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The immune remodel: Weight loss-mediated inflammatory changes to obesity.
Phillips, CL, Grayson, BE
Experimental biology and medicine (Maywood, N.J.). 2020;(2):109-121
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Abstract
UNLABELLED Obesity is an escalating world problem that contributes to the complexity and cost of treatment of metabolic disorders. Obesity is the result of increased storage of energy in the form of adipose tissue, reducing the quality of daily life, and interfering with longevity. Obesity is also a chronic, low-grade inflammatory disorder. The inflammatory processes affect many organ systems with expanded numbers of immune cells and increased cytokine production. Long-term weight loss is difficult to achieve and maintain. Lifestyle modifications, pharmacologic treatments, and surgical methods are increasingly utilized to ameliorate excess body weight and the comorbidities of obesity, such as diabetes, cardiovascular disease, dyslipidemia, and cancers. Weight loss is also touted to reduce inflammation. Here we review the current literature on human obesity-related systemic and local changes to the immune system and circulating inflammatory mediators. Further, we consider the impact of weight loss to reduce the burden of inflammation, bearing in mind the different methods of weight loss—behavioral change vs. surgical intervention. IMPACT STATEMENT As the prevalence and severity of obesity expand, the negative impact of excess adiposity affects every system of the body. Given that obesity is a subversive attack on the immune system, weight loss should improve inflammation locally and systemically. Weight management strategies like dieting, exercise, and bariatric surgery, thus have the opportunity to reduce the burden of inflammation.
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Association between Subcutaneous Adipose Tissue Inflammation, Insulin Resistance, and Calorie Restriction in Obese Females.
Sbierski-Kind, J, Mai, K, Kath, J, Jurisch, A, Streitz, M, Kuchenbecker, L, Babel, N, Nienen, M, Jürchott, K, Spranger, L, et al
Journal of immunology (Baltimore, Md. : 1950). 2020;(1):45-55
Abstract
The worldwide epidemic of overweight and obesity has led to an increase in associated metabolic comorbidities. Obesity induces chronic low-grade inflammation in white adipose tissue (WAT). However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal overweight or obese female subjects who either underwent CR for 3 mo followed by a 4-wk phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and s.c. WAT (SAT). The TCR repertoire was analyzed by next-generation sequencing and cytokine levels were determined in SAT. Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp. We found that insulin resistance correlates significantly with a shift toward the memory T cell compartment in SAT. TCR analysis revealed a diverse repertoire in SAT of overweight or obese individuals. Additionally, whereas weight loss improved systemic insulin sensitivity in the intervention group, SAT displayed no significant improvement of inflammatory parameters (cytokine levels and leukocyte subpopulations) compared with the control group. Our data demonstrate the accumulation of effector memory T cells in obese SAT and an association between systemic glucose homeostasis and inflammatory parameters in obese females. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR-induced weight loss.
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Interplay between the Adaptive Immune System and Insulin Resistance in Weight Loss Induced by Bariatric Surgery.
Villarreal-Calderón, JR, Cuéllar, RX, Ramos-González, MR, Rubio-Infante, N, Castillo, EC, Elizondo-Montemayor, L, García-Rivas, G
Oxidative medicine and cellular longevity. 2019;:3940739
Abstract
Low-grade chronic inflammation plays a pivotal role among other pathophysiological mechanisms involved in obesity. Innate and adaptive immune cells undergo systemic proinflammatory polarization that gives rise to an increased secretion of proinflammatory cytokines, which in turn leads to insulin resistance. Bariatric surgery is currently the most effective treatment for obesity, as it brings on significant weight loss, glucose metabolism improvement, and a decrease in systemic inflammation biomarkers. After bariatric surgery, several changes have been reported to occur in adaptive immunity, including reduction in CD4+ and CD8+ T cell counts, a decrease in the Th1/Th2 ratio, an increase in B regulatory cells, and reduction in proinflammatory cytokine secretion. Overall, there seems to be a major shift in several lymphocyte populations from a proinflammatory to an anti-inflammatory phenotype. Furthermore, increased antioxidant activity and reduced lipid and DNA oxidation products have been reported after bariatric surgery in circulating mononuclear cells. This paper highlights the shift in the adaptive immune system in response to weight loss and improved insulin sensitivity, as well as the interplay between immunological and metabolic adaptations as a result of bariatric surgery. Finally, based on data from research, we propose several mechanisms such as changes in adaptive immune cell phenotypes and their by-products, recruitment in adipose tissue, reduced oxidative stress, and modification in metabolic substrate availability as drivers to reduce low-grade chronic inflammation after bariatric surgery in severe obesity.
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Weight Loss Maintenance and Cellular Aging in the Supporting Health Through Nutrition and Exercise Study.
Mason, AE, Hecht, FM, Daubenmier, JJ, Sbarra, DA, Lin, J, Moran, PJ, Schleicher, SG, Acree, M, Prather, AA, Epel, ES
Psychosomatic medicine. 2018;(7):609-619
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Abstract
OBJECTIVE The aim of the study was to determine, within a weight loss clinical trial for obesity, the impact of intervention arm, weight change, and weight loss maintenance on telomere length (TL). METHODS Adults (N = 194) with a body mass index between 30 and 45 were randomized to a 5.5-month weight loss program with (n = 100) or without (n = 94) mindfulness training and identical diet-exercise guidelines. We assessed TL at baseline and 3-, 6-, and 12-month postbaseline in immune cell populations (primarily in peripheral blood mononuclear cells [PBMCs], but also in granulocytes and T and B lymphocytes). We defined weight loss maintenance as having lost at least 5% or 10% of body weight (tested in separate models) from preintervention to postintervention, and having maintained this loss at 12 months. We predicted that greater weight loss and weight loss maintenance would be associated with TL lengthening. RESULTS Neither weight loss intervention significantly predicted TL change nor did amount of weight change, at any time point. Across all participants, weight loss maintenance of at least 10% was associated with longer PBMC TL (b = 239.08, 95% CI = 0.92 to 477.25, p = .049), CD8+ TL (b = 417.26, 95% CI = 58.95 to 775.57, p = .023), and longer granulocyte TL (b = 191.56, 95% CI = -4.23 to 387.35, p = .055) at 12 months after accounting for baseline TL. Weight loss maintenance of 5% or more was associated with longer PBMC TL (b = 163.32, 95% CI = 4.00 to 320.62, p = .045) at 12 months after accounting for baseline TL. These tests should be interpreted in light of corrections for multiple tests. CONCLUSIONS Among individuals with obesity, losing and maintaining a weight loss of 10% or more may lead to TL lengthening, which may portend improved immune and metabolic function. TL lengthening in this study is of unknown duration beyond 12 months and requires further study. TRIAL REGISTRATION Clinicaltrials.govidentifierNCT00960414; Open Science Framework (OSF) preregistration: https://osf.io/t3r2g/.
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Baseline Anthropometric and Metabolic Parameters Correlate with Weight Loss in Women 1-Year After Laparoscopic Roux-En-Y Gastric Bypass.
Sans, A, Bailly, L, Anty, R, Sielezenef, I, Gugenheim, J, Tran, A, Gual, P, Iannelli, A
Obesity surgery. 2017;(11):2940-2949
Abstract
BACKGROUND In this study, we explored in a prospective cohort of morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass (LRYGP) correlations between baseline anthropometrics, metabolic parameters, resting energy expenditure (REE), body composition, and 1-year % excess body mass index loss (%EBMIL). We also investigated risk factors for insufficient %EBMIL. METHODS One hundred three consecutive women were prospectively evaluated at baseline (age 40.6 ± 11.2, weight 113.9 kg ± 15.3, BMI 43.3 ± 4.9 kg/m2) and 1 year after LRYGP. Weight, excess weight, brachial circumference, waist circumference, fat mass (FM) and fat-free mass (FFM) (measured with bioelectrical impedance analysis), REE, inflammation, insulin resistance, and lipid disturbances were determined before and 1 year after LRYGP. RESULTS At 1 year, mean weight loss was 39.8 kg ± 11.7 and mean EBMIL was 15.2 kg/m2 ± 4.2. Mean %EBMIL was 86% ± 21% (range 30-146%). Baseline brachial circumference, waist circumference and triceps skinfold thickness decreased significantly at 1 year (P < 0.001). Blood glucose and insulin levels, HDL cholesterol, LDL cholesterol, triglycerides, and CRP also decreased significantly (P < 0.001). The mean loss of initial FFM and FM was 9.1 kg ± 8.2 (15%) and 30.7 kg ± 11.8 (53%), respectively. REE on body weight ratio (REE/BW) increased from 15.3 kcal/kg ± 2.8 to 18.4 kcal/kg ± 2.5 (p < 0.0001) and REE on FFM ratio decreased from 31.2 to 28.7 kcal/day/kg (p < 0.001). Preoperative waist circumference (r = -0.3; P < 0.001), blood glucose level (r = -0.37; P < 0.001), and CRP (r = -0.28; P = 0.004) were negatively correlated with EBMIL% 1 year after surgery. Among baseline body composition parameters, only preoperative FM was negatively correlated with %EBMIL (r = -0.23; p = 0.02). One year after surgery FM change was negatively correlated with EBMIL% (r = -0.49; P < 0.001) while FFM/BW ratio was positively correlated with %EBMIL (r = 0.71; P < 0.001). Increase in REE/BW at 1 year was positively correlated with %EBMIL (r = 0.47; p < 0.001). On multivariate analysis, baseline blood glucose level (OR = 1.77; CI 95%: [1.3-2.4]) was the only predictive factor of EBMIL <60% at 1 year. CONCLUSION LRYGB has beneficial effects on clinical, biological parameters, and body composition. Increasing the proportion of FFM on total BW and REE/BW is associated with better results in terms of weight loss. Baseline glucose level may be helpful in identifying poor responders to LRYGBP. TRIAL REGISTRATION NCT02820285y ( https://clinicaltrials.gov/ct2/show/NCT02820285?term=Characterization+of+Immune+Semaphorin+in+Non-Alcoholic+Fatty+Liver+Disease+and+NASH&rank=1 ).
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Comparative physiogenomic analyses of weight loss in response to 2 modes of bariatric surgery: demonstration with candidate neuropsychiatric and cardiometabolic genes.
Seip, RL, Papasavas, P, Stone, A, Thompson, S, Ng, J, Tishler, DS, Ruaño, G
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2016;(2):369-77
Abstract
BACKGROUND Surgical weight loss response is variable, with suboptimal outcomes in some patients. We hypothesized that genetic biomarkers may be related to weight change. METHODS We tested 330 single nucleotide polymorphisms (SNPs) in genes relevant to metabolic regulation in 161 patients whose decrease in body mass index (BMI), 1 year after laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB), was small (lowest quartile response) or large (highest quartile response). LAGB patients whose BMI decreased≤4.7 or≥10.2 units comprised groups I (n = 43) and II (n = 40), respectively. RYGB patients whose BMI decreased≤13.6 or≥19.8 units comprised groups III (n = 39) and IV (n = 39), respectively. Within each surgery, SNPs with large differences in reference allele frequency (z score>2, corresponding to values displaced 2 standard deviations [SD] from the mean for all SNPs) in low versus high quartiles, were identified. We compared reference allele frequencies, within surgical procedure, using the χ(2) test (using Bonferroni correction for multiple testing). RESULTS The mean percent excess weight losses (±SD) corresponding to groups I, II, III, and IV were: 16 (±12), 64 (±30), 55 (±16), and 75 (±17), respectively. SNPs with z score>2 were identified in genes involved in LAGB response, lipid metabolic regulation (APOE, rs439401; APOC4, rs2288911), neural processes (DRD3, rs167771; HTR3 B, rs3758987), and xeno- or endobiotic metabolism (CYP3 A4, rs12333983); and for RYGB response, in lipid transport (SCARB1, rs10846744), folate metabolism (MTHFR, rs2066470), regulation of glycolysis in immune cells (HIF1 A, rs1951795), vitamin K cycling (VKORC1, rs2359612), and xeno- or endobiotic metabolism (CYP3 A4, rs2242480). For LAGB response, APOE SNP frequencies were significantly different. CONCLUSIONS With further validation, information derived from patient DNA may be useful to predict surgical weight loss outcomes and guide selection of surgical approach.
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Importance of substantial weight loss for altering gene expression during cardiovascular lifestyle modification.
Ellsworth, DL, Mamula, KA, Blackburn, HL, McDyer, FA, Jellema, GL, van Laar, R, Costantino, NS, Engler, RJ, Vernalis, MN
Obesity (Silver Spring, Md.). 2015;(6):1312-9
Abstract
OBJECTIVE To examine relationships between weight loss through changes in lifestyle and peripheral blood gene expression profiles. METHODS A prospective nonrandomized trial was conducted over 1 year in participants undergoing intensive lifestyle modification to reverse or stabilize progression of coronary artery disease. Cardiovascular risk factors, inflammatory biomarkers, and gene expression as a function of weight loss were assessed in 89 lifestyle participants and 71 retrospectively matched controls undergoing usual care. RESULTS Substantial weight loss (-15.2 ± 3.8%) in lifestyle participants (n = 33) was associated with improvement in selected cardiovascular risk factors and significant changes in peripheral blood gene expression from pre- to post-intervention: 132 unique genes showed significant expression changes (false discovery rate corrected P-value <0.05 and fold-change ≥1.4). Altered molecular pathways were related to immune function and inflammatory responses involving endothelial activation. In contrast, participants losing minimal weight (-3.1 ± 2.5%, n = 32) showed only minor changes in cardiovascular risk factors and markers of inflammation and no changes in gene expression compared to non intervention controls after 1 year. CONCLUSIONS Weight loss (≥10%) during lifestyle modification is associated with down-regulation of genetic pathways governing interactions between circulating immune cells and the vascular endothelium and may be required to successfully reduce CVD risk.
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Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.
Ryan, AM, Reynolds, JV, Healy, L, Byrne, M, Moore, J, Brannelly, N, McHugh, A, McCormack, D, Flood, P
Annals of surgery. 2009;(3):355-63
Abstract
BACKGROUND Esophagectomy represents an exemplar of controlled major trauma, with marked metabolic, immunologic, and physiologic changes as well as an associated high incidence of complications. Eicosapentaenoic acid (EPA) enriched enteral nutrition (EN) modulates immune function and limits catabolism in patients with advanced cancer, but its impact in the peri-operative period is unclear. OBJECTIVES To examine the effects of perioperative EPA enriched EN on the metabolic, nutritional, and immuno-inflammatory response to esophagectomy, and on postoperative complications. METHODS In a double-blind design, patients were randomized to a standard EN formula or a formula enriched with 2.2 g EPA/d for 5 days preoperatively (orally) and 21 days postoperatively (jejunostomy). Segmental bioelectrical impedance analysis was performed preoperatively and on POD 21. Postoperative complications were monitored, as well as the acute phase response, coagulation markers, and serum cytokines. RESULTS Fifty-three patients (28 EPA, 25 standard) completed the study, and both groups were well matched. Serum and peripheral blood mononuclear cell (PBMC) membrane EPA levels were significantly increased in the EPA group. There was no difference in the incidence of major complications. The EPA group maintained all aspects of body composition postoperatively, whereas patients in the standard EN group lost significant amounts of fat-free mass (1.9 kg, P = 0.030) compared with the EPA group [leg (0.3 kg, P = 0.05), arm (0.17 kg, P = 0.01), and trunk (1.44 kg, P = 0.03)]. The EPA group had a significantly (P < 0.05) attenuated stress response for TNFalpha, IL-10, and IL-8 compared with the standard group. CONCLUSIONS EPA supplemented early EN is associated with preservation of lean body mass post esophagectomy compared with a standard EN. These properties may merit longer-term study to address its impact on recovery of function and quality of life in models of complex surgery or multimodal cancer treatment regimens.
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Weight reduction can decrease circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels in overweight middle-aged men.
Nomata, Y, Kume, N, Sasai, H, Katayama, Y, Nakata, Y, Okura, T, Tanaka, K
Metabolism: clinical and experimental. 2009;(9):1209-14
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Abstract
Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been reported to be associated with acute coronary syndrome, but its association with obesity has not been elucidated. In this study, we examined whether weight reduction would reduce the serum levels of sLOX-1 in a 12-week weight reduction intervention. Thirty-eight overweight middle-aged men were enrolled in the study, and 32 completed the intervention. The serum level of sLOX-1 was measured using a chemiluminescent enzyme-linked immunoassay. After the intervention program, body weight and the serum level of sLOX-1 decreased significantly (-7.5% +/- 4.8% and -72.1% +/- 35.9%, respectively). Changes in serum levels of sLOX-1 were positively correlated with changes in body weight (r = 0.54, P = .003), body mass index (r = 0.57, P = .001), body fat mass (r = 0.57, P = .002), total cholesterol (r = 0.41, P = .03), subcutaneous fat area (r = 0.50, P = .007), high-sensitivity C-reactive protein (r = 0.56, P = .002), leptin (r = 0.47, P = .01), and tumor necrosis factor-alpha (r = 0.32, P = .09); but no correlations were observed with fasting glycemic-related factors (blood glucose, hemoglobin A(1c), and insulin). Changes in body mass index and high-sensitivity C-reactive protein were selected as significant predictors of sLOX-1 changes by multiple regression analyses. These results suggest that LOX-1 induction may be related to adipocyte metabolism, inflammation, and immune response associated with obesity.
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Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome.
de Mello, VD, Kolehmainen, M, Schwab, U, Mager, U, Laaksonen, DE, Pulkkinen, L, Niskanen, L, Gylling, H, Atalay, M, Rauramaa, R, et al
Metabolism: clinical and experimental. 2008;(2):192-9
Abstract
Inflammation is associated with obesity, the metabolic syndrome, and diabetes. No data are available on the effect of weight reduction on the gene expression of cytokines in immune cells in obesity and the metabolic syndrome. We assessed how long-term weight loss affects expression of cytokines in peripheral blood mononuclear cells (PBMCs) in individuals with impaired glucose metabolism and the metabolic syndrome. Data from 34 subjects randomized to either a weight reduction or a control group for a 33-week period were analyzed. The messenger RNA (mRNA) expression of interleukins (ILs) in PBMCs was measured using real-time polymerase chain reaction. Measures of insulin and glucose metabolism (intravenous and oral glucose tolerance tests), body composition, and circulating adipokines and inflammatory markers were also assessed. Weight reduction resulted in a decrease in the mRNA expression of IL-1beta (IL1B), IL-1 receptor antagonist, and tumor necrosis factor alpha (P < .001) and an increase in expression of IL-6 (IL6) and IL-8 (P < .01). The increase in IL6 expression was associated with a decrease in fasting glycemia (r = -0.53, P < .01). Interestingly, the decrease in IL1B expression was correlated with an increase in insulin sensitivity index (r = -0.68, P < .01). In general, a decrease in circulating levels of adipokines and inflammatory markers was also observed after weight loss. Weight loss altered gene expression of cytokines related to inflammation and the immune response in PBMCs. Changes in IL6 mRNA expression were associated with changes in fasting glycemia. The decrease in IL-1 receptor antagonist expression after weight loss and the strong correlation between the decrease in IL1B expression and the increase in insulin sensitivity suggest a contribution of these genes to insulin-resistant states found in obesity and the metabolic syndrome.