Kent L. Erickson

Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters

Background:Chemotactic cytokines, referred to as chemokines, play an important role in leukocyte trafficking. The circulating levels of chemokines have been shown to increase in inflammatory processes including obesity-related pathologies (e.g. atherosclerosis and diabetes). However, little is currently known about the relationship between chemokines and human obesity. In the present study, we investigated the circulating levels of selected chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), leukotactin-1, interleukin-8 (IL-8)) and the association between the chemokine levels and obesity-related parameters: body mass index (BMI), waist circumference, fasting glucose and insulin levels, lipids profile, and the level of C-reactive protein (CRP).Methods:A total of 100 subjects, 50 obese (BMI⩾25 kg/m2) and 50 who were not obese (BMI<25 kg/m2) participated in the present study. The levels of chemokines and CRP were measured in a fasting state serum by sandwich enzyme-linked immunosorbent assay. Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, glucose, and insulin levels were measured by enzymatic analysis and immunoassay.Results:The circulating levels of MCP-1 and IL-8 in the serum were significantly (P<0.05) higher in obese subjects (BMI>30 kg/m2) compared with those of nonobese controls (BMI<25 kg/m2). The levels of CRP were positively correlated with BMI (P<0.001) or waist circumference (P<0.0001). The levels of MCP-1 and IL-8 were positively related to BMI (MCP-1, P<0.02; IL-8, P<0.01) and/or waist circumference (MCP-1, P<0.009; IL-8, P<0.03). The levels of MCP-1 were positively related to the levels of CRP (P<0.007) or interleukin-6 (IL-6) (P<0.0001), and negatively related to the levels of HDL-cholesterol (P<0.01). Homeostasis model assessment (HOMA) score was positively related to the levels of MCP-1 (P<0.02) or IL-8 (P<0.03) in obese subject.Discussion:Our data demonstrated that the circulating levels of MCP-1 and IL-8 are related to obesity-related parameters such as BMI, waist circumference, CRP, IL-6, HOMA and HDL-cholesterol. These findings suggest that the circulating MCP-1 and/or IL-8 may be a potential candidate linking obesity with obesity-related metabolic complications such as atherosclerosis and diabetes.

Probiotic Immunomodulation in Health and Disease

Probiotics, microorganisms that have a favorable influence on physiologic and pathological processes of the host by their effect on the intestinal flora, may play a role in improving human health. One of the putative effects is the modulation of immune function. Thus, the mucosal immune system and methods to assess its function are reviewed briefly. Probiotic modulation of humoral, cellular and nonspecific immunity is reviewed, with emphasis placed on immune response in disease models. There are very few reports of human intervention studies with probiotics. However, some of the possible future directions for research with respect to probiotics, immunity, and human health are discussed. Although the application of probiotics has demonstrated trends with respect to altered aspects of immune response, the underlying mechanisms by which that occurs are unclear.

Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men

The purpose of this study was to examine the effects of feeding docosahexaenoic acid (DHA) as triacylglycerol on the fatty acid composition, eicosanoid production, and select activities of human peripheral blood mononuclear cells (PBMNC). A 120-d study with 11 healthy men was conducted at the Metabolic Research Unit of Western Human Nutrition Reach Center. Four subjects (control group) were fed the stabilization diet throughout the study; the remaining seven subjects were fed the basal diet for the first 30 d, followed by 6 g DHA/d for the next 90 d. DHA replaced an equivalent amount of linoleic acid; the two diets were comparable in their total fat and all other nutrients. Both diets were supplemented with 20 mg d α-tocopherol acetate per day. PBMNC fatty acid composition and eicosanoid production were examined on day 30 and 113; immune cell functions were tested on day 22, 30, 78, 85, 106, and 113. DHA feeding increased its concentration from 2.3 to 7.4 wt% in the PBMNC total lipids, and decreased arachidonic acid concentration from 19.8 to 10.7 wt%. It also lowered prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, in response to lipopolysaccharide, by 60–75%. Natural killer cell activity and in vitro secretion of interleukin-1β and tumor necrosis factor α were significantly reduced by DHA feeding. These parameters remained unchanged in the subjects fed the control diet. B-cell functions as reported here and T-cell functions that we reported previously were not altered by DHA feeding. Our results show that inhibitory effects of DHA on immune cell functions varied with the cell type, and that the inhibitory effects are not mediated through increased production of PGE2 and LTB4.

Conjugated linoleic acid supplementation in humans: effects on circulating leptin concentrations and appetite.

Conjugated linoleic acid (CLA) has been demonstrated to reduce body fat in animals. However, the mechanism by which this reduction occurs is unknown. Leptin may mediate the effect of CLA to decrease body fat. We assessed the effects of 64 d of CLA supplementation (3 g/d) on circulating leptin, insulin, glucose, and lactate concentrations in healthy women. Appetite was assessed as a physiological correlate of changes in circulating leptin levels. Analysis of plasma leptin concentrations adjusted for adiposity by using fat mass as a covariate showed that CLA supplementation significantly decreased circulating leptin concentrations in the absence of any changes of fat mass. Mean leptin levels decreased over the first 7 wk and then returned to baseline levels over the last 2 wk of the study in the CLA-treated group. Appetite parameters measured at around the time when the greatest decreases in leptin levels were observed showed no significant differences between supplementation and baseline determinations in the CLA-supplemented group or between the CLA and placebo-supplemented groups. There was a nonsignificant trend for mean insulin levels to increase toward the end of the supplementation period in CLA-treated subjects. CLA did not affect plasma glucose and lactate over the treatment period. Thus, 64 d of CLA supplementation in women produced a transient decrease in leptin levels but did not alter appetite. CLA did not affect these parameters in a manner that promoted decreases of adiposity.

Micronutrients and Innate Immunity

Micronutrients such as zinc, selenium, iron, copper, beta-carotene, vitamins A, C, and E, and folic acid can influence several components of innate immunity. Select micronutrients play an important role in alteration of oxidant-mediated tissue injury, and phagocytic cells produce reactive oxidants as part of the defense against infectious agents. Thus, adequate micronutrients are required to prevent damage of cells participating in innate immunity. Deficiencies in zinc and vitamins A and D may reduce natural killer cell function, whereas supplemental zinc or vitamin C may enhance their activity. The specific effects of micronutrients on neutrophil functions are not clear. Select micronutrients may play a role in innate immunity associated with some disease processes. Future studies should focus on issues such as age-related micronutrient status and innate immunity, alterations of micronutrients in disease states and their effect on innate immunity, and the mechanisms by which micronutrients alter innate immunity.

Dietary conjugated linoleic acid did not alter immune status in young healthy women

The purpose of this study was to examine whether conjugated linoleic acid (CLA) supplementation in human diets would enhance indices of immune status as reported by others for animal models. Seventeen women, 20–41 yr, participated in a 93-d study conducted in two cohorts of 9 and 8 women at the Metabolic Research Unit of Western Human Nutrition Research Center. Seven subjects were fed the basal diet (19, 30 and 51% energy from protein, fat, and carbohydrate, respectively) throughout the study. The remaining 10 subjects were fed the basal diet for the first 30 d, followed by 3.9 g CLA (Tonalin)/d for the next 63 d. CLA made up 65% of the fatty acids in the Tonalin capsules, with the following isomeric composition: t10, c12, 22.6%; c11, t13, 23.6%; c9, t11, 17.6%; t8, c10, 16.6%; and other isomers 19.6%. Most indices of immune response were tested at weekly intervals, three times at the end of each period (stabilization/intervention); delayed-type hypersensitivity (DTH) to a panel of six recall antigens was tested on study day 30 and 90; all subjects were immunized on study day 65 with an influenza vaccine, and antibody titers were examined in the sera collected on day 65 and 92. None of the indices of immune status tested (number of circulating white blood cells, granulocytes, monocytes, lymphocytes, and their subsets, lymphocytes proliferation in response to phytohemagglutinin, and influenza vaccine, serum influenza antibody titers, and DTH response) were altered during the study in either dietary group. Thus, in contrast to the reports with animal models, CLA feeding to young healthy women did not alter any of the indices of immune status tested. These data suggest that short-term CLA supplementation in healthy volunteers is safe, but it does not have any added benefit to their immune status.

Modulation of body composition and immune cell functions by conjugated linoleic acid in humans and animal models: Benefits vs. risks

We have reviewed the published literature regarding the effects of CLA on body composition and immune cell functions in humans and in animal models. Results from studies in mice, hamsters, rats, and pigs generally support the notion that CLA reduced depot fat in the normal or lean strains. However, in obese rats, it increased body fat or decreased it less than in the corresponding lean controls. These studies also indicate that t10,c12-CLA was the isomer that reduced adipose fat; however, it also increased the fat content of several other tissues and increased circulating insulin and the saturated FA content of adipose tissue and muscle. Four of the eight published human studies found small but significant reductions in body fat with CLA supplementation; however, the reductions were smaller than the prediction errors for the methods used. The other four human studies found no change in body fat with CLA supplementation. These studies also report that CLA supplementation increased the risk factors for diabetes and cardiovascular disease including increased blood glucose, insulin, insulin resistance, VLDL, C-reactive protein, lipid peroxidation, and decreased HDL. Most studies regarding the effects of CLA on immune cell functions have been conducted with a mixture of isomers, and the results have been variable. One study conducted in mice with the purified c9,t11-CLA and t10,c12-CLA isomers indicated that the two isomers have similar effects on immune cell functions. Some of the reasons for the discrepancies between the effects of CLA in published reports are discussed. Although significant benefit to humans from CLA supplementation is questionable, it may create several health risks in both humans and animals. On the basis of the published data, CLA supplementation of adult human diets to improve body composition or enhance immune functions cannot be recommended at this time.

Dietary lipid modulation of immune responsiveness

The influence of dietary fat concentration and saturation on blastogenesis, cytotoxicity, antibody response and fatty acid composition of murine splenic lymphocytes was studied. Blastogenesis of lymphocytes from dietarily manipulated mice in response to alloantigens from control mice was significantly greater for those mice fed a diet containing minimal essential fatty acids (EFA) as the only fat source (EFA control) than those fed an EFA-deficient diet. When the dietary fat concentration was increased, blastogenic responses decreased compared to the EFA control diet. Lymphocyte-mediated cytotoxicity against allogeneic melanoma cells was greater for mice receiving diets with EFA only than for those deficient in EFA. However, cytotoxicity responses of mice fed additional polyunsaturated fat (PUF) decreased as concentration increased, whereas responses of mice fed the saturated fat (SF) diets decreased only when the dietary fat concentration was greater than 8%. As compared to diets with EFA control, direct plaqueforming cell (PFC) response was decreased for mice fed high levels of PUF and increased for mice fed high levels of SF; however, no difference in the percentage of IgM-positive cells was observed. These changes in PFC response were inversely related to the levels of linoleic acid in the lymphocyte. Thus, high levels of dietary fat, and particularly PUF, suppress lymphocyte functions when EFA requirements are met, whereas low levels (EFA control) intensify these responses. EFA deficiency, however, suppresses some lymphocyte responses. Thus, dietary lipids differentially modulate the levels of T- and B-cell responsiveness.

Reduction of murine mammary tumor metastasis by conjugated linoleic acid

Recent studies have shown that conjugated linoleic acid (CLA) can inhibit the initiation and thus, incidence of mammary tumors in rodents. The concentration of CLA required for these effects was as low as 0.1% of the diet, with no increased effects above 1%. To date, there is little evidence that CLA has any effect on growth or metastasis of mammary tumors. In this report, we demonstrate that CLA, at the concentrations used in previous studies, had a significant effect on the latency, metastasis, and pulmonary tumor burden of transplantable murine mammary tumors grown in mice fed 20% fat diets. The latency of tumors from mice fed CLA was significantly increased when compared with the 0% CLA control diet. The volume of pulmonary tumor burden, as a result of spontaneous metastasis, decreased proportionately with increasing concentrations of dietary CLA. With 0.5 and 1% CLA, pulmonary tumor burden was significantly decreased compared to mice treated with the eicosanoid inhibitor, indomethacin and fed diets containing no CLA. Tumors of mice fed as little as 0.1% CLA and as much as 1% had significantly decreased numbers of pulmonary nodules when compared with diets containing no CLA. The decrease in the number of pulmonary nodules by CLA was nearly as effective as indomethacin, a known suppressor of tumor growth and metastasis in this malignant model. These data suggest that effects of CLA on mammary tumorigenesis may go beyond the reported alterations in tumor incidence and effect later stages, especially metastasis.

Trans-10,cis-12 CLA Increases Liver and Decreases Adipose Tissue Lipids in Mice: Possible Roles of Specific Lipid Metabolism Genes

Although consumption of CLA mixtures has been associated with several health effects, less is known about the actions of specific CLA isomers. There is evidence that the t10,c12-CLA isomer is associated with alterations in body and organ weights in animals fed CLA, but the mechanisms leading to these changes are unclear. The purpose of this study was to determine the effects of two commonly occurring isomers of CLA on body composition and the transcription of genes associated with lipid metabolism. Eight-week-old female mice (n=11 or 12/group) were fed either a control diet or diets supplemented with 0.5% c9,t11-CLA or t10,c12-CLA isomers or 0.2% of the peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate for 8 wk. Body and retroperitoneal adipose tissue weights were significantly lower (6–10 and 50%, respectively), and liver weights were significantly greater (100%) in the t10,c12-CLA and the fenofibrate groups compared with those in the control group; body and tissue weights in the c9,t11-CLA group did not differ from those in the control group. Livers from animals in the t10,c12-CLA group contained five times more lipids than in the control group, whereas the lipid content of the fenofibrate group did not differ from that in the control group. Although fenofibrate increased the mRNA for PPARα, t10,c12-CLA decreased it. These results suggest that PPARα did not mediate the effects of t10,c12-CLA on body composition. The CLA isomers and fenofibrate altered mRNA levels for several proteins involved in lipid metabolism, but the most striking difference was the reduction of mRNA for leptin and adiponectin in the t10,c12-CLA group. These initial results suggest that changes associated with energy homeostasis and insulin action may mediate the effects of t10,c12-CLA on lipid metabolism.