BACKGROUND: Early-life stress is associated with alterations in telomere length, a marker of accumulated stress and aging, and a risk factor for psychiatric disorders. Nonhuman primate maternal variable foraging demand (VFD) is a validated early-life stress model, resulting in anxiety-and depressive-like symptoms in offspring. Previous studies reported increased plasma glucagon-like peptide 1 (pGLP-1) along with insulin resistance in this model. We investigated whether VFD rearing related to adult telomere length and to these neuroendocrine markers.METHODS: Adult leukocyte telomere length was measured in VFD-reared (12 males, 13 females) and non-VFD- reared (9 males, 26 females) bonnet macaques. Associations between adult telomere length and adolescent fasting pGLP-1 or insulin resistance in VFD-reared versus non-VFD-reared groups were examined using regression modeling, controlling for sex, weight, and age.RESULTS: VFD subjects had relatively longer telomeres than non-VFD subjects (p = .017), and females relatively longer than males (p = .0004). Telomere length was positively associated with pGLP-1 (p = .0009) and with reduced insulin sensitivity (p , .0001) in both sexes, but not as a function of rearing group.CONCLUSIONS: Unexpectedly, VFD was associated with longer adult telomere length. Insulin resistance may lead to higher pGLP-1 levels in adolescence, which could protect telomere length in VFD offspring as adults. Associations between adult telomere length and adolescent insulin resistance and high pGLP-1 may reflect an adaptive, compensatory response after early-life stress exposure.

BACKGROUND:This is an exploratory pilot study of novel technology enabling people with mobility disability to walk with minimal effort, in the "sedentary range". The study's premise is that impairment of the leading physical activity of daily living, walking, is a major contributor to a dysmetabolic state driving many prevalent "civilization diseases" associated with insulin resistance.METHODS:We explore within-subject changes in standard oral glucose tolerance (OGT) tests including metabotropic molecules after 22 twice-weekly, 30-minute bouts of weight-supported light-moderate physical activity in 16 non-diabetic obese, otherwise healthy, reproductive-age, volunteer women walking on an "anti-gravity" lower-body positive pressure (LBPP) treadmill.RESULTS:Subjects had reference base-line fasting plasma glucose and triglycerides (TG) but 2-hr OGT insulin levels of 467 ± 276 pmol • liter-1 (mean± S.D.) indicating nascent insulin resistance, compared to post-study 308 ± 179 (p = 0.002). Fasting TG decreased from 0.80 ± 0.30 mmol • liter-1 to 0.71 ± 0.25 (p = 0.03). Concomitantly plasma total ghrelin decreased from 69.6 ± 41.6 pmol • liter-1 to 56.0 ± 41.3 (p = 0.008). There were no statistically significant changes in body weight or any correlations between weight change and cardiometabolic markers. However, there were robust positive correlations between changes among different classes of peptides including C-reactive protein-Interleukin 6, leptin-adiponectin, β-endorphin-oxytocin and orexin A (r 2 = 0.48-0.88).CONCLUSION:We conclude that brief, low-dose physical activity, walking on an anti-gravity LBPP treadmill may improve cardiometabolic risk, exhibiting favorable changes in neuro-regulatory peptides without weight loss in people with problems walking.

Background: Early life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a "thrifty phenotype" throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced "behavioral plasticity", which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations. Methods: 14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters. Results: Reduced LVESD (p < 0.05) was observed when controlled for age, sex, body weight and crown-rump length whereas ejection fraction (EF) (p = 0.037) was greater in VFD-reared versus non-VFD subjects. Pulse pressure was lower in VFD versus non-VFD females (p < 0.05). Male timidity in response to a human intruder was associated with reduced LVEDD (p < 0.05). Conclusions: ELS is associated with both structural and functional reductions of left ventricular measures, potentially implying a body-wide thrifty phenotype. Parallel "thrift" adaptations may occur in key brain areas following ELS and may play an unexplored role in mood and anxiety disorder susceptibility. (c) 2017 The Authors. Published by Elsevier Inc.

Lower body positive pressure (LBPP) treadmill activity might benefit patients with heart failure (HF). To determine the short-term effects of LBPP on left ventricular (LV) function in HF patients, LV ejection duration (ED), a measure of systolic function was prospectively assessed in 30 men with stable HF with LV ejection fraction ≤ 40% and 50 healthy men (N). Baseline measurements (100% body weight), including blood pressure (BP), heart rate (HR) and LVED, obtained via radial artery applanation tonometry, were recorded after 2 minutes of standing on weight support treadmill and after LBPP achieving reductions of 25%, 50%, and 75% of body weight in random sequence. Baseline, HR, and LVED (251 ± 5 vs 264 ± 4 ms; P = .035) were lower in the HF group. The LBPP lowered HR more (14% vs 6%, P = .009) and increased LVED more (15% ± 7% vs 10% ± 6%; P = .004) in N versus HF. Neither group had changes (Δ) in BP. On generalized linear regression, the 2 groups showed different responses ( P < .001). Multivariate analysis showed %ΔHR ( P < .001) and HF ( P = .026) were predictive of ΔED ( r2 = 0.44; P < .001). In conclusion, progressive LBPP increases LVED in a step-wise manner in N and HF patients independent of HR lowering. The ΔLVED is less marked in patients with HF.

OBJECTIVE Diabesity during gestation predisposes offspring to lifetime cardiometabolic risk. We demonstrated that maternal biliopancreatic diversion surgery (BPD) improved metabolic fitness and pregnancies reducing cardiometabolic risk in siblings born after (AMS) compared to before maternal surgery (BMS). We found differential methylation of inflammatory and glucoregulatory genes in peripheral blood cell DNA in offspring and in mothers after BPD compared to preoperative “control” women. Here we study offspring trajectories of cardiometabolic risk markers and determine persistence of the methylome related to body weight (BMI) and gestational weight gain (GWG). RESEARCH DESIGN AND METHODS Prospective, cross-sectional study of 133 mothers with 89 BMS and 183 AMS offspring born mean 4 years after BPD and 83 unoperated control women was conducted, and differential methylation patterns in mothers were compared with those of offspring during 2-26 years. RESULTS Independent of maternal or offspring BMI and GWG, postoperative maternal metabolic fitness was associated with improved cardiometabolic phenotype in AMS vs. BMS offspring sustained beyond puberty. BMS offspring exhibited increasing linear trajectories of weight, cardiometabolic and inflammation risk factors versus normative horizontal trajectories of AMS offspring. Methylation differences between AMS and BMS offspring identified 45 625 differentially methylated sites, 73% overlapping with those of mothers vs. controls; 4 446 demonstrated similar sustained directionality of differences in methylation levels; 154 sites exhibited significant correlation coefficients (r≥0.4) overrepresented within genes associated with cardiometabolic risk, growth and inflammation. CONCLUSION Maternal BPD appears to epigenetically prevent transmission of cardiometabolic risk independent of BMI.

Please cite this article as: Coplan JD, Rosenboym AV, Fulton SL, Panthangi V, Tang J, Thiramangalakdi L, Perera TD, Liu Y, Kamran H, Owens MJ, Nemeroff CB, Rosenblum LA, Kral JG, Salciccioli L, Lazar J, Reduced left ventricular dimension and function following early life stress: A thrifty phenotype hypothesis engendering risk for mood and anxiety disorders, Neurobiology of Stress (2017), doi: 10.1016/j.ynstr.2017.01.001.

Overnutrition and underactivity cause most chronic disease via inflammation and stress. Life-style change of diet is largely unsuccessful and exercise is painful, uncomfortable and difficult for people with diabesity, cardiorespiratory and joint diseases and cognitive decline affecting their ability to ambulate and adhere to exercise guidelines. Diets or exercise causing weight loss are stressful and trigger numerous redundant counter regulatory mechanisms defending lean body mass, explaining failures to sustain these behaviors. In this hypothesis generating pilot study we used a NASA-developed weight supporting lower-body positive pressure (LBPP) treadmill providing comfortable low-amount, low intensity walking, challenging current exercise guidelines. Methods: Sixteen nondiabetic, untrained, Black volunteer women (BMI 28-50), age 18-56 years were studied by anthropometry, analyses of energy expenditure and blood chemistry: oral glucose tolerance tests (OGTT) with insulin, C-peptide, GLP-1 and FFA and fasting lipids, cytokines, adipokines and appetitive peptides, before and after 10 weeks of twice weekly 30-minute weight supported LBPP treadmill sessions. Results: We found novel baseline associations between gluco- and neuro-regulatory peptides and plasma lipids, inflammatory cytokines and appetitive hormones related to neurogenesis, mood and energy balance. Post-study, independent of body weight or energy expended there were significant decreases in OGTT plasma insulin (p=0.002) and GLP-1 (p=0.060) and fasting triglycerides (p=0.029), ghrelin (p=0.008) and changes in most molecules including increased leptin and beta-endorphin. Correlations between changes among different classes of peptides were highly significant, notably leptin and adiponectin, and beta-endorphin and oxytocin and orexin A. We propose synergy between low-amount, low-intensity exercise at levels below thresholds of increased sympathetic tone, and baro-physiological effects of LBPP normalizing parasympathetic tone. Conclusion: Brief, low-dose, lower-body positive-pressure weight-supported treadmill exercise improved cardiometabolic fitness and exhibited favorable changes in neuro-regulatory peptides without weight loss in inner-city obese Black women.

Introduction Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.”

To the Editor: We read with great interest the article entitled “Using heart rate (HR) to prescribe physical exercise during head-out water immersion” (HOWI) by Kruel et al. (3). They studied HR effects of HOWI in 395 individuals and found HR to decrease with decrements related to water depth. Interestingly, HR lowering was correlated with baseline HR. The authors suggested that Karvonen's maximal HR prediction formula be modified for HOWI-induced HR lowering (predicted HRmax = 220 − age − ΔHR) to assess the intensity of HOWI exercise. Body weight support (WS) treadmill exercise also induces lower-body compression, intrathoracic blood pooling, and augmented venous return. Although originally developed to simulate microgravity conditions of aerospace, such systems have been used for orthopedic/neurologic patients and are now widely available to the general public (1). Weight support treadmills generally consist of a computerized treadmill equipped with a pressurized air chamber that generates a vertical upward force on the lower body that opposes the force of gravity to effectively decreasing body weight. Variable WS degrees can be achieved by adjusting lower-body positive pressure. Interestingly, waist and chest level HOWI equate to 54% and 35% of body WS (2). Accordingly, while resting HR reflects vagal tone, do the authors think that a HOWI-related HR decrease is a measure of vagal reserve? Also, could modifying Karvonen's formula be applicable to WS treadmill exercise? To date, we have prospectively studied 40 healthy males aged 30 ± 8 years. Baseline HR measurements (100% body weight) were recorded using telemetry monitoring after 2 minutes of standing on the WS treadmill, (AlterG Anti-Gravity Treadmill; Alter G, Fremont, CA, USA), and were repeated after 2 minutes of WS to 75, 50, and 25% of body weight, selected in random order (2). On repeated-measures analysis, WS decreased mean HR 81 to 71 b·min−1 progressively with increasing WS (p < 0.001). Changes in HR were correlated with baseline HR (r = 0.37–0.40, all p ≤ 0.02) at 75, 50 and 25% of body weight. We previously studied chest/waist HOWI effects in 21 subjects with results comparable to Kruel and recently reanalyzed our data (4). ΔHR was significantly correlated with baseline HR at chest/waist levels (both r = 0.68, p = 0.001). Therefore, HR decreases during WS seem similar to those of HOWI and are also related to resting HR at different body WS levels. Accordingly, if predicted HR responses are validated by direct measurement during HOWI exercises, then a modified Karvonen's formula may also apply to WS treadmill exercise.

ABSTRACTThis latest in our series of papers describes transgenerational methylation related to midchildhood food availability in 19th century Överkalix, Sweden. Failed vs. bountiful crops differentially influenced methylation in grandchildren of paternal grandparents exposed to feast or famine during their Slow Growth Period (SGP), a sensitive period preceding the pre-pubertal growth spurt. In this case-study of 8 tracked 75-year old progeny with differential ancestral exposure, we found, in 40 posited gene ontology pathways, 39 differentially methylated CpG regions (DMRs) related to famine, excess food and food-insecurity stress, 9 of which with DMRs above 5%. Three gene ontology terms (GOs) “insulin processing”, “adipose development” and “hypothalamus development” were key, with DMRs >14%. An unbiased test of known pathways revealed four nuclear transcription factors upstream of promotors repressing the pathway following paternal grandparental famine experience, as well as 4 upregulated GOs with average DMRs >20%. We conclude that this is the first demonstration of human transgenerational inheritance of epigenetic marks following ancestral childhood exposure to variable food availability inducing early developmental origins of adult disease.

OBJECTIVE:Data on the effects of eating behavior and genetics on outcomes of gastrointestinal surgery for diabesity have been sparse, often flawed, and controversial. We aimed to assess long-term outcomes of bariatric operations in patients characterized for eating behavior and rare mutations in the melanocortin-4 receptor (MC4R) gene, which is strongly implicated in energy balance.RESEARCH DESIGN AND METHODS:Between 1996 and 2005, 1,264 severely obese Swiss patients underwent current laparoscopic adjustable gastric banding, gastroduodenal bypass, or a hybrid operation. Of these, 872 patients were followed for a minimum of 6 years and were screened for MC4R mutations. Using regression models, we studied relationships between eating behavior and MC4R mutations and postoperative weight loss, complications, and reoperations after 6 years.RESULTS:At baseline, rare functional MC4R mutation carriers exhibited a significantly higher prevalence of binge eating disorder (BED) or loss-of-control eating independent of age, sex, and BMI. Six years after bariatric surgery, the mutation carriers had more major complications than wild-type subjects independent of age, baseline BMI, sex, operation type, and weight loss. Furthermore, high baseline BMI, male sex, BED, and functional MC4R mutations were independent predictors of higher reoperation rates.CONCLUSIONS:Sequencing of MC4R and eating typology, combined with stratification for sex and baseline BMI, might significantly improve patient allocation to banding or bypass operations for diabesity as well as reduce both complication and reoperation rates.

Leptin triggers signaling events with significant transcriptional responses that are essential to metabolic processes affecting obesity and glucose disposal. We asked whether hexamethylene bis-acetamide inducible-1 (Hexim1), an inhibitor of RNA II polymerase-dependent transcription elongation, regulates leptin-Janus kinase 2 signaling axis in the hypothalamus. We subjected C57BL6 Hexim1 heterozygous (HT) mice to high-fat diet and when compared with wild type, HT mice were resistant to high-fat diet-induced weight gain and remain insulin sensitive. HT mice exhibited increased leptin-pY(705)Stat3 signaling in the hypothalamus, with normal adipocyte size, increased type I oxidative muscle fiber density, and enhanced glucose transporter 4 expression. We also observed that normal Hexim1 protein level is required to facilitate the expression of CCAAT/enhancer-binding proteins (C/EBPs) required for adipogenesis and inducible suppressor of cytokine signaling 3 (SOCS) expression. Further support on the role of Hexim1 regulating C/EBPs during adipocyte differentiation was shown when HT 3T3L1 fibroblasts failed to undergo adipogenesis. Hexim1 selectively modulates leptin-mediated signal transduction pathways in the hypothalamus, the expression of C/EBPs and peroxisome proliferator-activated receptor-γ (PPAR γ) in skeletal muscle and adipose tissue during the adaptation to metabolic stress. We postulate that Hexim1 might be a novel factor involved in maintaining whole-body energy balance.

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Many neurological and psychiatric disorders with predominantly cerebral cortical pathology, including most severe strokes, traumatic brain injuries, malignant brain tumors, intractable focal epilepsies and dementias such as Alzheimer’s disease are currently difficult, if not impossible, to treat. This causes suffering in almost 100 million people worldwide. We propose that bioengineered cranial bones with multiple intelligent functions, including sitespecific transmeningeal drug delivery and neurotoxin drainage with EEG feedback, can provide effective treatment of these brain disorders by drug combinations that act on both synapses and genes with concomitant selective drainage of harmful extracellular molecules. After examining and summarizing the rationale and feasibility of this proposal, we suggest novel methods for extending the functions of the involved components including synergies with existing devices and we highlight relevant preclinical results, discussing medical prospects of this novel neurotherapeutic approach. Finally, we discuss key engineering, scientific, clinical and ethical challenges to introducing bioengineered cranial bones with multiple intelligent functions to the clinic within a decade.

Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A(∗)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.

Scopo di questo lavoro è studiare gli effetti di una struttura ergono-mica a vibrazione multifocale (MFV) sul sistema neuromuscolare e posturale in soggetti sani.30 volontari (16 maschi e 14 femmine, di età compresa tra 19 e 25 anni) sono stati sottoposti all'esame elettromiografico (EMG) e stabilometrico prima della seduta di risonanza propriocettiva globale mediante vibrazioni multifocali, ripetendo gli stessi esami subito dopo la MFV.Gli effetti della MFV sull'elettromiografia di superficie dei muscoli masseteri e temporali anteriori hanno evidenziato cambiamenti statisticamente significativi nei muscoli masseteri (p < 0,05). Effetti significativi sono stati evidenziati anche nei test posturali e stabilometrici (p < 0,05).La vibrazione multifocale ha indotto modificazioni sia nei test neuromuscolari sia nei test posturali.The purpose of this study was to investigate the effects of an ergo-nomic structure using multi focal vibrations (MFV) on muscle performance and body balance in healthy subjects.30 volunteers (16 males and 14 females, aged 19-25 years) underwent, in a randomized order, both electromyography (EMG) and stabilometry before being subjected to global proprioceptive MFV resonance and immediately after it.The effects of MFV on the surface EMG of masseter and anterior temporalis muscles induced statistically ignificant changes in masseter muscles (p < 0.05). Similar effects were recorded by postural and stabilometric tests (p < 0.05).MFV induced changes in both neuromuscular and postural tests.

This study investigated the possible influence of the Subdural Pharmacotherapy Device (SPD) on spatial memory in 3 adult, male bonnet macaques (Macaca radiata). The device was implanted in and above the subdural/subarachnoid space and cranium overlaying the right parietal/frontal cortex: a circuitry involved in spatial memory processing. A large test chamber, equipped with four baited and four non-baited food-ports at different locations, was used: reaches into empty food ports were counted as spatial memory errors. In this study of within-subject design, before SPD implantation (control) the animals made mean 373.3 ± 114.9 (mean ± SEM) errors in the first spatial memory test session. This value dropped to 47.7 ± 18.4 by the 8th session. After SPD implantation and alternating cycles of transmeningeal saline delivery and local cerebrospinal fluid (CSF) drainage in the implanted cortex the spatial memory error count, with the same port locations, was 33.0 ± 12.2 during the first spatial memory test session, further decreasing to 5.7 ± 3.5 by the 8th post-implantation session (P<0.001 for trend). Replacing transmeningeal saline delivery with similar delivery of the GABAA receptor agonist muscimol (1.0mM) by the SPD did not affect the animals' spatial memory performance, which in fact included at least one completely error-free session per animal over time. The study showed that complication-free implantation and use of the SPD over the parietal and frontal cortices for months leave spatial memory processes intact in nonhuman primates.

Maternal obesity and excess gestational weight gain with compromised metabolic fitness predispose offspring to lifelong obesity and its comorbidities. We demonstrated that compared to offspring born before maternal gastrointestinal bypass surgery (BMS) those born after (AMS) were less obese, with less cardiometabolic risk reflected in the expression and methylation of diabetes, immune and inflammatory pathway genes. Here we examine relationships between gestational obesity and offspring gene variations on expression levels. Methods Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. Results Significant interactions (p ≤ 1.22x10-12) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. Conclusion We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.