Long-term Changes In Body Weight Research Articles

DNA Methylation at ABCG1 and Long-term Changes in Adiposity and Fat Distribution in Response to Dietary Interventions: The POUNDS Lost Trial.

To examine whether participants with different levels of diabetes-related DNA methylation at ABCG1 might respond differently to dietary weight loss interventions with long-term changes in adiposity and body fat distribution. The current study included overweight/obese participants from the POUNDS Lost trial. Blood levels of regional DNA methylation at ABCG1 were profiled by high-resolution methylC-capture sequencing at baseline among 673 participants, of whom 598 were followed up at 6 months and 543 at 2 years. Two-year changes in adiposity and computed tomography-measured body fat distribution were calculated. Regional DNA methylation at ABCG1 showed significantly different associations with long-term changes in body weight and waist circumference at 6 months and 2 years in dietary interventions varying in protein intake (interaction P < 0.05 for all). Among participants assigned to an average-protein (15%) diet, lower baseline regional DNA methylation at ABCG1 was associated with greater reductions in body weight and waist circumference at 6 months and 2 years, whereas opposite associations were found among those assigned to a high-protein (25%) diet. Similar interaction patterns were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (interaction P < 0.05 for all). Baseline DNA methylation at ABCG1 interacted with dietary protein intake on long-term decreases in adiposity and body fat distribution. Participants with lower methylation at ABCG1 benefitted more in long-term reductions in body weight, waist circumference, and body fat distribution when consuming an average-protein diet.

Abstract 65: DNA Methylation at ABCG1 and Long-Term Changes in Adiposity in Response to Diet Interventions: The POUNDS Lost Trial

Introduction: Epigenome-wide association studies identified that DNA methylation (DNAm) at the ABCG1 gene (cg06500161) was associated with obesity. However, little is known about whether DNAm at ABCG1 is associated with long-term changes in adiposity and body fat distribution in response to dietary weight-loss interventions. Hypothesis: We hypothesized that participants with varying DNAm at ABCG1 might respond differently to dietary weight-loss interventions on long-term changes in adiposity and body fat distribution. Methods: The current study included 673 participants with overweight/obesity, who were randomly assigned to 1 of 4 diets varying in macronutrient components. Blood DNAm level was profiled by a high-resolution methylC-capture sequencing at baseline. The regional DNAm at ABCG1 was defined as the average methylation level over CpGs within ± 250 bp of cg06500161. Two-year changes in adiposity and Computed Tomography (CT)-measured body fat distribution were calculated. Results: We found that regional DNAm at ABCG1 significantly interacted with dietary protein intake on long-term changes in body weight and waist circumference (WC) at 6 months and 2 years (P-interaction&lt;0.05 for all, Figure ). Among participants assigned to an average-protein (15%) diet, lower regional DNAm at ABCG1 was associated with greater reductions in body weight and WC at 6 months and 2 years, while opposite associations were found among those assigned to a high-protein (25%) diet. Similar interactions were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (P-interaction&lt;0.05 for all). Conclusion: Our data indicate that DNAm at ABCG1 interacted with dietary protein intake on long-term changes in adiposity and body fat distribution. Participants with hypomethylation at ABCG1 benefited more in long-term improvement in adiposity and body fat distribution by consuming an average-protein diet.

Long-term changes in body weight and serum cholesterol in heart transplant recipients.

Long-term changes in weight and blood lipids beyond 12 months after heart transplantation are largely unknown. We quantified changes in weight, body mass index (BMI), blood cholesterol, and triglycerides in heart transplant recipients (HTRs) during the 36 months after transplantation, and we assessed the influence of statin therapy on these outcomes. Retrospective cohort study of adult HTRs, transplanted 1990-2017, in Queensland, Australia. From each patient's medical charts, we extracted weight, total cholesterol, triglycerides, and statin therapy at four time-points: time of transplant (baseline), and 12-, 24-, 36-month post-transplant. Changes in weight and blood lipids were assessed according to baseline BMI. Among 316 HTRs, 236 (median age 52 years, 83% males) with available information were included. During the 36 months post-transplant, all patients gained weight (83.5-90.5kg; p<.001), especially those with baseline BMI<25.0km/m2 (67.9-76.2kg; p<.001). Mean blood cholesterol (4.60-4.90mmol/L; p=.004) and mean blood triglycerides (1.79-2.18mmol/L; p=.006) also increased significantly in all patients, particularly in those with baseline BMI ≥ 25.0km/m2 but the differences were not significant (total cholesterol 4.42-5.13mmol/L; triglycerides 1.76-2.47mmol/L). Total cholesterol was highest in patients not taking statins, and levels differed significantly (p=.010) according to statin dosing changes during the 36 months post-transplant. Patients demonstrate significant rises in weight and blood lipids in the 36 months after heart transplantation.

Long-term body weight change assessed by non-contact load cells under the bed in older people with and without eating assistance: a preliminary study

Utilizing automatic daily body weight (BW) measurements may be helpful for assessing nutritional status and detecting underlying diseases particularly in older people who require nursing care. This preliminary study aimed to verify effectiveness of eating assistance for maintaining BW in older people using a contact-free load cells under the bed (Bed Sensor System: BSS). BW was measured every night for 3 months in eight nursing home older people with severe cognitive and physical dysfunctions. Body composition of the subject's trunk and each limb was measured using a segmented multi-frequency bioelectrical impedance analyzer (BIA). A monthly BW loss was estimated as a slope of linear regression of the daily BW plot. BSS successfully measured daily BW for the study period in all participants. The 4 residents with eating assistance gained slightly more weight, while the 4 residents without eating assistance lost weight. There was a significant difference between the two groups in the monthly BW change (− 0.79 ± 0.51 kg/month versus 0.20 ± 0.49 kg/month, P = 0.030). None of the BIA-derived parameters was associated with the monthly BW change. BSS revealed effectiveness of eating assistance to maintain BW in nursing home residents with severe cognitive and physical dysfunctions.

FC 116WEIGHT CHANGE AS A PREDICTOR OF MORTALITY IN CHRONIC HEMODIALYSIS PATIENTS

Abstract Background and Aims Serial decrease in body weight can be a prognostic marker reflecting Protein Energy Wasting (PEW) condition in haemodialysis patients. However, the impact of longitudinal body weight changes on mortality have rarely been evaluated. Therefore, we applied landmark analysis and time-scale mixed regression analyses to clarify the impact of long-term changes in body weight on all-cause mortality. Method This study is a post-hoc analysis of the participants in the Olmesartan Clinical Trial in Okinawan Patients Under OKIDS (OCTOPUS) conducted between June 2006 and June 2011. We additionally followed up with the participants until 31 July, 2018. During the OCTOPUS trial, the body weight of surviving participants was repeatedly measured every 6 months. The primary aim of the study was to clarify the association of serial change in body weights and all-cause mortality. The participants were categorized into 4 groups based on weight change slope during the first 2 years (bottom to highest group correspond with the first quartile to the fourth quartile group). We conducted a landmark analysis to evaluate the influence of weight change slope on the subsequent survival with Cox-proportional hazard regression. We also conducted time-scale multilevel regression analyses to draw marginal plots of body weight with a backward time scale to describe the difference in trajectories of body weight between deceased and surviving patients. Results Out of 461 patients in the cohort, 404 participants were analysed in the landmark analysis. Of the participants, 168 (41.6%) were deceased, and 236 participants (58.4%) survived. Although baseline body weights and indices about body components such as a creatinine index were similar among the 4 groups, multivariate Cox-proportional hazard regression showed that the higher rate of body weight loss was associated with higher mortality. Hazard ratios were 2.02 (1.28–3.20), 1.77 (1.10–2.85), 1.00 (Reference), and 1.11 (0.67–1.83) for first quartile, second quartile, third quartile (Reference), and fourth quartile group, respectively (P for trend was &amp;lt;0.001). The association was also described using Kaplan-Meier plots, with the P-value of general Log-rank test being 0.015 (Fig 1a). Marginal plots drawn with a multivariate adjusted time-scale multilevel regression model, which included all 461 participants, with a backward time-scale, showed that body weight constantly decreased in deceased patients, while body weight was longitudinally stable in surviving patients (Fig 1b). These trends of weight change have been soundly observed in sensitivity analyses. Conclusion In chronic haemodialysis patients, the higher rate of body weight loss, such as a decrease in body weight by 1 kg (1.7%) per 6 months, was significantly associated with higher mortality. Persistent loss of body weight is a significant predictor of death among chronic dialysis patients.

Diet Quality and Lower Refined Grain Consumption are Associated With Less Weight Gain in a Multi-Ethnic Asian Adult Population.

The prevalence of obesity is increasing in many Asian countries. However, longitudinal data on the impacts of dietary factors on weight gain in Asian populations are sparse. We evaluated the relationship between changes in intakes of nutrients, foods, and beverages and diet quality and long-term changes in body weight. We used data (n= 3064) from the Singapore Multi-Ethnic Cohort, a prospective cohort including Chinese, Indian, and Malay residents aged 21-65 years. Dietary intakes were assessed using an FFQ, and body weight and waist circumference were measured during health examinations. Diet quality was evaluated using the Dietary Approaches to Stop Hypertension (DASH) and Alternative Healthy Eating Index (AHEI-2010) scores. Data were collected at baseline (2004-2010) and follow-up (2011-2016), with a mean follow-up of 6.0 years. Linear regression was used to assess the associations between dietary changes and weight change, adjusted for socio-demographic and lifestyle variables. Improvements in dietary quality scores (DASH, -0.34kg per 5 points; AHEI-2010, -0.35kg per 10 points) and replacement of carbohydrates with protein (-0.44kg per 5% of energy) were significantly associated with less weight gain. Increased intakes of white rice (+0.25kg per serving/d), soft drinks (+0.69kg), red meat (+0.58kg), and poultry with skin (+0.74kg) were directly associated with weight gain. The replacement of 1 serving per day of white rice with whole grains (-0.68kg), vegetables (-0.33kg), poultry without skin (-0.79kg), and eggs (-0.87kg) was associated with less weight gain. Similar associations were observed between changes in dietary factors and changes in waist circumference. Among Asian adults, increasing dietary quality, reducing soft drink consumption, and replacing white rice with whole grains, vegetables, and selected high-protein foods was associated with less weight gain.

Changes in Body Weight and Serum Albumin Levels in Patients Requiring Home Long-term Oxygen Therapy.

Purpose: To investigate the long-term changes in body weight and serum albumin levels in patients with respiratory failure, and those with chronic heart failure, who were treated with home long-term oxygen therapy (LTOT) to understand the current status and contribute to future measures.Methods: Patients with chronic obstructive pulmonary disease (COPD), those with interstitial pneumonia (IP), and those with chronic heart failure (CHF) undergoing home LTOT for 6 months or more between January 2011 and January 2019 were included in the study. Body weight and serum albumin levels were assessed at the start of home LTOT and at the end of the observation period, a minimum of 6 months after commencing home LTOT.Results: Sixty-two patients (29 COPDs, 23 IPs, and 10 CHFs) were included. In COPD patients and IP patients, body weight decreased (P = 0.0017, P = 0.0018, respectively, Wilcoxon signed-rank test). Serum albumin levels decreased in IP patients (P = 0.0185) but not in COPD patients. There was neither significant decrease in body weight nor serum albumin levels in patients with CHF.Conclusion: Chronic respiratory failure patients who have home LTOT were likely to have a decreased nutritional status. In order to provide prolonged home LTOT, medical staff need to pay close attention to the nutritional status of patients receiving home LTOT.

Longitudinal Changes in Food Addiction Symptoms and Body Weight among Adults in a Behavioral Weight-Loss Program.

Interest in food addiction (FA) has increased, but little is known about its clinical implications or potential treatments. Using secondary analyses from a randomized controlled trial, we evaluated the associations between changes in FA, body weight, and “problem food” consumption during a 22-month behavioral weight-loss program consisting of an initial four-month in-person intervention, 12-month extended-care, and six-month follow-up (n = 182). Food addiction was measured using the Yale Food Addiction Scale. “Problem foods” were identified from the literature and self-reporting. Multilevel modeling was used as the primary method of analysis. We hypothesized that reductions in problem food consumption during the initial treatment phase would be associated with long-term (22-month) FA reductions. As expected, we found that reductions in problem foods were associated with greater initial reductions in FA symptoms; however, they were also associated with a sharper rebound in symptoms over time (p = 0.016), resulting in no significant difference at Month 22 (p = 0.856). Next, we hypothesized that long-term changes in FA would be associated with long-term changes in body weight. Although both FA and weight decreased over time (ps < 0.05), month-to-month changes in FA were not associated with month-to-month changes in weight (p = 0.706). Instead, higher overall FA (i.e., mean scores over the course of the study) were associated with less weight loss (p = 0.008) over time. Finally, we hypothesized that initial reductions in problem food consumption would be associated with long-term reductions in weight, but this relationship was not significant (ps > 0.05). Given the complexity of the findings, more research is needed to identify interventions for long-term changes in FA and to elucidate the associations between problem foods, FA, and weight.

Does Colectomy Improve Type 2 Diabetes?

Gastrectomy and gastric bypass improve type 2 diabetes (T2DM), potentially through alterations in intestinal hormones and the microbiome. The aim of this study was to analyze whether colorectal resections result in improvement of T2DM. A total of 171 patients with T2DM who underwent colectomy for benign diseases were studied with a median postoperative follow-up of 3years (interquartile range [IQR] 1-5). The median BMI and glycated hemoglobin (HbA1c) at baseline and post-colectomy were 30.3kg/m2 (IQR 26.6-34.6) versus 30.4kg/m2 (IQR 26.2-35) (p = 0.1), and 6.7% (IQR 6.2-7.5) versus 6.5% (IQR 6.5-7.1) (p = 0.5), respectively. The proportion of patients taking diabetes medications at baseline versus post-colectomy did not differ significantly. Changes in BMI, HbA1c, and status of diabetes medications were not statistically different between the subtypes of colorectal resection. Our experience suggests that colectomy for benign colorectal diseases is not associated with long-term changes in body weight or glycemic control.

Adipose lipid turnover and long-term changes in body weight.

The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.

Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance

Synthesis of triiodothyronine (T3) in the hypothalamus induces marked seasonal neuromorphology changes across taxa. How species-specific responses to T3 signaling in the CNS drive annual changes in body weight and energy balance remains uncharacterized. These experiments sequenced and annotated the Siberian hamster (Phodopus sungorus) genome, a model organism for seasonal physiology research, to facilitate the dissection of T3-dependent molecular mechanisms that govern predictable, robust, and long-term changes in body weight. Examination of the Phodopus genome, in combination with transcriptome sequencing of the hamster diencephalon under winter and summer conditions, and in vivo-targeted expression analyses confirmed that proopiomelanocortin (pomc) is a primary genomic target for the long-term T3-dependent regulation of body weight. Further in silico analyses of pomc promoter sequences revealed that thyroid hormone receptor 1β-binding motif insertions have evolved in several genera of the Cricetidae family of rodents. Finally, experimental manipulation of food availability confirmed that hypothalamic pomc mRNA expression is dependent on longer-term photoperiod cues and is unresponsive to acute, short-term food availability. These observations suggest that species-specific responses to hypothalamic T3, driven in part by the receptor-binding motif insertions in some cricetid genomes, contribute critically to the long-term regulation of energy balance and the underlying physiological and behavioral adaptations associated with the seasonal organization of behavior.

Prospective analyses of white adipose tissue gene expression in relation to long-term body weight changes.

Transcriptome analysis of abdominal subcutaneous white adipose tissue (sWAT) has identified important obesity-associated disturbances. However, the relation between sWAT transcriptome and long-term future changes in body weight remains elusive. To investigate sWAT transcriptome signatures before and after long-term weight changes and assess their predictive value for body weight changes. A total of 56 women were followed longitudinally and subdivided into weight-stable (WS, n = 25), weight-gaining (WG, n = 14) and weight-losing (WL, n = 17) groups between baseline and follow-up (13 ± 1 years). The fasting sWAT transcriptome was analyzed by gene microarray at baseline and follow-up. Key genes associated with weight changes were validated using quantitative real-time PCR. In total 285 transcripts exhibited difference (FDR < 30%) in expression fold change over time between WL and WS women. WL women displayed decreased pro-inflammatory (NLRP3) but increased insulin-response gene (FASN and GLUT4) expression over time. In comparison, 461 transcripts displayed difference in expression fold change over time between WG and WS women (P < 0.05). Genes involved in autophagic processes (CDK5, SQSTM1 and FBXL2) were generally upregulated in WG women. At baseline, 307 and 302 transcripts were differentially expressed (FDR < 30%) in WL and WG women, respectively, when independently compared against WS women. Baseline expression of adipogenic and lipogenic genes (PPARG, IRS2 and HACD2) was lower, while pro-fibrotic (COL6A1) was higher, in WL than WS women; whereas protein processing genes were lower expressed in WG than in WS women. In adult women, long-term body weight change associates with altered sWAT transcriptome. Expression of genes associated with inflammation, insulin response, adipogenesis and lipogenesis are linked to weight loss. However, other pathways such as autophagy not only associate but also predict future weight gain suggesting that intrinsic factors in sWAT impact tissue expansion.

Long-term changes in body weight and physical activity in relation to all-cause and cardiovascular mortality: the HUNT study

BackgroundMost previous studies have relied on single measurements of body weight and physical activity and have not considered the interplay between long-term changes in body weight and physical activity in relation to mortality. The aim of the current study was therefore to examine the joint effect of changes in body weight and leisure-time physical activity over a period of ~ 10 years on all-cause and cardiovascular mortality.MethodsThe study population comprised 34,257 individuals who participated in the first (1984–86) and second (1995–97) waves of the HUNT Study, and were followed up through the Norwegian Cause of Death Registry until December 31st, 2013. We used Cox regression to estimate hazard ratios (HR) with 95% confidence intervals (CI) of death associated with changes in body weight and leisure-time physical activity.ResultsCompared to the reference group with stable weight who were long-term physically active, people who gained ≥5% of their weight had a HR for all-cause mortality of 1.54 (95% CI: 1.28–1.85) if they were long-term physically inactive; a HR of 1.23 (1.09–1.40) if they became physically active, and a HR of 1.00 (95% CI 0.94–1.06) if they were long-term physically active. The corresponding HRs for cardiovascular mortality were 1.57 (95% CI 1.17–2.12), 1.28 (95% CI 1.04–1.58) and 1.06 (95% CI 0.96–1.16), respectively. Long-term physical inactivity was associated with increased all-cause (HR 1.29; 95% CI 1.08–1.53) and cardiovascular (HR 1.37; 95% CI 1.05–1.79) mortality among those who were weight stable.ConclusionsThe risk of all-cause and cardiovascular mortality is particularly evident among people who gain weight while remaining inactive during a ~ 10 year period. However, participants who remained physically active had the lowest risk of premature mortality, regardless of maintenance or increase in weight. These findings suggest that there is an interplay between long-term changes in body weight and physical activity that should receive particular attention in the prevention of premature mortality.

Design of the Rural LEAP randomized trial: An evaluation of extended-care programs for weight management delivered via group or individual telephone counseling

Obesity is a major contributor to the greater prevalence of chronic disease morbidity and mortality observed in rural versus nonrural areas of the U.S. Nonetheless, little research attention has been given to modifying this important driver of rural/urban disparities in health outcomes. Although lifestyle treatments produce weight reductions of sufficient magnitude to improve health, the existing research is limited with respect to the long-term maintenance of treatment effects and the dissemination of services to underserved populations. Recent studies have demonstrated the feasibility of delivering lifestyle programs through the infrastructure of the U.S. Cooperative Extension Service (CES), which has >2900 offices nationwide and whose mission includes nutrition education and health promotion. In addition, several randomized trials have shown that supplementing lifestyle treatment with extended-care programs consisting of either face-to-face sessions or individual telephone counseling can improve the maintenance of weight loss. However, both options entail relatively high costs that inhibit adoption in rural communities. The delivery of extended care via group-based telephone intervention may represent a promising, cost-effective alternative that is well suited to rural residents who tend to be isolated, have heightened concerns about privacy, and report lower quality of life. The Rural Lifestyle Eating and Activity Program (Rural LEAP) is a randomized trial, conducted via CES offices in rural communities, targeted to adults with obesity (n = 528), and designed to evaluate the effectiveness and cost-effectiveness of extended-care programs delivered via group or individual telephone counseling compared to an education control condition on long-term changes in body weight.

Plasma ANGPTL-4 is Associated with Obesity and Glucose Tolerance: Cross-Sectional and Longitudinal Findings.

Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL-4 levels in obesity, T2D, and after changes in body weight. Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow-up 2 years later. ANGPTL-4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow-up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes.

Mediterranean and Nordic diet scores and long-term changes in body weight and waist circumference: results from a large cohort study.

Dietary patterns, which represent a broader picture of food and nutrient consumption, have gained increasing interest over the last decades. In a cohort design, we followed 27 544 women aged 29-49 years from baseline in 1991-1992. We collected data from an FFQ at baseline and body weight (BW) and waist circumference (WC) data both at baseline and at follow-up in 2003. We calculated the Mediterranean diet score (MDS, ranging from 0 to 9) and the Nordic diet score (NDS, ranging from 0 to 6). We used linear regression to examine the association between MDS and NDS (exposures) with subsequent BW change (ΔBW) and WC change (ΔWC) (outcomes) both continuously and categorically. Higher adherence to the MDS or NDS was not associated with ΔBW. The multivariable population average increment in BW was 0·03 kg (95 % CI -0·03, 0·09) per 1-point increase in MDS and 0·04 kg (95 % CI -0·02, 0·10) per 1-point increase in NDS. In addition, higher adherence to the MDS was not associated with ΔWC, with the multivariable population average increment per 1-point increase in MDS being 0·05 cm (95 % CI -0·03, 0·13). Higher adherence to the NDS was not significantly associated with gain in WC when adjusted for concurrent ΔBW. In conclusion, a higher adherence to the MDS or NDS was not associated with changes in average BW or WC in the present cohort followed for 12 years.

267. Image-Guided, Liver-Targeted Hydrodynamic Gene Delivery in Dogs – Preclinical Assessment of Effectiveness and Safety of the Procedure

Image-guided, liver-targeted hydrodynamic gene delivery was evaluated in dogs to assess the safety and effectiveness of the procedure for human clinical trial. The procedure involves image-guided catheter insertion to hepatic veins in the dogs followed by computer-controlled hydrodynamic gene delivery using newly developed injector for clinical use. Optimum parameters for the procedure, including the location of the balloon catheter in the hepatic vein, intravascular pressure upon injection, injection volume, and sequential injections to multiple lobes of the injected liver, were employed as previously we reported. Hydrodynamic injection of human factor IX expressing plasmid (pBS-hFIX) was performed in 7 dogs (female, 20 kg) and short- and long-term effects of the procedure were assessed. We demonstrate that plasma level of human factor IX and coagulation activity in dogs increased from the background level at ~20 ng/ml and ~8% to 21768.1 ng/ml and 36.8%, respectively in 1 week after hydrodynamic gene delivery and sustained for 4 weeks. Transgene expression in the hepatocytes was also confirmed by immunohistochemical stainings. For safety assessment, we demonstrated that the impacts of image-guided liver-targeted hydrodynamic gene delivery are localized in the site of injection in the liver. Histological analysis showed significant expansion of sinusoids at the injected site to 190% of their original size. Hepatic microcirculation analysis of liver-targeted hydrodynamic injection using reflectance spectrophotometry showed significant decrease of the oxygen saturation of the Hb in the blood of the injected lobe from 30 to 0 unit upon the injection and recovered smoothly after the injection. Serum analysis showed a transient, 10- to 20-fold increase in hepatobiliary enzymes, including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase after hydrodynamic injections, which recovered within 4 days. We also explored for the first time, the levels of the cytokines following the hydrodynamic injections to the large animals. There was no increase in the systemic inflammatory cytokines of IFN-γ, IL-8, IL-18, and IL-4, although an increase in serum levels of TNF-α, IL-10, MCP-1, canine KC, and IL-6, which were related to vascular stretching representing the sinusoidal expansion was observed. No impacts on their respiratory, cardiovascular conditions, or long-term body weight changes were observed throughout the study. These results of preclinical assessments support the clinical applications of image-guided, liver-targeted hydrodynamic gene delivery.This work was supported in part by NIH grants RO1EB002946 and RO1HL075542, and by Japanese Society for the Promotion of Science Grants 22890064, 23790595, and 26860354.

Multi-omic signature of body weight change: results from a population-based cohort study.

BackgroundExcess body weight is a major risk factor for cardiometabolic diseases. The complex molecular mechanisms of body weight change-induced metabolic perturbations are not fully understood. Specifically, in-depth molecular characterization of long-term body weight change in the general population is lacking. Here, we pursued a multi-omic approach to comprehensively study metabolic consequences of body weight change during a seven-year follow-up in a large prospective study.MethodsWe used data from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort. At follow-up (F4), two-platform serum metabolomics and whole blood gene expression measurements were obtained for 1,631 and 689 participants, respectively. Using weighted correlation network analysis, omics data were clustered into modules of closely connected molecules, followed by the formation of a partial correlation network from the modules. Association of the omics modules with previous annual percentage weight change was then determined using linear models. In addition, we performed pathway enrichment analyses, stability analyses, and assessed the relation of the omics modules with clinical traits.ResultsFour metabolite and two gene expression modules were significantly and stably associated with body weight change (P-values ranging from 1.9 × 10−4 to 1.2 × 10−24). The four metabolite modules covered major branches of metabolism, with VLDL, LDL and large HDL subclasses, triglycerides, branched-chain amino acids and markers of energy metabolism among the main representative molecules. One gene expression module suggests a role of weight change in red blood cell development. The other gene expression module largely overlaps with the lipid-leukocyte (LL) module previously reported to interact with serum metabolites, for which we identify additional co-expressed genes. The omics modules were interrelated and showed cross-sectional associations with clinical traits. Moreover, weight gain and weight loss showed largely opposing associations with the omics modules.ConclusionsLong-term weight change in the general population globally associates with serum metabolite concentrations. An integrated metabolomics and transcriptomics approach improved the understanding of molecular mechanisms underlying the association of weight gain with changes in lipid and amino acid metabolism, insulin sensitivity, mitochondrial function as well as blood cell development and function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0282-y) contains supplementary material, which is available to authorized users.

Long-term changes in body weight are associated with changes in blood pressure levels

Background and aimsHypertension and obesity are highly prevalent in Western societies. We investigated the associations of changes in body weight with changes in blood pressure and with incident hypertension, incident cardiovascular events, or incident normalization of blood pressure in patients who were hypertensive at baseline, over a 5-year period. Methods and resultsData of men and women aged 20–81 years of the Study of Health in Pomerania were used. Changes in body weight were related to changes in blood pressure by linear regression (n = 1875) adjusted for cofounders. Incident hypertension, incident cardiovascular events, or incident blood pressure normalization in patients who were hypertensive at baseline were investigated using Poisson regression (n = 3280) models. A change of 1 kg in body weight was positively associated with a change of 0.45 mm Hg (95% confidence interval (CI): 0.34–0.55 mm Hg) in systolic blood pressure, 0.32 mm Hg (95% CI: 0.25–0.38 mm Hg) in diastolic blood pressure, and 0.36 mm Hg (95% CI: 0.29–0.43 mm Hg) in mean arterial pressure (all p-values <0.001). A 5% weight loss reduced the relative risk (RR) of incident hypertension (RRs 0.84 (95% CI: 0.79–0.89)) and incident cardiovascular events (RRs 0.81 (95% CI: 0.68–0.98)) and increased the chance of incident blood pressure normalization in patients who were hypertensive at baseline by 15% (95% CI: 7–23%). ConclusionsAbsolute and relative changes in body weight are positively associated with changes in blood pressure levels and also affect the risk of cardiovascular events.

Effects of behavioral treatment on long‐term weight loss: Lessons learned from the look AHEAD trial

The eight-year weight loss findings from the Look AHEAD Study (1) reported in this issue of Obesity have important implications for treatment of overweight and obesity. As the largest and longest randomized controlled trial of a behavioral intervention for weight loss, the results from Look AHEAD provide vital information about the short- and long-term effects of an intensive lifestyle intervention for weight management. Over the course of eight years, participants in Look AHEAD’s intensive lifestyle intervention achieved significantly larger mean reductions in body weight than those randomized to a diabetes support and education group. Moreover, at year 8, significantly greater percentages of lifestyle intervention participants attained weight reductions of 5% or greater and 10% or greater compared with those in the diabetes support and education condition. The ramifications of these findings with respect to lifestyle treatment of obesity are indeed notable. The Look AHEAD results demonstrate that weight losses can be achieved and, for the most part, sustained via behavioral management of diet and physical activity. At year 1, the lifestyle program produced a mean body weight reduction of 8.5%. Over the next four years, a gradual regaining of weight was observed, followed by the maintenance of losses of approximately 4-5% in subsequent years. At year 8, the lifestyle program participants sustained on average more than half (55%) of their year 1 weight losses. Moreover, the majority succeeded in achieving reductions in body weight of 5% or more. Look AHEAD’s findings stand in contrast to those of prior trials showing that participants regain the majority of lost weight within 3-5 years. The success of Look AHEAD is likely due to the intensive and comprehensive nature of the lifestyle intervention, and confidence in the study’s findings is underscored by the trial’s excellent rate of retention (i.e., more than 88% of the study’s 5,145 participants completed the year 8 assessment). The weight changes observed in Look AHEAD were accomplished in a diverse sample of participants. Thirty-seven percent were selfidentified as members of ethnic or racial minority groups, and more than 40% were men. Prior trials have been less inclusive with respect to ethnic/racial and gender representation, and it has commonly been assumed that non-white participants achieve poorer outcomes in lifestyle programs. While non-Hispanic whites in Look AHEAD had larger year 1 weight losses, subsequent assessments at years 4 and 8 showed comparable weight reductions for the four ethnic/racial groups in the study (African American, Hispanic, American Indian/ Other, and non-Hispanic white participants). The Look AHEAD findings also indicated that men and women had comparable weight loss outcomes at all assessment points. These results show that the lifestyle intervention produced long-term weight losses independent of the participant’s race, ethnicity, or gender. However, older participants (those 66-76 years at baseline) had somewhat greater weight losses than younger ones (age groups: 45-55 and 56-65 years), particularly at year 8, but it is difficult to discern whether this difference was due to the effects of aging and disease progression or to greater adherence among older participants. Relatedly, it is unknown whether the patterns of long-term weight changes observed in Look AHEAD are generalizable to younger adults (ages 21-44 years) and to individuals who do not have diabetes. The problem of poor maintenance of lost weight has been one of the greatest challenges associated with lifestyle interventions. The Look AHEAD findings demonstrate that a substantial degree of long-term weight loss is possible. However, the achievement of that outcome appears to require intensive, ongoing care, based on sound behavioral principles. It has long been recognized that the prescription of changes in diet and exercise, without clinical decision making based on behavioral theory and analysis, is unlikely to produce long-term changes in body weight. The lifestyle intervention in Look AHEAD included a comprehensive array of empirically supported behavioral treatment components, individually tailored through the use of problem-solving and “tool box” strategies, and delivered via structured programs of ongoing group and individual contacts.