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Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential methylation analysis between a sibling cohort of 25 BMS and 25 AMS (2-25 y-old) offspring from 20 mothers was conducted to identify biological functions and pathways potentially involved in the improved cardiometabolic profile found in AMS compared with BMS offspring. Links between gene methylation and expression levels were assessed by correlating genomic findings with plasma markers of insulin resistance (fasting insulin and homeostatic model of insulin resistance). A total of 5,698 genes were differentially methylated between BMS and AMS siblings, exhibiting a preponderance of glucoregulatory, inflammatory, and vascular disease genes. Statistically significant correlations between gene methylation levels and gene expression and plasma markers of insulin resistance were consistent with metabolic improvements in AMS offspring, reflected in genes involved in diabetes-related cardiometabolic pathways. This unique clinical study demonstrates that effective treatment of a maternal phenotype is durably detectable in the methylome and transcriptome of subsequent offspring.

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. 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. 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). 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.

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. 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. 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. 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.\"

Early-Life Stress and the Development of Obesity and Insulin Resistance in Juvenile Bonnet Macaques Daniel Kaufman 1 2 , Mary Ann Banerji 2 3 , Igor Shorman 1 2 , Eric L.P. Smith 2 4 , Jeremy D. Coplan 2 4 , Leonard A. Rosenblum 2 4 and John G. Kral 1 2 1 Department of Surgery, State University of New York Downstate Medical Center, Brooklyn, New York 2 Primate Behavior Laboratory, State University of New York Downstate Medical Center, Brooklyn, New York 3 Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 4 Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, New York Address correspondence and reprint requests to John G. Kral, MD, PhD, Department of Surgery, Box 40, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. E-mail: jkral{at}downstate.edu Abstract Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance. CRF, corticotrophin-releasing factor CRL, crown-rump length csf, cerebrospinal fluid GLP-1, glucagon-like peptide-1 HFD, high foraging demand HOMA, homeostasis model assessment HPA, hypothalamo-pituitary-adrenal IGR, insulin-to-glucose ratio LFD, low foraging demand TG, triglyceride VFD, variable foraging demand Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 18, 2006. Received October 5, 2006. DIABETES

About the Authors: David Meyre * E-mail: meyred@mcmaster.ca Affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Philippe Froguel Affiliations Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8199, Lille Pasteur Institute, Lille, Nord, France, Department of Genomics of Common Disease, Imperial College London, London, United Kingdom Fritz F. Horber Affiliations Department of Internal Medicine, Landesspital, Vaduz, Liechtenstein, University of Berne, Berne, Switzerland John G. Kral Affiliation: Department of Surgery, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America Citation: Meyre D, Froguel P, Horber FF, Kral JG (2014) Comment On: Valette et al. The authors failed to describe any quality control procedures to ensure the integrity of their genotyping such as: call rate, Hardy-Weinberg equilibrium test, double-genotyping concordance rate and comparison of the MAF with published databases in comparable ethnic groups [5].The very significant departure of the genotypic distribution of the variant rs17782313 described by Valette et al from Hardy-Weinberg equilibrium (P<10−20) suggests an error in technique. [...]the stated purpose of the paper was to evaluate surgical weight loss in patients with MC4R mutations and polymorphisms.

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. Significant interactions (p ≤ 1.22 x 10(-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. 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.

Background Biliopancreatic diversion (BPD) is a complex bariatric operation requiring meticulous surveillance which has impeded its broad adoption. Improvements in surgical care and technique, better teaching programs, and stringent norms for follow-up have contributed to increased safety of BPD for patients with BMI <50, achieving better long-term results than other bariatric operations. Here we report 20-year outcomes of 2615 consecutive patients (median 8) having open BPD with duodenal switch (DS) between 1992 and 2010. Methods Chart of 92 % of patients with complete clinical, biochemical, and physical examinations completed before 2013 was reviewed. The research was conducted at Academic Medical Center, Quebec City. Results There was total mortality of 4.7 %, equivalent to that of the general population of Quebec. Incident diabetes (38.8 %) was cured in 93.4 % (blood glucose <6 mmol/l; HbA1c <6.5 %) with 4 % relapse rate after mean 9.6 years with no new cases. Dyslipidemia (24.2 %) was cured in 80 %. Hypertension (60 %) was cured in 64 % and improved in 31 %. Mean weight loss of 55.3 kg (71 % excess weight loss (EWL); 20 BMI units) was maintained for 5 to 20 years. Operative mortality was reduced from 1.3 % in 1992 to 0.2 % during 2005–2010, with cumulated rate surgical mortality of 0.5, revision rate 3, and reoperations in 13 %. Nutritional deficiencies were present in 2 % for calcium, iron, and vitamin A. Side effects were considered minor by the great majority of patients, rating global satisfaction as 4.5/5 (91 % “satisfied”). Conclusions BPD deserves more consideration as a primary procedure for eligible patients in experienced centers with sufficient resources for delivering high-quality care and long-term follow-up.

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.

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

Obesity surgery is an effective means of achieving and maintaining weight loss, curing or improving otherwise chronic, serious comorbidities and reducing mortality. This article describes evolving aspects of patient selection and various surgical options; it also details outcomes and many of the neurogastrointestinal mechanisms of surgery affecting appetite regulation. Obesity is very prevalent. Most treatments fail owing to hard-wired survival mechanisms, linking stress and appetite, which have become grossly maladaptive in the industrial era. Antiobesity (bariatric) surgery is a seemingly drastic, efficacious therapy for this serious disease of energy surfeit. Technical progress during the last two decades has greatly improved its safety. The surgical principles of gastric restriction and/or gastrointestinal diversion have remained largely unchanged over 40 years, although mechanisms of action have been elucidated concomitant with advances in knowledge of the molecular biology of energy balance and appetite regulation. Results of bariatric surgery in large case-series followed for at least 10 years consistently demonstrate amelioration of components of the insulin-resistance metabolic syndrome and other comorbidities, significantly improving quality of life. Furthermore, bariatric surgery has convincingly been demonstrated to reduce mortality compared with nonoperative methods. This surgery requires substantial preoperative and postoperative evaluation, teaching, and monitoring to optimize outcomes. In the absence of effective societal changes to restore a healthy energy balance, bariatric surgery is an important tool for treating a very serious disease. Key Points Bariatric surgery is safe; complications are fewer after restrictive procedures but weight loss and comorbidity reduction are greater after diversionary procedures Most obesity comorbidity is durably (>10 years) ameliorated after surgery and mortality is less than after nonsurgical care After bariatric surgery most patients do not reach 'normal' weight; however, the weight loss induced by surgery is sufficient to improve morbidity and mortality A dedicated, comprehensive team is needed to assess, educate and manage the patient before and after surgery