Non-obese Research Articles

Type 2 diabetes is associated with impaired jejunal enteroendocrine GLP-1 cell lineage in human obesity

ObjectivesAltered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes.MethodsEEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals.ResultsThe RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals.ConclusionsThese results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.

Prevalence of normal weight obesity and its associated cardio-metabolic risk factors - Results from the baseline data of the Kerala Diabetes Prevention Program (KDPP).

BackgroundCardiometabolic disorders are frequently observed among those who have obesity as measured by body mass index (BMI). However, there is limited data available on the cardiometabolic profile of those who are non-obese by BMI but with a high body fat percentage (BFP), a phenotype frequently observed in the Indian population. We examined the prevalence of individuals with normal weight obesity (NWO) and the cardiometabolic profile of NWO individuals at high risk for type 2 diabetes(T2D) in a south Asian population.Material and methodsIn the Kerala Diabetes Prevention Program, individuals aged between 30 to 60 years were screened using the Indian Diabetes Risk Score(IDRS) in 60 rural communities in the Indian state of Kerala. We used data from the baseline survey of this trial for this analysis which included 1147 eligible high diabetes risk individuals(IDRS >60). NWO was defined as BMI within the normal range and a high BFP (as per Asia-pacific ethnicity based cut-off); Non-obese (NO) as normal BMI and BFP and overtly obese (OB) as BMI ≥25 kg/m2 irrespective of the BFP. Data on demographic, clinical and biochemical characteristics were collected using standardized questionnaires and protocols. Body fat percentage was assessed using TANITA body composition analyser (model SC330), based on bioelectrical impedance.ResultsThe mean age of participants was 47.3 ± 7.5 years and 46% were women. The proportion with NWO was 32% (n = 364; 95% CI: 29.1 to 34.5%), NO was 17% (n = 200) and OB was 51% (n = 583). Among those with NWO, 19.7% had T2D, compared to 18.7% of those who were OB (p value = 0.45) and 8% with NO (p value = 0.003). Among those with NWO, mean systolic and diastolic blood pressure were 129 ± 20; 78 ± 12 mmHg, compared to 127 ± 17; 78±11 mmHg among those with OB (p value = 0.12;0.94) and 120 ± 16; 71±10 mmHg among with NO (p value<0.001; 0.001), respectively. A similar pattern of association was observed for LDL cholesterol and triglycerides. After adjusting for other risk factors, the odds of having diabetes (OR:2.72[95% CI:1.46–5.08]) and dyslipidemia (2.37[1.55–3.64]) was significantly more in individuals with NWO as compared to non-obese individuals.ConclusionsAlmost one-third of this South Asian population, at high risk for T2D, had normal weight obesity. The significantly higher cardiometabolic risk associated with increased adiposity even in lower BMI individuals has important implications for recognition in clinical practice.

245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity-associated hypoxia in disturbing the methylation of genes involved in inflammation and vascular dysfunction and propose a mediating role of the hypoxia-inducible factor, HIF1α and the DNA hydroxymethylase, TET1. Methods: We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non-obese (NOB) adults having elective surgeries (n=36; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to increasing pressure gradients. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and promoter methylation/gene expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNɣ were measured in the AT biopsy. Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound. Results: Flow-induced dilation (FID) was 40-50% higher in NOB than OB adults across all pressure gradients (p&amp;lt;0.05). NO production was higher, and ROS generation was lower in the OB arterioles compared to NOB. HIF1α and TET1 proteins were 2 to 4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID and NO and brachial artery FMD (r=0.82, 0.64, 0.91, respectively; p&amp;lt;0.001) and positively with arteriolar ROS production (r=-0.71, p&amp;lt;0.01). Global hydroxymethylation was observed in OB compared to NOB as well as DNA promoter hypomethylation and increased gene expression of the targeted adipocytokines. Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines in the hypoxic AT. A downstream target for this pathway could reside in endothelial cells of nearby arterioles and remote arteries resulting in vascular dysfunction. Disclosure M.M. Ali: None. C. Hassan: None. M. Masrur: None. F. Bianco: Consultant; Self; Intuitive, Medtronic. S.A. Phillips: None. A.M. Mahmoud: None. Funding National Institutes of Health (4R00HL140049, 031K99, HL14004901)

Obesity‐associated Hypoxia Contributes to Aberrant Methylation of Genes Implicated in Inflammation and vascular Function

IntroductionObesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity‐associated hypoxia in disturbing the methylation/expression of genes involved in inflammation/vascular function. We also propose a mediating role of the hypoxia‐inducible factor, HIF1α and the DNA hydroxymethylase, TET1.MethodsWe obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non‐obese (NOB) adults having elective surgeries (n=30; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT‐isolated arterioles were tested for vasoreactivity in response to pressure gradients of Δ10‐Δ100 cmH2O. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and methylation/expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF‐α, and IFNγ were measured in the AT.ResultsFlow‐induced dilation (FID) was 40–50% higher in NOB than OB adults across all pressure gradients (p&lt;0.05). NO production was higher, and ROS generation was lower in OB arterioles compared to NOB. HIF1α and TET1 proteins were 2–4‐fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID, NO, and brachial artery FID (r=0.82, 0.64, 0.91, respectively; p&lt;0.001) and positively with ROS (r=−0.71, p&lt;0.01). Global hydroxymethylation and adipocytokine promoter hypomethylation and increased expression were observed in OB compared to NOB.ConclusionOur results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines. This conclusion was also supported by invitro mechanistic studies.Support or Funding InformationThis research was funded by the National Heart, Lung, and Blood Institute (NHLBI), grants K99HL140049 and 4 R00 HL140049‐03 (AM) and HL095701 (S.P.)

Impact of metabolically healthy obesity on the risk of incident gastric cancer: a population-based cohort study

BackgroundThe risk of colon or breast cancer in metabolically healthy obese (MHO) were lower than that in metabolically abnormal obese (MAO). We hypothesized that the risk of incident gastric cancer in MHO is lower than that in MAO.MethodsThis historical cohort study included 19,685 Japanese individuals who received health-checkup programs from 2003 to 2016. Each subject was classified as metabolically healthy (MH) (no metabolic abnormalities) or metabolically abnormal (MA) (one or more metabolic abnormalities), according to four metabolic factors (hypertension, impaired fasting glucose, hypertriglyceridemia and low HDL-cholesterol). Obese (O) or non-obese (NO) was classified by a BMI cutoff of 25.0 kg/m2. Hazard ratios of metabolic phenotypes for incident gastric cancer were calculated by the Cox proportional hazard model with adjustments for age, sex, alcohol consumption, smoking and exercise.ResultsOver the median follow-up period of 5.5 (2.9–9.4) years, incident rate of gastric cancer was 0.65 per 1000 persons-years. Incident rate of MHNO, MHO, MANO and MAO were 0.33, 0.25, 0.80 and 1.21 per 1000 persons-years, respectively. Compared with MHNO, the adjusted hazard ratios for development of gastric cancer were 0.69 (95% CI 0.04–3.39, p = 0.723) in MHO, 1.16 (95% CI 0.63–2.12, p = 0.636) in MANO and 2.09 (95% CI 1.10–3.97, p = 0.024) in MAO.ConclusionsThis study shows that individuals with MAO, but not those with MHO, had an elevated risk for incident gastric cancer. Thus, we should focus more on the presence of metabolic abnormalities rather than obesity itself for incident gastric cancer.

Determination of insulin resistance and its relationship with hyperandrogenemia,anti-Müllerian hormone, inhibin A, inhibin B, and insulin-like peptide-3 levels in adolescent girls with polycystic ovary syndrome

Background/aim This study aims to investigate the association between polycystic ovary syndrome (PCOS) and obesity and insulin resistance (IR) with respect to anti-Müllerian hormone (AMH), inhibin A (INH-A), inhibin B (INH-B), and insulin-like peptide 3 (INSL3) levels, all factors which may have an impact on IR.Materials and methods In this cross sectional study, 52 adolescent girls diagnosed with PCOS[groups: nonobese (NO), n = 23; overweight/obese (OW/O), n = 29] were included. Blood samples were obtained to measure AMH, INH-B, INH-A, and INSL3 levels, together with hormonal and biochemical assessments. Oral glucose tolerance test (OGTT) was performed and the indexes of IR [homeostasis model assessment: insulin resistance (HOMA-IR) and Matsuda index] were calculated.Results Insulin resistance was 56.5% with OGTT and 30.4% with HOMA-IR in nonobese-PCOS girls. There was a correlation between INH-A and HOMA-IR even when controlled for body mass index (BMI). INH-B and FAI also had correlations with HOMA-IR which disappeared when controlled for BMI. In regression analyses, AMH (odds ratio = [0.903, P = 0.015) and FAI (odds ratio = 1.353, P = 0.023) are found to be contributors to IR. Their effect was BMI-independent. In ROC analysis, the cutoff value for FAI was 5.93 (sensitivity 71%) to define IR in PCOS girls.ConclusionAMH and FAI may contribute to IR (defined by OGTT) in PCOS. FAI might be used as a supporting IR marker (defined by OGTT) in adolescent girls with PCOS.

SLUG/HIF1-α/miR-221 regulatory circuit in endometrial cancer

Background and purposeThe pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor. MethodsFormalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα+/PR+) from those with a poorer prognosis (ERα−/PR−). Immunohistochemistry for HIF1-α and SLUG was also performed. Body mass index (BMI) was registered at the time of diagnosis: patients with BMI ≥ 30 kg/m2 were defined obese (OB). Total RNA was isolated for miR-221 analysis. ResultsWe showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα+/PR+ and ERα−/PR− groups. However, the obesity factor impacted more in the ERα+/PR+ group since the ratio between OB and non-obese (NOB) patients with high expression of HIF1-α and SLUG was higher in ERα+/PR+ than in the ERα−/PR− group. miR-221 levels were significantly higher in the OB than NOB patients, and, also in this case, obesity impacted more in the ERα+/PR+ group. ConclusionsA molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.

Oncological safety of laparoscopic versus open colorectal cancer surgery in obesity: a systematic review and meta-analysis.

Colorectal cancer resection in the obese (OB) patients can be technically challenging. With the increasing adoption of laparoscopic surgery, the benefits remain uncertain. Hence, the aim of this study is to assess the short- and long-term outcomes of laparoscopic compared to open colorectal cancer resection in the OB patients. A systematic review and meta-analysis was performed according to the PRISMA guidelines. The outcome measures were 5-year disease-free survival, overall survival, circumferential resection margin and local and distant recurrence. A total of 20 studies were included, with a total number of 6779 participants, of whom 1785 (26.3%) were OB and 4994 (73.7%) were non-obese (NOB) participants. The OB patients had higher R1 resection (OB 6.9% versus NOB 3.1%; P = 0.011) and lower mean number of lymph nodes harvested, with standard mean difference of -0.29; P = 0.023, favouring the NOB patients. However, there was no statistical difference for local (OB 2.8% versus NOB 3.4%) or distant recurrence (OB 12.9% versus NOB 15.2%) rate between the two cohorts. There was no difference in 5-year disease-free survival (OB 81% versus NOB 77.4%; odds ratio 1.25, P = 0.215) and overall survival (OB 89.4% versus NOB 87.9%; odds ratio 1.16, P = 0.572). Lastly, the OB group had higher mean total blood loss, total operative time and length of hospital stay when compared to NOB patients. From a pooled non-randomized study, laparoscopic colorectal cancer resection is safe in OB patients with equivalent long-term outcomes compared to NOB patients. However, there is a higher morbidity rate with an increased demand on hospital resources for the OB cohort.

Epicardial fat: the role of testosterone and lipid metabolism in a cohort of patients with Klinefelter syndrome

ContextKlinefelter syndrome (KS), in which subjects have additional copies of X chromosomes, is the most common male sex chromosome abnormality, with a prevalence of 1 in 660 and an incidence of about 1 in 500–700 newborns. Its sign and symptoms include infertility, generally low testosterone levels, and an increased prevalence of obesity and metabolic syndrome. Epicardial fat thickness (EFT) reflects visceral adiposity rather than general obesity. ObjectiveThe aim of this study was to analyze echocardiographic EFT in a cohort of patients with KS in comparison with non-obese and obese euploid controls, and to evaluate its correlation with biochemical parameters. Design, setting and participantsTwo hundred and twenty-one KS patients referred to our Rare Endocrine Diseases clinic and 77 age-matched controls underwent Doppler echocardiography and a full investigation of anthropometric and body composition, Serum levels of total testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), fasting plasma glucose, insulin, cholesterol and triglycerides were obtained. All participants underwent dual energy X-ray absorptiometry (DEXA) scan to assess truncal body fat (TrBF). Main outcome measureEFT, body composition and metabolic parameters in KS patients and how they are affected by genotype. ResultsEFT was greater in KS patients than in healthy non-obese (NOb) controls, but lower than in obese (OB) controls. When KS patients were divided into groups (hypogonadal; eugonadal; receiving testosterone replacement therapy [TRT]), EFT was greater in hypogonadal patients than in NOb controls and eugonadal patients, but showed no difference from the OB controls or TRT patients. Hypogonadal patients showed increased TrBF in comparison with NOb controls and eugonadal and TRT patients, and similar TrBF to OB controls. As expected, there was a strong correlation between BMI and EFT in both KS patients and controls (P < 0.0001). In contrast, there was a strong inverse correlation between testosterone and EFT in the control group, but not in KS patients. EFT was significantly correlated with TrBF in both populations (P < 0.0001). Multivariate analyses showed that the major determinants of both EFT and TrBF were BMI and the presence of KS itself. Testosterone and triglycerides were not included as variables in the models. ConclusionEFT in hypogonadal KS subjects was similar to that of the obese eugonadal controls. Even though there was a direct correlation between BMI and EFT in both populations, the influence of TrBF on EFT was stronger. The presence of the supernumerary X chromosome appeared to be one of the strongest determinants of EFT and TrBF, independent of testosterone levels.

Healthy dietary pattern and their corresponding gut microbiota profile are linked to a lower risk of type 2 diabetes, independent of the presence of obesity

Prediabetes and old age are both high risk factors for developing Type 2 Diabetes (T2D), while obesity is one of the most important factors triggering the disease. Nutritional interventions are the most effective tool for preventing T2D, as they improve different biochemical and anthropometric outcomes and growth-promoting/inhibiting gut microbiota populations. However, to date there are no specific dietary recommendations to stop the development of T2D in elderly groups, for whom hypocaloric diets and other commonly used weight-loss programs could be considered dangerous. The objective of our study, thus, was to understand the impact of dietary patterns on T2D risk as related to gut microbiota profile in obese and non-obese elderly prediabetic subjects. A cross-sectional study was performed in 182 subjects ≥65 years old with prediabetes, divided into obese (OB) or non-obese (NOB) subgroups, and their risk of developing T2D was measured according to FINDRISK score and biochemical parameters. Also, clusters into different dietary patterns in each group by PCA analysis was related with gut microbiota, which was analyzed from stool samples by qPCR. The creation of clusters was used to re-evaluate T2D risk. OB was at higher risk of developing T2D and showed worse metabolic outcomes. Unhealthier and healthier dietary pattern clusters were observed for both OB (OB-6 and OB-5 respectively) and NOB (NOB-2 and NOB-3 respectively) groups. Results obtained from the gut microbiota showed that only Prevotella was higher in NOB, but when comparisons were made between clusters, a clear relation with dietary pattern was observed; showing in healthier dietary clusters a decrease in Prevotella, an increase of Faecalibacterium prausnitzii and an increase in lactic acid bacteria. T2D risk was greater in the obese group between unhealthier dietary clusters. No difference between healthier dietary clusters was observed. A healthy dietary pattern and the growth-promoting beneficial and growth-inhibiting disadvantageous gut microbiota populations linked to it provide protection against the development of T2D in an obese population with advanced age and preDM.

Obesity phenotype and patient-reported outcomes in moderate and severe chronic kidney disease: a cross-sectional study from the CKD-REIN cohort study.

To evaluate the association between obesity phenotypes and health-related quality of life (HRQoL) in non-dialysis-dependent CKD patients. Data from the national CKD-REIN cohort which included 3033 patients with stage 3-4 CKD were used. Patients were divided into three groups: non-obese (NO) patients (BMI < 30kg/m2), metabolically healthy obese (MHO) (BMI ≥ 30kg/m2 and ≤ 1 criterion NCEP/ATP III), and metabolically unhealthy obese (MUO) (BMI ≥ 30kg/m2 and ≥ 2 criteria NCEP/ATP III). HRQoL was measured by the KDQOL-36™ which comprised three disease-specific dimensions: symptoms, effects, and burden and two summaries scores: physical (PCS) and mental (MCS). We used a mixed effect model with adjustment on sociodemographic characteristics and comorbidities. A total of 2693 patients completed the self-administered questionnaires. MHO patients accounted for 3.4% of the cohort and for 12% of obese patients. In the NO group, average HRQoL scores were 77.2 ± 15.9 for symptoms, 83.5 ± 16.5 for effects, 76.8 ± 22.7 for burden, 43.5 ± 9.7 for PCS, and 47.9 ± 7.0 for MCS. In the multivariate analysis, scores were similar in MHO and NO patients, but significantly different with those in MUO patients: symptoms (- 0.7; p = 0.71 vs. - 3.0; p = 0.0025), effects (+ 1.2; p = 0.57 vs. - 4.3; p < 0.0001), burden (+ 2.7; p = 0.31 vs. - 3.6; p = 0.0031), and PCS (- 0.6; p = 0.58 vs. - 4.3; p < 0.0001). MCS was not associated with obesity phenotypes. This study demonstrated an association between obesity phenotypes and QoL in non-dialysis-dependent CKD patients. MUO patients had worse QoL than NO and MHO patients even after adjustment on comorbidities.

1380. Effect of Absolute Body Weight on Clinical Outcomes of Obese Patients Treated with Cefepime

BackgroundDifferences in pharmacokinetic and pharmacodynamic parameters for obese (OB) patients compared with nonobese (NOB) patients are well known, but drug safety and efficacy when using package insert dosing remain unclear. The purpose of this study was to evaluate the clinical outcomes of cefepime (FEP) for OB patients vs. NOB patients.MethodsThis retrospective cohort included inpatient adults ≥18 years treated with FEP monotherapy for ≥72 hours between July 2015 and July 2017. Exclusion criteria were source control not achieved within 72 hours and polymicrobial infections requiring > 1 antibiotic for definitive therapy. Additional data collected were demographics, comorbid conditions, laboratory markers, site of infection, and microbiology. The primary endpoint was clinical treatment failure, defined as change in definitive therapy at >72 hours due to clinical worsening, leukocytosis (WBC > 10 × 109/L) for >72 hours after treatment initiation, fever (single temperature >100.9°F) after >72 hours of treatment initiation, or readmission within 30 days due to re-infection. Secondary outcomes were 30-day inpatient all-cause mortality and 30-day readmission.ResultsOne hundred fourteen subjects were included (58 OB; 56 NOB). Median (IQR) age 58[46–66] years; 66(58%) males. Median [IQR] weight 107[95–124] kg OB patients; 75[63–84] kg NOB patients. Median Charlson score was 3[2–5] (P = 0.478). Sixty-two percent OB patients vs. 46% NOB patients experienced a respiratory infection (P = 0.094); 28% OB patients vs. 39% NOB patients experienced a urinary tract infection (P = 0.185). 62% OB patients and 59% NOB patients received FEP 1g q8h (P = 0.732). Most common minimum inhibitory concentration (MIC) in both groups was 1 mg/L (74% OB vs. 83% NOB; P = 0.289). Clinical failure occurred in 52% (67% OB vs. 36% NOB; P = 0.001). OB patients more likely to need a second antibiotic (31% vs. 14%; P = 0.033) and have persistent leukocytosis (50% vs. 30%; P = 0.033). Inpatient all-cause mortality occurred in 17% (22% OB vs. 12% NOB; P = 0.164). 72% of patients were not readmitted within 30 days of discharge.ConclusionOB patients experienced higher treatment failure than NOB patients. Further examination is needed to assess impact of FEP dose and organism MIC on clinical failure in OB patients.Disclosures All authors: No reported disclosures.

Obesity-associated severe asthma in an adult Japanese population.

Severe asthma is increasingly being recognized as an important public health issue. Obesity has been identified as a risk factor for poor asthma control and for worsening of asthma severity. However, most studies investigating obese patients with asthma have been performed in Western countries. Reports on the characteristics of obese Japanese individuals with severe asthma are lacking. Herein, we investigated the clinical characteristics of patients with obesity-associated severe asthma in a Japanese population and the association between obesity and poor asthma control. We conducted a retrospective observational study of adult patients with severe asthma. Patients were classified into two groups based on the definition of obesity recommended by the Japan Society for the Study of Obesity: obese (OB) group (body mass index [BMI] ≥25 kg/m2) and non-obese (NOB) group (BMI <25 kg/m2). The two groups were compared. The characteristics of obesity and the metabolic functions are known to differ between males and females; therefore, we analyzed male-only and female-only cohorts separately. A total of 492 patients were enrolled. Age, smoking history in terms of number of pack-years, daily controller medications use, and spirometric data were not significantly different between the OB and NOB groups in either cohort. In the female cohort, the annual exacerbation ratio and the percentage of frequent exacerbators were significantly higher in the OB group compared to the NOB group. A multivariate logistic regression analysis showed that obesity was independently associated with frequent asthma exacerbations in the female cohort. Our study revealed that obesity, defined as a BMI ≥25 kg/m2, was independently associated with poor asthma control (including acute exacerbations) in adult Japanese females with severe asthma.

Differential protein profiling as a potential multi-marker approach for obese patients with heart failure: A retrospective study

Identification of novel circulating biomarkers predicting death and major cardio-metabolic events in obese patients with heart failure (HF) remains a research priority. In this study, we compared multi-marker profile of non-obese (NOB) and obese (OB) HF patients in relation to mortality outcome. The new multiplex proximity extension assay technology was used to analyze the levels of 92 proteins in plasma samples from HF patients according to body mass index (BMI) categories. At 2-year follow-up, all-cause mortality rates were significantly greater in NOB patients (BMI < 30 kg/m2) compared to the OB patients (BMI > 30 kg/m2) with HF (odds ratio 26; 95% CI: 1.14–624, p < 0,04). Quantitative proteomic analysis revealed thirteen distinct proteins expression profiles of OB and NOB HF patients. Among these proteins, RAGE, CXCL6, CXCL1, CD40, NEMO, VEGF-A, KLK6, PECAM1, PAR1, MMP1, BNP and NTproBNP were down-regulated, whereas leptin was up-regulated in OB HF patients. In addition, an inverse correlation between plasma BNP levels and leptin in OB HF patients was observed (r = −0.58 p = 0.02). This study identifies specific plasma protein signature in OB and NOB patients with HF in relation to mortality outcome.

CompMS2Miner: An Automatable Metabolite Identification, Visualization, and Data-Sharing R Package for High-Resolution LC-MS Data Sets.

A long-standing challenge of untargeted metabolomic profiling by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) is efficient transition from unknown mass spectral features to confident metabolite annotations. The compMS2Miner (Comprehensive MS2 Miner) package was developed in the R language to facilitate rapid, comprehensive feature annotation using a peak-picker-output and MS2 data files as inputs. The number of MS2 spectra that can be collected during a metabolomic profiling experiment far outweigh the amount of time required for pain-staking manual interpretation; therefore, a degree of software workflow autonomy is required for broad-scale metabolite annotation. CompMS2Miner integrates many useful tools in a single workflow for metabolite annotation and also provides a means to overview the MS2 data with a Web application GUI compMS2Explorer (Comprehensive MS2 Explorer) that also facilitates data-sharing and transparency. The automatable compMS2Miner workflow consists of the following steps: (i) matching unknown MS1 features to precursor MS2 scans, (ii) filtration of spectral noise (dynamic noise filter), (iii) generation of composite mass spectra by multiple similar spectrum signal summation and redundant/contaminant spectra removal, (iv) interpretation of possible fragment ion substructure using an internal database, (v) annotation of unknowns with chemical and spectral databases with prediction of mammalian biotransformation metabolites, wrapper functions for in silico fragmentation software, nearest neighbor chemical similarity scoring, random forest based retention time prediction, text-mining based false positive removal/true positive ranking, chemical taxonomic prediction and differential evolution based global annotation score optimization, and (vi) network graph visualizations, data curation, and sharing are made possible via the compMS2Explorer application. Metabolite identities and comments can also be recorded using an interactive table within compMS2Explorer. The utility of the package is illustrated with a data set of blood serum samples from 7 diet induced obese (DIO) and 7 nonobese (NO) C57BL/6J mice, which were also treated with an antibiotic (streptomycin) to knockdown the gut microbiota. The results of fully autonomous and objective usage of compMS2Miner are presented here. All automatically annotated spectra output by the workflow are provided in the Supporting Information and can alternatively be explored as publically available compMS2Explorer applications for both positive and negative modes ( https://wmbedmands.shinyapps.io/compMS2_mouseSera_POS and https://wmbedmands.shinyapps.io/compMS2_mouseSera_NEG ). The workflow provided rapid annotation of a diversity of endogenous and gut microbially derived metabolites affected by both diet and antibiotic treatment, which conformed to previously published reports. Composite spectra (n = 173) were autonomously matched to entries of the Massbank of North America (MoNA) spectral repository. These experimental and virtual (lipidBlast) spectra corresponded to 29 common endogenous compound classes (e.g., 51 lysophosphatidylcholines spectra) and were then used to calculate the ranking capability of 7 individual scoring metrics. It was found that an average of the 7 individual scoring metrics provided the most effective weighted average ranking ability of 3 for the MoNA matched spectra in spite of potential risk of false positive annotations emerging from automation. Minor structural differences such as relative carbon-carbon double bond positions were found in several cases to affect the correct rank of the MoNA annotated metabolite. The latest release and an example workflow is available in the package vignette ( https://github.com/WMBEdmands/compMS2Miner ) and a version of the published application is available on the shinyapps.io site ( https://wmbedmands.shinyapps.io/compMS2Example ).

Influence of Obesity on Outcomes of Patients with Relapsed Refractory Multiple Myeloma

The prevalence of obesity is increasing worldwide. It has been associated with increased risk of some malignancies, including multiple myeloma (MM). However, its influence on the outcomes of patients with MM remains to be defined. We investigated the association between BMI and outcomes of patients with relapsed and/or refractory MM treated on a prospective clinical trial (MC0789) which treated patients in different cohorts of Pomalidomide (2 vs. 4 mg; 21 vs. 28 days cycle) with fixed dose dexamethasome (dex) (40 mg oral weekly). Patients were divided in 2 groups, BMI less than 30 (non-obese; NO) or BMI 30 or more (obese; O). Responses were assessed according to established criteria. Continuous and categorical variables were compared between the two groups using two-sample t-test, Fisher's exact test or Chi squared test. Kaplan-Meier method was used to estimate overall survival and progression free survival. Results from the MC0789 clinical trial have been reported previously. Data on 331 patients was analyzed for this study, 101 were obese (O) and 229 non-obese (NO). 27% and 39% respectively were female. Median weight (range) of O vs.NO was 97.9 (69-147) vs. 73.4 (36-105) kg; and BMI 32.4 (30-50) vs 25.7(14.6-29.9). Only 2 patients were underweight (BMI <18.5). 93% and 82% of O and NO had ECOG performance status of 0–1. Disease characteristics were similar in the 2 groups. 32% were ISS stage III in both. O and NO patients had received median of 3 (1-10) vs. 3 (1-14) prior regimens. 91%, 69% and 66% of O were previously treated with lenalidomide, bortezomib, or both vs 94%, 71% and 66% of NO. Cytogenetic information was available only for a subset of patients; 17% of both cohorts had 17p deletion. Median number of treatment cycles received by O and NO were 6 (1-74) and 4 (1-74). Grade > 2 hyperglycemia occurred in 25% and 10% (p=0.001) and dex dose reduction was done in 45% and 59% of O and NO patients, (p=NS). Partial response or better occurred in 41% of O vs 36% of NO (p=NS). Kaplan-Meier estimate of median PFS of O vs. NO was 47.9(14.6-NR)m vs. 9.2(6.6-12.8)m (p=0.006) and median OS was 47.9 (26.8-NR) vs. 20.5(13.9-31.7)m (p=0.007).

COMPARITIVE EVALUATION OF SALIVARY Ig A LEVELS AND DENTAL CARIES IN OBESE AND NON OBESE CHILDREN.

20Jan 2017 COMPARITIVE EVALUATION OF SALIVARY Ig A LEVELS AND DENTAL CARIES IN OBESE AND NON OBESE CHILDREN. B. Jagadesh Babu , N. Venugopal Reddy , B. V. Thimma Reddy , V. Daneswari and Niharika Puppala. Senior lecturer, Dept of Pediatric Dentistry, Sree Sai Dental College & Research Institute, Srikakulam; A.P. Professor & HOD, Dept of Pediatric Dentistry, Mamata Dental College, Khammam; Telangana State. Professor, Dept of Pediatric Dentistry, Panineeya Institute Of Dental Sciences, Hyderabad; Telangana State. Professor, Dept of Pediatric Dentistry, Mamata Dental College, Khammam; Telangana State. Reader, Dept of Pediatric Dentistry, Mamata Dental College, Khammam; Telangana State.

Obesity and its implications for morbidity and mortality after cholecystectomy: A matched NSQIP analysis

BackgroundThe risks from super obesity (SO) following cholecystectomy have not been studied. MethodsNSQIP analysis of patients undergoing cholecystectomy from 2005 to 2011. Non-obese (NO) patients (BMI 18.5–30) were matched 1:1 by age, sex, race and comorbidities to morbidly obese (MO) (BMI 35–50), and separately to SO (BMI≥50) individuals. Clavien 4 complications and 30-day mortality were compared. Results13780 MO and 1410 SO patients were matched to NO patients. Obese patients were more likely to present with chronic (CC) rather than acute cholecystitis (AC). Compared to NO patients, Clavien 4 complications were significantly increased among SO patients overall especially with AC where rate of open surgery was significantly higher. ConclusionSO patients have an increased risk of serious morbidity after cholecystectomy especially with AC where rate of open surgery remains high. Aggressive recommendation for cholecystectomy to reduce presentation with AC and increase likelihood for laparoscopic surgery may be beneficial in SO patients.

Differential representation of liver proteins in obese human subjects suggests novel biomarkers and promising targets for drug development in obesity

The proteome of liver biopsies from human obese (O) subjects has been compared to those of nonobese (NO) subjects using two-dimensional gel electrophoresis (2-DE). Differentially represented proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based peptide mass fingerprinting (PMF) and nanoflow-liquid chromatography coupled to electrospray-tandem mass spectrometry (nLC-ESI-MS/MS). Overall, 61 gene products common to all of the liver biopsies were identified within 65 spots, among which 25 ones were differently represented between O and NO subjects. In particular, over-representation of short-chain acyl-CoA dehydrogenase, Δ(3,5)-Δ(2,4)dienoyl-CoA isomerase, acetyl-CoA acetyltransferase, glyoxylate reductase/hydroxypyruvate reductase, fructose-biphosphate aldolase B, peroxiredoxin I, protein DJ-1, catalase, α- and β-hemoglobin subunits, 3-mercaptopyruvate S-transferase, calreticulin, aminoacylase 1, phenazine biosynthesis-like domain-containing protein and a form of fatty acid-binding protein, together with downrepresentation of glutamate dehydrogenase, glutathione S-transferase A1, S-adenosylmethionine synthase 1A and a form of apolipoprotein A-I, was associated with the obesity condition. Some of these metabolic enzymes and antioxidant proteins have already been identified as putative diagnostic markers of liver dysfunction in animal models of steatosis or obesity, suggesting additional investigations on their role in these syndromes. Their differential representation in human liver was suggestive of their consideration as obesity human biomarkers and for the development of novel antiobesity drugs.

The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity

Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response toinsulin, which differed from the small effects observed in NO subjects. In the obese, 231 genes were altered; 71 were enriched in ISO subjects (e.g., phosphorylation processes), and 52 were enriched in IRO subjects (e.g., cellular stimuli). Common cardio-metabolic risk factors and gender do not influence these findings. This study demonstrates that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity.