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Background: One of the major challenges in obesity treatment is to explain the high variability in the individual's response to specific dietary and physical activity interventions. With this study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss., Methods: We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ± SD age = 49 ± 9 years, body mass-index (BMI) = 30.2 ± 3.3 kg/m 2 ) from the 18-month CENTRAL randomized controlled trial who underwent either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity., Results: Analyses comparing male subjects with the most prominent body weight-loss (responders, mean weight change - 16%) vs. non-responders (+ 2.4%) (N = 10 each) revealed significant variation in DNA methylation of several genes including LRRC27, CRISP2, and SLFN12 (all adj. P < 1 × 10 -5 ). Gene ontology analysis indicated that biological processes such as cell adhesion and molecular functions such as calcium ion binding could have an important role in determining the success of interventional therapies in obesity. Epigenome-wide association for relative weight-loss (%) identified 15 CpGs being negatively correlated with weight change after intervention (all combined P < 1 × 10 - 4 ) including new and also known obesity candidates such as NUDT3 and NCOR2. A baseline DNA methylation score better predicted successful weight-loss [area under the curve (AUC) receiver operating characteristic (ROC) = 0.95-1.0] than predictors such as age and BMI (AUC ROC = 0.56)., Conclusions: Body weight-loss following 18-month lifestyle intervention is associated with specific methylation signatures. Moreover, methylation differences in the identified genes could serve as prognostic biomarkers to predict a successful weight-loss therapy and thus contribute to advances in patient-tailored obesity treatment.

Introduction: Intense military operations during deployment or training are associated with elevations in inflammatory cytokine markers. However, the influence of an inflammatory response on military-specific skills is unclear. This study examined the association between brain-derived neurotrophic factor (BDNF), glial fibrillar acidic protein, markers of inflammation, marksmanship and cognitive function following a week of intense military field training., Methods: Twenty male soldiers (20.1±0.6 years; 1.78±0.05m; 74.1±7.9kg) from the same elite combat unit of the Israel Defense Forces volunteered to participate in this study. Soldiers completed a five-day period of intense field training including navigation of 27.8km/day with load carriages of ~50% of their body mass. Soldiers slept approximately fivehours per day and were provided with military field rations. Following the final navigational exercise, soldiers returned to their base and provided a blood sample. In addition, cognitive function assessment and both dynamic and static shooting (15 shots each) were performed following a 200 m gauntlet, in which soldiers had to use hand-to-hand combat skills to reach the shooting range., Results: Results revealed that tumour necrosis factor-α (TNF-α) concentrations were inversely correlated with dynamic shooting (r=-0.646, p=0.005). In addition, a trend (r=0.415, p=0.098) was noted between TNF-α concentrations and target engagement speed (ie, time to complete the shooting protocol). BDNF concentrations were significantly correlated with the Serial Sevens Test performance (r=0.672, p=0.012)., Conclusion: The results of this investigation indicate that elevated TNF-α concentrations and lower BDNF concentrations in soldiers following intense military training were associated with decreases in marksmanship and cognitive function, respectively., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Hoffman, JR, Hoffman, MW, Zelicha, H, Gepner, Y, Willoughby, DS, Feinstein, U, and Ostfeld, I. The Effect of 2-Weeks of Inactivated Probiotic Bacillus coagulans on Endocrine, Inflammatory and Performance Responses During Self-Defense Training in Soldiers. J Strength Cond Res 33(9): 2330-2337, 2019-The effect of 2 weeks of inactivated Bacillus coagulans (iBC) ingestion on performance and inflammatory cytokines was examined during a self-defense course in soldiers. Sixteen male soldiers were randomly assigned to either iBC (n = 8) or placebo (PL; n = 8) in this double-blind study. Participants were garrisoned on base and participated in the same training tasks. Assessments were conducted in a single day before (PRE) and after the supplementation period (POST). During each testing session, participants were assessed for vertical jump power (VJP), muscle endurance, simulated casualty drag, and 2 100-m shuttle runs. Resting blood measures for testosterone, cortisol, creatine kinase, and inflammatory cytokines were also assessed. Mann-Whitney analysis of change (Δ) scores indicated no significant change (p's > 0.05) in any of the performance or blood variables. However, a trend (p = 0.089) was noted in the Δ score for VJP in iBC compared with PL. In addition, trends were observed in the change in IL-10 (p = 0.057) and IFNγ (p = 0.057). Magnitude based inferential analysis indicated that changes in VJP and simulated casualty drag were likely beneficial (90.7 and 80.4% likelihood effect, respectively) for iBC. In addition, iBC supplementation very likely augmented IL-10 concentrations, but was possibly negative for changes in IL-6, and likely negative for changes in TNFα and IFNγ. Changes in all other performance and blood markers were unclear. Results indicated that 2 weeks of iBC supplementation appeared to be beneficial for maintaining power and short-term speed performance, while attenuating the inflammatory response during intense training in a military self-defense course.

Hoffman, JR, Gepner, Y, Hoffman, M, Zelicha, H, Shapira, S, and Ostfeld, I. Effect of high dose, short-duration β-alanine supplementation on circulating IL-10 concentrations during intense military training. J Strength Cond Res 32(10): 2978-2981, 2018-This study examined the effect of β-alanine as a potential anti-inflammatory agent during intense military training. Twenty soldiers (20.1 ± 0.6 years) from an elite combat unit were randomly assigned to either a β-Alanine (BA) or placebo (PL) group. Soldiers were provided with 12 g·d of either BA or PL for 7 days between 2 intensive periods of navigational training and restricted sleep. During the initial training period, soldiers navigated on average 27.8 km·d with ∼50% of their body mass in their packs for 5 days. Soldiers returned to base and began a 7-day supplementation program before departing for an additional period of intense field training. During the second period of field training, soldiers navigated 10 km·d for an additional 5 days, carrying similar loading as the initial week, performed tactical missions, and slept approximately 5 hours per day. Blood samples were obtained after the initial training period and after the second training period and analyzed for IL-10. Magnitude-based inferences that were used to provide inferences on the true effect BA may have had on IL-10 concentrations compared with PL, calculated from 90% confidence intervals. Data analysis indicated that changes in circulating IL-10 concentrations (mean difference 0.86 pg·ml) were possibly greater (57%) for BA than PL. Results of this study suggest that 1 week of high-dose BA ingestion may enhance the anti-inflammatory response during intense military training, suggesting a potential therapeutic role of BA during intense training.

Background & Aims: The ability to mobilize pancreatic-fat and the meaning of decreased fat in the pancreas remain controversial. We followed the dynamics of pancreatic-fat and its morphology during various long weight-loss induced lifestyle-interventions., Methods: In isolated workplace with monitored/provided lunch, we randomly assigned healthy persons with abdominal obesity or dyslipidemia for one of two 18-month equal-caloric diets: low-fat (LF) or Mediterranean/low-carbohydrate (Med/LC, with provided 1oz walnuts/day), with or without added moderate exercise (supervised gym membership). We used magnetic-resonance-imaging to quantify pancreatic-fat and morphology., Results: At baseline, 277 eligible participants (mean age = 48 years; 88% men; pancreatic-fat = 17.4 ± 5.1%) had higher pancreatic-fat in men (17.7 ± 4.9% vs 14.9 ± 5.5% in women; p = 0.004). Following 18-month intervention (adherence = 86.3%) and moderate weight-loss (mean = -3.0 ± 5.5 kg), pancreatic-fat decreased moderately but significantly (-0.26 ± 2.18% units; p = 0.049). Med/LC diet induced a greater decrease in pancreatic-fat compared to LF (p = 0.043), and the combination of Med/LC diet + exercise exhibited the highest reduction (-0.69% units) as compared to LF diet without exercise (+0.12%units; p = 0.027 between groups). In multivariate regression models, after further adjusted for visceral adipose-tissue (ΔVAT), pancreatic-fat loss associated with both decreases in pancreatic-morphology ratio (perimeter divided by area; beta = 0.361; p < 0.001) and superficial-subcutaneous adipose-tissue loss (beta = 0.242; p = 0.001), but not with changes in intrahepatic-fat (beta = -0.034; p = 0.638). Pancreatic-fat loss associated with increased intake of polyunsaturated-fat (beta = -0.137; p = 0.032), as with improved high-density lipoprotein-cholesterol (HDL; beta = -0.156; p = 0.023) and triglycerides/HDL ratio (beta = 0.162; p = 0.015), independently of ΔVAT, but not with glycemic-control parameters (e.g. HbA1c, HOMA-IR and HOMA-beta; p > 0.2 for all)., Conclusions: Pancreatic-fat loss is mainly associated with improved lipid, rather than glycemic profiles. Med/LC diet, mostly with exercise, may benefit pancreatic-fat loss. Pancreatic-morphology could serve as a biomarker of pancreatic-fat state. (ClinicalTrials.gov identifier: NCT01530724)., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots., Methods: We performed an 18-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to isocaloric low-fat or Mediterranean/low-carbohydrate (MED/LC) diet+28 g walnuts/day with/without added moderate physical activity (PA; 80% aerobic; supervised/free gym membership). Overall primary outcome was body fat redistribution, and the main specific end point was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots (deep and superficial subcutaneous, liver, pericardial, muscle, pancreas, and renal sinus) by magnetic resonance imaging., Results: Of 278 participants (age, 48 years, 89% men, body mass index, 30.8 kg/m 2 ), 86% completed the trial with good adherence. The low-fat group preferentially decreased reported fat intake (-21.0% versus -11.5% for the MED/LC; P <0.001), and the MED/LC group decreased reported carbohydrates intake (-39.5% versus -21.3% for the low-fat group; P <0.001). The PA + groups significantly increased the metabolic equivalents per week versus the PA - groups (19.0 versus 2.1; P =0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in the MED/LC PA+ group ( P <0.05). VAT (-22%), intrahepatic (-29%), and intrapericardial (-11%) fats declines were higher than pancreatic and femur intermuscular fats (1% to 2%) loss. Independent of weight loss, PA + with either diet had a significantly greater effect on decreasing VAT (mean of difference, -6.67cm 2 ; 95% confidence interval, -14.8 to -0.45) compared with PA - . The MED/LC diet was superior to the low-fat diet in decreasing intrahepatic, intrapericardial, and pancreatic fats ( P <0.05 for all). In contrast, renal sinus and femoral intermuscular fats were not differentially altered by lifestyle interventions but by weight loss per se. In multivariate models further adjusted for weight loss, losing VAT or intrahepatic fat was independently associated with improved lipid profile, losing deep subcutaneous adipose tissue with improved insulin sensitivity, and losing superficial subcutaneous adipose tissue remained neutral except for an association with decreased leptin., Conclusions: Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomic sites., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01530724., (© 2017 American Heart Association, Inc.)