

The importance of the neonatal leptin surge in rodents in neurodevelopmental processes has aroused curiosity in its implication in other physiological systems. Given the role of leptin in neuro-immune interactions, we hypothesized that the neonatal leptin surge could have an effect on the oxidative and inflammatory stress situations of both systems. We blocked the neonatal leptin surge by a leptin antagonist and measured several parameters of oxidative and inflammatory stress in the spleen, hypothalamus and adipose tissue of peripubertal/adolescent rats. The treated rats showed lower activity of several antioxidant enzymes in the spleen and their leukocytes released lower levels of mitogen-stimulated IL-10 and IL-13 and higher levels of TNF-alpha. In conclusion, the neonatal leptin surge may have a key role in the establishment of adequate redox and inflammatory states in the immune system, which is important for the generation of adequate immune responses and to obtain and maintain good health

The supplementations with 2-hydroxyoleic acid and n-3 polyunsaturated fatty acids revert oxidative stress in various organs of diet-induced obese mice

Obesity and its related diseases have been associated with oxidative stress. Thus, the search for nutritional strategies to ameliorate oxidative stress in obese individuals seems important. We hypothesized that the supplementation with monounsaturated (2-hydroxyoleic acid (2-OHOA)) and with combined n-3 polyunsaturated (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) fatty acids would ameliorate oxidative stress in different organs, including brain, liver, lungs, and kidneys of adult diet-induced obese (DIO) mice. Adult female ICR-CD1 mice were fed a high-fat diet (HFD) for 14 weeks. During the last 6 weeks of HFD feeding, one group of DIO mice received the same HFD, supplemented with 1500 mg of 2-OHOA per kg of HFD and another group with 1500 mg of EPA and 1500 mg of DHA per kg of HFD. At the end of the experiment, several parameters of oxidative stress were assessed. The supplementation with 2- OHOA or with EPA and DHA in DIO mice was able to revert oxidative stress, enhancing the activities of catalase and glutathione reductase, as well as diminishing the activity of xanthine oxidase, the concentration of thiobarbituric acid reactive substances (TBARS) and the ratio between oxidized glutathione and reduced glutathione in several organs. These reached similar values to those of control mice, which were fed a standard diet. These data suggest that supplementation with 2-OHOA and with EPA and DHA could be an effective nutritional intervention to restore an appropriate redox state in DIO mice