Acute and Chronic Effects of 12 Weeks of Combined Exercise Training on Plasma IL-6 in Post-Menopausal Women

Post-menopausal women exhibit higher levels of IL-6, a pro-inflammatory cytokine and anti-inflammatory myokine, and up-regulation of cellular receptors and cofactors for IL-6. Exercise is associated with an acute elevation of IL-6, but consistent exercise training diminishes this response. PURPOSE: to analyze the acute and chronic effects of 12 weeks of combined resistance and aerobic exercise training on plasma IL-6 in overweight or obese, post-menopausal women (55-75 years). METHODS: Forty-three women were randomly assigned to an exercise (EX, n=22) or an education (ED, n=21) group. EX completed resistance training (2 sets of 8 resistance exercises at 80% of 1RM) followed by aerobic training (25-minute treadmill walk at 70-80% of HRR) three times per week for 12 weeks. ED attended classes and activities two times per week for 12 weeks to control for seasonal variation and social interaction. Blood samples were collected a total of 8 times: 4 times before training (BT) (before the acute exercise bout (PRE), immediately after exercise (PO), 1 hour after exercise (1HR), and 2 hours after exercise (2HR)) and 4 times after training (AT). Lean, post-menopausal, and age-matched women were recruited for collection of one resting blood sample to serve as healthy controls (LN, n=11). Plasma IL-6 was determined using an ELISA kit according to manufacturer instructions. RESULTS: Baseline IL-6 concentration was significantly lower in the LN group compared to the EX (LN BT PRE: 1.0 ± 0.5; EX BT PRE: 2.8 ± 1.3 pg/mL; p\u3c0.001) and ED (LN BT PRE: 1.0 ± 0.5; ED BT PRE: 3.8 ± 1.7 pg/mL; p\u3c0.001) groups. No statistically significant BT/AT x group interaction was observed (p\u3e0.05) when the BT and AT PRE time points of the EX and ED groups were compared. In the EX group, PO was significantly higher than PRE (PRE 2.6 ± 1.2; PO 4.3 ± 1.8 pg/mL; p\u3c0.001), and PO was significantly higher than 1 HR (PO 4.3 ± 1.8; 1HR 3.4 ± 1.2 pg/mL; p=0.038) and 2HR (PO 4.3 ± 1.8; 2 HR 3.9 ± 1.6 pg/mL; p=0.005). No statistically significant differences were observed when corresponding time points before and after the intervention within a group were compared (i.e., EX BT PRE to EX AT PRE) (p\u3e0.05). CONCLUSION:The training intervention may not have been long enough and/or intense enough to observe a chronic effect of combined exercise training on plasma IL-6. Significant elevation of IL-6 immediately post-exercise was observed in the EX group, but this response was not blunted by consistent exercise training

HIT vs. LSD: Four Days of Intensive Training does not Influence Lactoferrin, but LSD Increases Resting IL-6 while Attenuating the Acute Exercise Response, yet HIT Elevates Salivary Cortisol Levels

High intensity training programs (HIT) induce comparable endurance performance adaptations to those of continuous long slow distance training (LSD). HIT has increased, as athletes are able to maintain their VO2 max or performance with less time, and reduced training volume. High training volume may be immunosuppressive. PURPOSE: To examine a major mucosal immune component (salivary lactoferrin), the circulating cytokines (IL-6, IL-8, TNF-α), and cortisol response to HIT and LSD during 4 days of intensified training (IT). METHODS: Eight endurance-trained males (23.1±2.0yr,VO2 max 53.9±5.3 ml×kg-1×min-1) performed two, 4-day IT protocols: HIT and LSD conditions (separated by ³ 21 days). Both conditions included 2 exercise sessions / day (morning (AM) and late afternoon (PM)). LSD consisted of 50 min cycle ergometery in the AM (70% VO2max) and 90 min running in the PM (70% VO2max). The AM HIT session included 8 all-out, 30 sec cycling sprints (resistance=0.075kg×kg-1 body mass) with 4.5-8.5 min active recovery. The PM HIT session was the same as that for LSD. Blood and saliva samples were obtained at various time points based on the dependent variable. Plasma cytokines and creatine kinase (CK) activity were assessed both before and after the AM exercise sessions (pre-(PR), post(PO)-exercise) in both conditions on the first (before training; BT) and fourth (after training; AT) day of IT. Creatine kinase activity and cytokines were assessed in plasma. Salivary lactoferrin, and cortisol were assessed at 3 time points on days 1, 2 and 4 (PR and PO for AM, and PR for PM) in UHIT and LSD. Additionally, saliva was also collected at one time point (PR for the AM session) on the third and fifth day. RESULTS: Values above are listed as IL-6 (pg·mL-1), CK (U/L). BT= Day 1, AT= Day 4. Same letters indicate differences between time points for IL-6 serum levels (p\u3c0.05). Same numbers indicate differences between time points for CK activity (p\u3c0.05). Additionally, a significant time x day interaction occurred for lactoferrin secretion rate (PO\u3ePR on days 1 and 4, 1735\u3e5639 and 2290\u3e5663 ng·min-1, respectively; p=0.032). Moreover, a significant condition x time interaction occurred for lactoferrin secretion rate (p=0.047). A main effect for condition revealed that salivary cortisol was greater in HIT vs. LSD (p=0.028). CONCLUSION: Four days of IT did not attenuate the lactoferrin response to acute exercisese. LSD resulted in elevated resting IL-6, which may be responsible for the attenuation of the IL-6 response to acute exercise in this condition due to a feedback inhibition mechanism. Cortisol response is frequently linked to that of Il-6. Il-6 response to acute exercise was maintained in HIT, which may explain the elevated cortisol levels

The Melanocortin 3 Receptor: A Novel Mediator of Exercise-Induced Inflammation Reduction in Postmenopausal Women?

The purpose of this study was to determine whether resistance exercise training-induced reductions in inflammation are mediated via melanocortin 3 receptor expression in obese (BMI 32.7 ± 3.7) women (65.6 ± 2.8 yrs) randomized to either a control (N = 11) or resistance training group (N = 12). The resistance trained group performed resistance training 3 days/week for 12 weeks. Resting blood samples were collected before and after the training intervention in both resistance trained and control groups. Resistance training upregulated melanocortin 3 receptor mRNA by 16-fold (P = .035) and decreased monocyte count, without changing leukocyte number, body composition, or body weight. Resistance trained individuals exhibited increased sensitivity to inflammatory stimuli, whereas control individuals exhibited no change. While there was no change in whole blood tumor necrosis factor alpha mRNA between the groups, whole blood interleukin 10 mRNA was higher in the resistance trained group following the intervention period. In summary, it appears that resistance training may modulate melanocortin 3 receptor expression, providing a possible mechanism for the anti-inflammatory effects of exercise training

The Relationship of Visceral Adipose Tissue with Markers of Energy Homeostasis Following Weight-Loss

Excess levels of adipose tissue, in particular visceral adipose tissue (VAT), is closely associated with the metabolic syndrome and dysregulation of energy homeostasis. It is hypothesized that leptin resistance results in overconsumption of calories and reduced satiety. Recently, brain derived neurotrophic factor (BDNF), beyond functioning in learning and memory, is shown to play a role in energy homeostasis via its positive satiety effects on the hypothalamus. However, it remains to be elucidated how changes in visceral adipose tissue are associated with changes in circulating leptin and BDNF after weight-loss. PURPOSE: To identify changes in adiposity and circulating leptin and BDNF following a 3-month weight-loss program. METHODS: Sixty-five obese (mean±SEM; age=47.9±1.1 years; BMI=34.5±0.8 kg/m2;), men and women completed a 3-month weight-loss program that consisted of a reduced energy intake of 1200-1500 kcals/day using a high-volume low-calorie diet combined with a progressive walking program to target 300 min/wk. Fasted (12 hr) blood samples were collected at baseline and post-weight-loss (3 months) and assayed for concentrations of glucose, insulin, BDNF, and leptin. Using DXA, total VAT and subcutaneous (SubQ) adipose tissue mass were measured at baseline and post-weight-loss (3 months). To identify significant changes over time, ANOVA with repeated measures was performed with significance set at p\u3c0.05. RESULTS: Following the 3-month weight-loss program, both BMI and HOMA-IR were significantly reduced 9.3% and 49%, respectively. The reduction in BMI and HOMA-IR were matched by a significant reduction in both VAT (-658 g; -33%, p\u3c0.001) and SubQ (-367 g; -17%, p\u3c0.001). Interestingly, leptin was reduced and BDNF was increased by 43% (p\u3c0.001) and 42% (p=0.011), respectively. Linear regression revealed that changes in VAT were associated with changes in leptin (b=0.298, p=0.026), but not with BDNF (b=0.027, p=0.896). CONCLUSION: This study shows that the reduction in VAT, by caloric restriction and physical activity, was associated with the reduction in circulating leptin concentrations, but not with changes in BDNF. Changes in leptin and BDNF may be in part responsible for the normalization of the energy homeostasis observed after weight-loss; however, changes in BDNF may be independent of VAT

The Influence of Physical Activity on Monocyte Phenotype on Circulating Platelet-Monocyte Complexes in Overweight/Obese Persons

Elevated platelet-monocyte complexes (PMC) promote atherosclerosis and are associated with cardiovascular disease. It is unknown whether consistent physical activity (PA) decreases circulating PMCs. Additionally, no one has determined the monocyte phenotype most associated with PMCs. Purposes: 1) to examine the influence of PA on PMCs and their association with inflammatory /prothrombotic markers such as C-reactive protein (CRP), L-selectin (LS), platelet factor 4 (PF4), von Willebrand Factor (vWF), and hemoglobin A1C (HbA1c) and 2) to determine the monocyte phenotype most likely to form PMCs. Methods: Thirty-one overweight/obese subjects (44±5yr, BMI 34.2±5 kg×m2) were divided into two groups: sedentary (SED, n=17) and physically active (PA, n=14) based on physical activity logs. SED participated in \u3c 1 h of formal exercise while PA participated in moderate-high intensity exercise at least 3 h per week. Flow cytometry was used to identify PMCs on the monocyte phenotypes: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14+CD16++). Platelets were identified using the marker CD42a. Results: Percentage of circulating PMCs and median fluorescence intensity of CD42a (MedFI; marker of platelet density per monocyte) were not different between groups; however, monocyte phenotype significantly impacted PMC percentage and MedFI where the lower the CD16 expression, the greater the adhesion of platelets. Classical monocytes (CD16-) had the highest % of PMC, etc. (Fig 1). HbA1c was greater (p=0.031) and LS (p=0.019) was lower in SED compared to PA (Fig. 2). There were no significant associations between any blood marker and PMC percentage, but PF4 was correlated with percent of CD16 -(r= -0.482, p=0.031) and CD16+(r= 0.473, p=0.035) monocytes. Conclusions: The absence of a separation between groups in VO2max may partially explain the lack of a difference in PMCs between groups. Regarding our second aim, classical monocytes appear to be more involved in PMC formation than do CD16+ monocytes with CD16++ having the lowest percentage of cells with platelets adhered (PMC). This observation may be due to the shedding of adhesion molecules from platelets and monocytes during activation from classical (CD16-) to a more inflammatory state (ie. CD16+)

The Effect of Gender on Circulating Adipokines during Weight Loss and Weight Maintenance

During obesity, the altered release of adipokines, leptin and adiponectin, have been strongly associated with development of the metabolic syndrome. Treatment with weight loss has been shown to increase adiponectin, in particular high molecular weight (HMW) adiponectin, and reduce circulating leptin levels indicating an increased leptin sensitizing effect. Interestingly, a gender dichotomy has been identified with women generally possessing higher plasma concentrations of both adipokines. Weight loss effects have been well established; however, it remains to be determined how the gender differences in adiponectin and leptin will affect these adipokines during prolonged weight maintenance. PURPOSE: To identify gender differences in adiponectin and leptin concentrations following a 6-month weight loss and weight maintenance program. METHODS: Sixty-five obese (mean±SEM; age=47.9±1.1 years; BMI=34.3±0.7 kg/m2;) adults (M=20, F=45) completed a 3-month weight loss program that consisted of a reduced energy intake of 1200-1500 kcals/day using a high-volume low-calorie diet combined with a progressive walking program to target 300 min/wk. During the 3-month weight maintenance program, participants consumed sufficient calories to maintain weight loss with continued walking to target 300 min/wk. Fasted (12 hr) blood samples were collected at baseline, post- weight loss (3 months), and weight maintenance (6 months) and assayed for glucose, insulin, total and HMW adiponectin, and leptin. To identify significant changes over time and between gender, a repeated measures (time x gender) ANOVA was performed with significance set at P\u3c0.05. Results: At baseline, no significant difference in BMI or HOMA-IR were observed between genders. Following 3 months of weight loss, BMI was significantly reduced 9.9% and 8.5% in men and women, respectively, and BMI remained unchanged through the weight maintenance program. Interestingly, only men demonstrated a significant reduction in HOMA-IR following weight loss. Following weight maintenance in women, HOMA-IR increased slightly such that it was not significantly different than the baseline or weight loss time points. At baseline, women had significantly higher circulating levels of total and HMW adiponectin, and leptin. No significant changes in total or HMW adiponectin were observed over time for either gender. Following weight-loss, leptin concentrations were reduced 49.6% and 39.2% in men and women, respectively. Interestingly, only women demonstrated a transient reduction in leptin through the weight maintenance program. Conclusions: At baseline, we identified the presence of a clear gender dichotomy for total and HMW adiponectin, and leptin concentrations. Despite these significant differences in circulating adipokines at baseline, both men and women responded similarly to a 6-month weight loss and weight maintenance program

Exercise-Induced Th17 Lymphocyte Response and Their Relationship to Cardiovascular Disease Risk Factors in Obese, Post-Menopausal Women

Obesity-induced inflammation promotes type 2 diabetes and cardiovascular disease (CVD). A causative link between adaptive immunity and pathogenesis of obesity-associated diseases has been established. PURPOSE: To examine the effects of exercise on circulating T-helper (Th) 17 lymphocytes in overweight/obese post-menopausal women. METHODS: Twenty-seven overweight/obese women (BMI 32.7 ± 5.1 kg×m-2, 55-75 yr) were randomly assigned to the exercise (EX, n=14) or education (ED, n=13) groups. EX performed a 25-min walk (75-80% HRR) and 2 sets of 8 resistance exercises (70-80% 1RM) with blood samples obtained at: pre-exercise, post-exercise, one-hour and two-hour post-exercise. Blood samples were obtained at the same time points in resting ED. Whole blood was stained using the extracellular markers CD4, CD196, CD194, CD26, and CD161 to identify Th17 lymphocytes via flow cytometry. RESULTS: Acute exercise increased lymphocyte number (p = 0.0001), but decreased percent of CD4+ cells (p = 0.019) at PO. We observed a diurnal response (main effect) where CD26 expression was significantly lower by 2H compared to PRE (PR: 10631 ± 208; 2H: 9961 ± 271 MFI). There was a main effect (p=0.024) of group for CD26 expression (EX: 10745 ± 251; ED 9880 ± 260 MFI). The difference may have been driven by the apparent exercise-induced plateau of CD26 expression at 2H, which minimized the diurnal reduction observed in ED (p \u3e 0.05). There was a tendency (p = 0.09) for a group x time interaction in Th17 cell number at 1HR (EX = 25.3 ± 4.8; ED =37.2 ± 5.2 x 103 cells×ml-1). BMI was significantly correlated with Th17% (r = 0.5, p = 0.008). HbA1c was positively correlated with Th17 number and percentage (r = 0.598, p = 0.003; r = 0.614, p = 0.001, respectively), as well as CCR4+ Th17 cells (r = 0.421, p = 0.036). Multiple regression analysis revealed that BMI, fat percentage, and HbA1c were significant predictors (69%, r2 = 0.685) of Th17 cell %. CONCLUSION: Exercise reduced CD26 expression, the receptor responsible for Th17 cell migration, but did not significantly alter Th17 concentration (p = 0.09). CD26 upregulation may indicate that Th17 cells, via chemokine release, promote the stress-dependent migratory response of T-helper cells (CD4+). Obese individuals may experience a preferential differentiation of Th17 cells, based on their association with adiposity (BMI and %fat) and HbA1c

Acute Exercise-Induced Response of Platelet-Monocyte Complexes in Obese, Postmenopausal Women

Inactivity-related diseases such as cardiovascular disease (CVD) are linked to chronic low-grade, systemic inflammation. Platelet-monocyte complexes (PMCs) are markers of in vivo platelet activation and atherosclerosis, and may be early indicators of subclinical inflammation. PURPOSE: To examine the effects of an exercise bout on PMCs in those at risk for CVD. METHODS: Twenty-five overweight-obese (BMI 32.7 ± 5.2 kg×m-2, 55-75 yr) women were randomly assigned to either the exercise (EX, n=13) or non-exercise control (CON, n=12) group. EX performed 2 sets of 8 resistance exercises and a 25-min treadmill walk at 70-80% HRR. Blood was obtained pre-exercise (PR), post- (PO), 1-hour and 2 hours post-exercise (1HR and 2HR). Blood was obtained at the same time points in CON. PMCs were identified via flow cytometry and analyzed in each monocyte phenotype. Monocyte phenotypes were defined as: Mon1 (CD14+CD16−CCR2+), Mon2 (CD14+CD16+CCR2+), and Mon3 (CD14+CD16+CCR2−). All events positive for both CD14 and CD42a (marker for platelets) were considered PMCs. RESULTS: A main effect for time revealed an increase in PMC number at PO (p=0.036) which appears to have been driven by EX (EX = 61.5%; CON = 33.8% increase). PMCs formed with Mon1 and Mon2 followed a similar response. A significant group x time interaction for Mon3 PMC number (p=0.002) indicated an increase from PR to PO (PR = 5218±1170, PO = 8195±1152 cells·ml-1), and a decrease from PO to 1HR and 2HR (1HR = 3767±820 cells·ml-1 2HR = 3818±814 cells·ml-1) in EX. PMC number remained constant for CON at all timepoints. Estimated VO2max was negatively correlated with CD42a MFI (a marker of platelet density per monocyte) (r = -0.583, p = 0.003). Systolic blood pressure (SBP) positively correlated with percent PMC (% CD42a positive monocytes; r = 0.458, p = 0.042). CONCLUSION: Aerobic fitness appears to reduce platelet activation indicated by the negative relationship between VO2max and CD42a MFI. Chronic elevations in resting SBP are linked to PMC percentage, possibly due to sheer stress-induced platelet activation. It is possible that PMC elevation at PO is at least partially driven by exercise-induced increases in BP. These results support previous literature, indicating that PMCs are a CVD risk marker and may elucidate one mechanism by which physical fitness reduces risk for CVD