Relationships Between Telomere Length, Plasma Glucagon-like Peptide 1, and Insulin in Early-Life Stress-Exposed Nonhuman Primates.

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.

Gestational diabetes status and dietary intake modify maternal and cord blood allostatic load markers.

INTRODUCTION: Allostatic load (AL) defines cardiometabolic, inflammatory, and neuroendocrine changes in the body in response to internal and external stressors. It is largely unknown whether gestational diabetes mellitus (GDM) alters maternal and fetal AL, which in turn affects GDM outcomes. Whether dietary intakes and quality can modify AL and thus influence GDM progression is also unknown. RESEARCH DESIGN AND METHODS: In this study, we recruited 35 GDM and 30 non-GDM women in gestational week 25-33. Fasting blood samples were collected at enrollment, and cord venous blood samples were collected at delivery for the measurement of a series of AL biomarkers to calculate the composite AL index. Three-day dietary recalls were conducted at enrollment. RESULTS: Results suggest that GDM women had 60% higher composite AL index scores (p value=0.01). Maternal AL index was associated with shorter duration of gestation (ß=-0.33, p value=0.047) and higher fetal AL index (ß=0.47, p value=0.006) after adjusting for GDM status. Dietary intake of monounsaturated fatty acids was negatively associated with maternal AL index (ß=-0.20, p value=0.006). GDM women had lower total caloric intake and dietary glycemic load, yet their linolenic acid, vitamin C and E intakes were also decreased (all p value<0.05). These dietary differences were not related to birth outcomes measured. CONCLUSIONS: In this study, GDM status and dietary intakes modify AL in this population. AL may serve as an indicator of GDM control. Future research on dietary interventions that can improve maternal AL markers during GDM is warranted.

A pilot study of metabolic fitness effects of weight-supported walking in women with obesity.

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, ß-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.

The Effect of Lower Body Positive Pressure on Left Ventricular Ejection Duration in Patients With Heart Failure.

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 (r 2 = 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.

Reduced left ventricular dimension and function following early life stress: A thrifty phenotype hypothesis engendering risk for mood and anxiety disorders.

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.

Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis".

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."

Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.

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.

Eating Behavior, Low-Frequency Functional Mutations in the Melanocortin-4 Receptor (MC4R) Gene, and Outcomes of Bariatric Operations: A 6-Year Prospective Study.

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.

Hexim1, a Novel Regulator of Leptin Function, Modulates Obesity and Glucose Disposal.

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.