Metabolically Healthy Obese Patients Research Articles

Abstract TMP100: Acute Ischemic Stroke in Young Adults: A Comparative Analysis of Outcomes and Mortality in Metabolically Healthy Obese vs. Normal Weight Individuals, 2016-2019 Cohort

Introduction: Rising obesity rates and the increasing prevalence of stroke in the metabolically healthy obese (MHO) necessitate examining its association in younger (18-44 year) populations. Analyzing acute ischemic stroke (AIS) trends and outcomes in MHO vs. metabolically healthy normal weight (MH-NW). Methods: Data from the National Inpatient Sample (2016-2019) was analyzed to identify young MHO and MH-NW AIS patients using ICD-10 codes. Demographics, trends, and outcomes were compared using multivariable statistical approaches. Results: Of 26,949,310 young metabolically healthy individuals studied between 2016 and 2019, 47,795 had AIS, 4,985 were MHO, and 42,810 were MH-NW. The median AIS patient age was 35. The MHO cohort was primarily female, white, in the lowest income quartile, with private insurance. Most were hospitalized in southern US urban teaching hospitals. Notably, the MHO cohort had higher rates of specific comorbidities like depression, chronic pulmonary disease, and obstructive sleep apnea but lower rates of drug abuse and peripheral vascular disease. The in-hospital mortality rate was significantly lower in MHO patients (6.0% vs. 8.6%). Hospitalization length and cost did not significantly differ between groups. From 2016 to 2019, AIS incidence rose slightly, significant only for the MH-NW cohort. Adjusted multivariable odds ratios revealed no significant difference in AIS occurrence between MHO and MH-NW overall (aOR: 1.02, p=0.701), in males (aOR: 0.88, p=0.161) or females (aOR: 1.06, p=0.363). However, MHO-associated AIS had lower odds of in-hospital mortality than MH-NW (aOR: 0.60, p=0.021). Conclusion: AIS incidence was consistent across young metabolically healthy groups regardless of obesity status. However, we noted a paradoxical 40% reduction in in-hospital mortality in the MHO cohort. This underscores the complex MHO-stroke relationship in young adults, signaling a need for in-depth research and tailored interventions.

Abstract 13509: Cardiovascular Outcomes in Metabolically Healthy Obese Asian-American Population Insights From a National Inpatient Sample

Background: Cardio-metabolic risk factors usually predict major adverse cardio and cerebrovascular events (MACCE). However, outcomes in young metabolically healthy obese (MHO) Asian Americans (AA) have not been studied yet. Methods: Using the National Inpatient Sample (2019), we identified hospitalizations among young obese AA [aged 18-44] to obtain propensity-matched MHO+ and MHO- cohorts. Multivariable regression analyses were performed after controlling baseline demographic and comorbid variables to assess the risk of MACCE, including all-cause mortality, acute myocardial infarction, cardiac arrest, and stroke. Multivariable predictors of MACCE were also analyzed. P <0.05 was statistically significant. Results: Of total 327,065 young AA hospitalizations, 25,470 were obese. Propensity-matched cohorts of MHO+ (n=14,200) and MHO-(n=14,200) were comparable for demographics (Median age 32 years, females 85.9% vs 84.8%). After adjusting for baseline demographics and comorbidities, the odds of MACCE (aOR 0.98, 95%CI 0.70-1.37, p=0.886) were higher, and ACM (aOR 1.26, 95CI% 0.4-3.99, p=0.690) was lower in MHO+ compared to MHO- group however, it was not statistically significant. MHO patients also had higher rates for MACCE among males (OR 10.18, 95%Cl 3.39-30.53, p <0.001), drug abusers (OR 2.87, 95%Cl 1.05-7.86, p=0.04), cancer (OR 9.70, 95%Cl 2.14-44.01, p =0.003) and congenital circulatory anomalies (OR 21.77, 95Cl 4.07-116.60, p <0.001). Conclusion: Obese AA population without cardiometabolic risk factors define a subgroup of at-risk population with males, drug abusers, cancers, and congenital abnormalities pose an increased risk of adverse cardio and cerebrovascular events. Targeted interventions, early risk stratification, and preventive measures are warranted in these populations.

Association of body mass index, metabolic health status and clinical outcomes in acute myocardial infarction patients: a national registry-based study.

Obesity is an important risk factor for acute myocardial infarction (AMI), but the interplay between metabolic health and obesity on AMI mortality has been controversial. In this study, we aimed to elucidate the risk of short- and long-term all-cause mortality by obesity and metabolic health in AMI patients using data from a multi-ethnic national AMI registry. A total of 73,382 AMI patients from the national Singapore Myocardial Infarction Registry (SMIR) were included. These patients were classified into four groups based on the presence or absence of metabolic diseases, diabetes mellitus, hyperlipidaemia, and hypertension, and obesity: (1) metabolically-healthy-normal-weight (MHN); (2) metabolically-healthy-obese (MHO); (3) metabolically-unhealthy-normal-weight (MUN); and (4) metabolically-unhealthy-obese (MUO). MHO patients had reduced unadjusted risk of all-cause in-hospital, 30-day, 1-year, 2-year, and 5-year mortality following the initial MI event. However, after adjusting for potential confounders, the protective effect from MHO on post-AMI mortality was lost. Furthermore, there was no reduced risk of recurrent MI or stroke within 1-year from onset of AMI by the MHO status. However, the risk of 1-year mortality was higher in female and Malay AMI patients with MHO compared to MHN even after adjusting for confounders. In AMI patients with or without metabolic diseases, the presence of obesity did not affect mortality. The exception to this finding were female and Malay MHO who had worse long-term AMI mortality outcomes when compared to MHN suggesting that the presence of obesity in female and Malay patients may confer worsened outcomes.

Evolution of Metabolic Phenotypes of Obesity in Coronary Patients after 5 Years of Dietary Intervention: From the CORDIOPREV Study.

Background: Obesity phenotypes with different metabolic status have been described previously. We analyzed metabolic phenotypes in obese coronary patients during a 5-year follow-up, and examined the factors influencing this evolution. Methods: The CORDIOPREV study is a randomized, long-term secondary prevention study with two healthy diets: Mediterranean and low-fat. All obese patients were classified as either metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO). We evaluated the changes in the metabolic phenotypes and related variables after 5 years of dietary intervention. Results: Initially, 562 out of the 1002 CORDIOPREV patients were obese. After 5 years, 476 obese patients maintained their clinical and dietary visits; 71.8% of MHO patients changed to unhealthy phenotypes (MHO-Progressors), whereas the MHO patients who maintained healthy phenotypes (MHO-Non-Progressors) lost more in terms of their body mass index (BMI) and had a lower fatty liver index (FLI-score) (p < 0.05). Most of the MUO (92%) patients maintained unhealthy phenotypes (MUO-Non-Responders), but 8% became metabolically healthy (MUO-Responders) after a significant decrease in their BMI and FLI-score, with improvement in all metabolic criteria. No differences were found among dietary groups. Conclusions: A greater loss of weight and liver fat is associated with a lower progression of the MHO phenotype to unhealthy phenotypes. Likewise, a marked improvement in these parameters is associated with regression from MUO to healthy phenotypes.

Exploring extra dimensions to capture saliva metabolite fingerprints from metabolically healthy and unhealthy obese patients by comprehensive two-dimensional gas chromatography featuring Tandem Ionization mass spectrometry

This study examines the information potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOF MS) and variable ionization energy (i.e., Tandem Ionization™) to study changes in saliva metabolic signatures from a small group of obese individuals. The study presents a proof of concept for an effective exploitation of the complementary nature of tandem ionization data. Samples are taken from two sub-populations of severely obese (BMI > 40 kg/m2) patients, named metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Untargeted fingerprinting, based on pattern recognition by template matching, is applied on single data streams and on fused data, obtained by combining raw signals from the two ionization energies (12 and 70 eV). Results indicate that at lower energy (i.e., 12 eV), the total signal intensity is one order of magnitude lower compared to the reference signal at 70 eV, but the ranges of variations for 2D peak responses is larger, extending the dynamic range. Fused data combine benefits from 70 eV and 12 eV resulting in more comprehensive coverage by sample fingerprints. Multivariate statistics, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) show quite good patient clustering, with total explained variance by the first two principal components (PCs) that increases from 54% at 70 eV to 59% at 12 eV and up to 71% for fused data. With PLS-DA, discriminant components are highlighted and putatively identified by comparing retention data and 70 eV spectral signatures. Within the most informative analytes, lactose is present in higher relative amount in saliva from MHO patients, whereas N-acetyl-D-glucosamine, urea, glucuronic acid γ-lactone, 2-deoxyribose, N-acetylneuraminic acid methyl ester, and 5-aminovaleric acid are more abundant in MUO patients. Visual feature fingerprinting is combined with pattern recognition algorithms to highlight metabolite variations between composite per-class images obtained by combining raw data from individuals belonging to different classes, i.e., MUO vs. MHO.Graphical abstract

Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin.

Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels of all analyzed serum pro-inflammatory markers (TNFα, IL6, IL1β and MCP1) and a downwards trend in IL18 levels associated with a lower production of oxidative stress markers in leukocytes (mitochondrial ROS and myeloperoxidase (MPO)). A reduction in protein levels of MCP1, NFκB, NLRP3, ASC, ATG5, Beclin1 and CHOP and an increase in p62 were also observed in the VAT of the diabetic group. This downregulation of both the NLRP3 inflammasome and autophagy in VAT may be associated with the improved inflammatory profile and leukocyte homeostasis seen in obese T2D patients treated with metformin with respect to MHO subjects and endorses the cardiometabolic protective effect of this drug.

Effect of body shape on the development of cardiovascular disease in individuals with metabolically healthy obesity.

Studies about the effects of metabolically healthy obesity on cardiovascular disease (CVD) have yielded conflicting results. These heterogeneous results could be due to the limited usefulness of BMI in measuring general adiposity, as body mass index (BMI) does not accurately reflect body composition. This study aimed to evaluate the effect of body shape on CVD outcomes across different obesity phenotypes, and to provide an explanation for the heterogeneous effects of metabolically healthy obese (MHO) phenotype on CVD.We analyzed data from the Korean Genome and Epidemiology Study, a population-based cohort study conducted between 2001 and 2012. We divided the participants into 4 groups: metabolically healthy non-obese (MHNO), MHO, metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). To assess body shape, we calculated the z-score of the log-transformed a body shape index (LBSIZ). We computed Pearson correlation coefficients to examine the association of LBSIZ with muscle mass index, percentage of total fat mass (%Total FM), and percentage of abdominal fat mass (%Abdominal FM). We also used Cox proportional hazards regression to evaluate the effect of LBSIZ on CVD events according to the obesity phenotypes.A total of 9460 participants were assessed in this study. The incidence of CVD was 8.53 cases per 1000 person-year. LBSIZ showed strong positive correlation with %Total FM and %Abdominal FM, but negative correlation with muscle mass index. In Cox regression, MHO individuals did not show increased risk of CVD compared with MHNO individuals (hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.96-1.73). However, MHO individuals in the 3rd (HR, 2.40; 95% CI, 1.28-4.51) and 4th (HR, 3.67; 95% CI, 1.99-6.74) quarters of LBSIZ showed significantly higher risk of CVD compared with MHNO individuals in the 1st quarter of LBSIZ. Moreover, LBSIZ showed a linear relationship with CVD among MHO individuals.While the MHO individuals showed similar CVD risk to the MHNO individuals, CVD risk increases with LBSIZ among the MHO individuals. LBSIZ appears to be a useful measure for CVD risk assessment in clinical practice and epidemiologic studies, especially for MHO patients.

Effectiveness of Bariatric Surgery in Patients with the Metabolically Healthy Obese Phenotype.

To evaluate the effectiveness and safety of bariatric surgery in metabolically healthy obese (MHO) patients. In this retrospective, observational study, we reviewed the medical records of patients who underwent bariatric surgery at a tertiary care hospital between January 2007 and March 2015. Patients who underwent revisional surgery and patients with type 1 diabetes were excluded from the analysis. MHO patients were defined as those without a previous diagnosis of diabetes or atherogenic dyslipidemia and absence of hypoglycemic treatment or treatment with fibrates. A total of 188 patients were included (mean age 48.97 ± 10.32years, 68.6% of women). Sleeve gastrectomy was performed in 121 patients (64%) and a gastric bypass in 67 patients (36%). Prior to surgery, 36 patients (19%) were MHO. In the second- and third-year post-surgery, MHO patients presented a higher percentage of total weight loss (%TWL) (35.16% vs. 30.34%; p = 0.02 and 33.97% vs. 27.78%; p = 0.013 respectively). Multiple regression analysis showed that MHO was associated with a higher weight loss irrespective of age, sex, baseline BMI, and type of surgery. We did not detect any differences in acute complications between patients with and without MHO after bariatric surgery. Bariatric surgery in MHO patients in our study was associated with higher weight loss than that in MUHO patients. There were no differences between the two groups in respect to acute complications following surgery.

A Proteomics-Based Approach Reveals Differential Regulation of Urine Proteins between Metabolically Healthy and Unhealthy Obese Patients.

Metabolic dysfunction associated with obesity threatens to inundate health care resources by increasing the incidences of obesity-related diseases. The aim of the present study was to investigate the changes in the urinary proteome of 18 individuals classified into metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) patients. Proteome analysis was performed using the two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). Upon analysis, a total of 54 proteins were found to be affected with ≥1.5-fold change (ANOVA, p ≤ 0.05), of which 44 proteins were upregulated and 10 proteins were downregulated. These differentially abundant proteins were related to nuclear factor κB (NF-κB) and p38 mitogen-activated protein (MAP) kinase pathways and were involved in cellular compromise, inflammatory response, and cancer. Proteins involved in inflammation (fibrinogen alpha (FIBA), serotransferrin (TRFE, and kininogen-1 (KNG1)) and insulin resistance (ADP-ribosylation factor (ARF)-like protein 15 (ARL15) and retinol-binding protein 4 (RET4)) were found to be significantly increased in the urine samples of MUHO compared to MHO patients. Investigating the effects of obesity on urinary proteins can help in developing efficient diagnostic procedures for early detection and prevention of obesity-related complications.

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.

The influence of metabolic profile of obese men on the severity of erectile dysfunction: are metabolically healthy obese individuals protected?

To determine the prevalence of erectile dysfunction (ED) in metabolically healthy obese (MHO) individuals, and to compare ED severity and hypogonadism prevalence in MHO, metabolically unhealthy obese (MUO) and metabolically healthy non-obese individuals. ED patients (n=460) were evaluated by standardized protocol, that included clinical evaluation, abridged 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire survey, and Penile Duplex Doppler Ultrasound (PDDU) exam. Patients were classified as obese [body mass index (BMI) ≥30.0 kg/m2] and non-obese (BMI <30.0 kg/m2), and metabolic health status was defined by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria. Statistical analysis was performed and statistical significance was considered at p-level <0.05. The mean age of the subjects was 56.2±10.5 years. MHO was present in 40% of obese individuals (n=37). MUO had lower mean peak systolic velocity (mPSV) compared to MHO (28.1 cm/s vs. 36.9 cm/s; p=0.005), and IIEF-5 scores were also lower in MUO compared to MHO patients (10.2 vs. 13.1; p=0.018). No statistical differences in IIEF-5 score, mPSV and hypogonadism prevalence between MHO and metabolically healthy non-obese (MHNO) patients were observed. Our results lead us to conclude that healthy metabolic profile protects obese individuals from severity of ED. The strong association between obesity and ED may be otherwise attributed to metabolic abnormalities present in the obese.

Metabolically healthy and metabolically unhealthy obese children both have increased carotid intima-media thickness: a case control study

BackgroundThe cardiovascular disease risk was assessed in metabolically healthy obese (MHO) children, obese children with metabolic disorders (MUO), and to a control group of normal-weight children using carotid intima-media thickness (CIMT).MethodsParticipants were 204 obese children (114 M, 90 F), including 162 MUO (74 M, 88 F) and 42 MHO (24 M, 18 F), and 99 gender- and age-matched controls (45 M, 54 F). Glucose, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and other serum values were determined in peripheral blood. Anthropometric parameters, blood pressure, and a carotid Doppler ultrasound scan were also acquired. The mean CIMT of obese subjects and controls was compared by analysis of variance. Abnormality of even one of the metabolic parameters assessed involved assignation to the MUO group. Mean CIMT was compared in MHO and MUO children.ResultsMean CIMT in control children was 402.97 ± 53.18 μm (left carotid artery) and 377.85 ± 52.47 μm (right carotid artery). In MHO and MUO patients CIMT was respectively 453.29 ± 62.04 and 460.17 ± 92.22 μm (left carotid artery) and 446.36 ± 49.21 and 456.30 ± 85.7 μm (right carotid artery). The mean CIMT was not significantly different in MUO and MHO children, whereas it showed a significant difference between both groups of obese children and controls (p < 0.01).ConclusionCIMT was significantly greater in obese patients, also in those without metabolic alterations, than in normal-weight children. Obesity is therefore an important risk factor for cardiovascular disease in itself, also in the absence of metabolic abnormalities.

Impact of short‐ and long‐term weight loss on the inflammatory profile of metabolically healthy and unhealthy obese patients

Study ObjectiveObesity is a predisposing factor for cardiometabolic and kidney disease. Inflammation has been identified as an underlying risk factor. However, studies report conflicting results on the impact of short‐ and long‐term weight loss on obesity‐related inflammation. Here we investigate levels of inflammation in lean, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) patients, and the impact of short‐ and long‐term weight loss, using multiplex arrays and bioinformatics analysis.MethodsObese patients scheduled to undergo gastric bypass surgery were age‐ and sex‐matched to lean controls (ClinicalTrials.gov NCT02322073), and sub‐classified as metabolically healthy (MHO: n=4) or unhealthy (MUO: n=7) using International Diabetes Guidelines (i.e. metabolically unhealthy is defined as having more than two cardiometabolic risk factors: central adiposity, hyperglycemia, elevated triglycerides, decrease HDL‐cholesterol, elevated blood pressure). Gender was not a part off inclusion/exclusion criteria, thus three patients were male and eight were female. Plasma was collected at baseline and following short‐ and long‐term weight loss. The short‐term weight loss consisted of a 3‐week diet regime, which takes place before surgery and resulted in 8.7 kg weight loss. The long‐term weight loss was measured 1‐year post‐surgery, at which time the patients had lost on average 46.7 kg. A multiplex array of 96 inflammation‐related plasma proteins (Olink Inflammation Panel) was analyzed using R‐studio program software version 1.1.38 and Graph Pad Prism.ResultsInflammation (measured as C‐reactive protein) was higher in both MHO and MUO patients than in lean controls, although multivariate analysis of the multiplex array identified 11 proteins that were significantly different between the MHO/MUO groups at baseline. Hierarchal cluster analysis further revealed that the MHO group clustered together at baseline and after short‐term dieting, but not after long‐term weight loss. Both MHO and MUO groups presented with higher levels of macrophage inflammatory protein (MIP)‐1α, C‐C motif chemokine (CCL)‐4, oncostatin‐M and TNSF‐14, as compared to lean controls. CCL‐4 was not affected by weight loss, but oncostatin‐M and TNSF‐14 were significantly lowered by long‐term weight loss in both obese groups. MIP‐1α was further elevated by short‐term dieting, but reduced following long‐term weight loss. IL‐8 and CDCP1 were only increased in the MUO group, while IL‐18 and the anti‐inflammatory LAP TGF‐β1 were only increased in the MHO group; none of these proteins were attenuated by weight loss. Surprisingly, CCL25 and Fractalkine (chemotactics for T‐cells and monocytes) were not elevated in MHO or MUO groups at baseline compared to lean controls, but they were significantly higher 1‐year post‐surgery.ConclusionIn summary, our study revealed that although obesity increases inflammatory markers, these may be differently regulated in MHO versus MUO patients and by short‐ and long‐term weight loss. Currently ongoing investigations are delineating the specific pathways involved.Support or Funding InformationThe Borgeson lab is supported by the Knut &amp; Alice Wallenberg Foundation, Wallenberg Centre for Molecular &amp; Translational Medicine, the Swedish Research Council, (no. 2016/82), the Swedish Society for Medical Research (no. S150086), Ake Wiberg's Foundation (no. M15‐0058), Konrad &amp; Helfrid Johansson's foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comprehensive Lipidome and Proteome Analyses to Identify the Inflammatory and Cardiometabolic Fingerprints of Metabolically “Healthy” Versus “Unhealthy” Obese Subjects

Study ObjectiveObesity‐related co‐morbidities pose a serious health care system burden. However, 30% of obese subjects do not present with cardiometabolic complications. Here we perform comprehensive lipidome and proteome analyses to identify inflammatory and cardiometabolic fingerprints that characterize metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) phenotypes.MethodsObese patients (BMI 35–50) donated plasma before undergoing bariatric surgery (clinicaltrial.gov NCT02322073). Patients were classified as MHO (n=5) versus MUO (n=9) according to International Diabetes Federation criteria. Metabolically healthy lean (MHL, n=14) subjects were age‐ and sex‐matched to the obese cohort. Plasma samples were analyzed for 480 protein biomarkers related to inflammation and cardiometabolic processes in a multiplexed array. Samples were also subjected to untargeted lipidomics and targeted oxylipin lipidomics analyses.ResultsGene‐ontology term analysis of the 15 proteins that were significantly decreased/elevated in MHO vs. MUO patients revealed differences in inflammation, metabolism, apoptosis and fibrosis signaling pathways. Furthermore, lipidomics show distinct differences in the lipid profile of MHO and MUO groups. The MUO group displayed increased levels of ceramides, which are implicated in development of insulin resistance and cardiovascular diseases. In contrast, the MHO group exhibited increased levels of anandamide and dihomo‐gamma‐linolenoyl ethanolamide, which are lipids associated with anti‐inflammatory effects. The MUO group also exhibited elevated levels of the cardiometabolic risk factor plasminogen activator inhibitor 1 (PAI‐1). Interestingly, MHO patients presented with increased levels of myeloblastin, which is a serine protease that degrades the PAI‐1–stabilizing protein vitronectin.ConclusionIn conclusion, we have performed a comprehensive lipidomic and proteomic fingerprinting of MHO and MUO subjects. Our analyses reveal clear stratification of the groups and identify lipid mediators that may be of possible therapeutic use as novel interventions for obesity‐associated pathophysiologies. Work is ongoing to explore the molecular mechanism by which the identified proteins and lipid mediators affect cardiometabolic health in obese patients.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease

AimThis cross-sectional study evaluated liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), and compared the characteristics of metabolically healthy obese (MHO) with metabolically unhealthy obese (MUHO) patients. MethodsThe study was nested within a randomized clinical trial (RCT) and included obese patients with NAFLD, as determined by liver ultrasonography. Fibrosis was assessed by transient elastography, and AST-to-platelet ratio index (APRI) and NAFLD score. Patients were compared according to obesity phenotype using various accepted criteria. ResultsThe RCT included 1024 patients with NAFLD, of whom 428 (41.7%) were included in the present study. The prevalence of MHO ranged from 1.2% to 63%, depending on the criteria used. According to various criteria for metabolic health, obese patients had less liver fibrosis. MHO patients, as defined by all criteria, showed a significantly lower prevalence of advanced liver fibrosis (F3–F4) than MUHO on transient elastography (16.5% vs. 28%, respectively; P≤0.05). ConclusionMUHO patients are at higher risk of liver fibrosis and, therefore, the identification of obese patients with ‘healthy’ characteristics is imperative as their entire clinical work-ups are likely to differ.

Vitamin D status is not related to insulin resistance in different phenotypes of moderate obesity

Low plasma 25-hydroxy-vitamin D (25OHD) and high levels of parathyroid hormone (PTH) are associated with obesity and could play a role in the occurrence of complications such as insulin resistance. The objective of the study was to evaluate whether the relationship between 25OHD status and phosphocalcic parameters differs between metabolically healthy obese (MHO) and insulin-resistant obese (IRO). This cross-sectional study included 158 consecutive adults (121 females) with obesity (body mass index (BMI) 35.15 ± 2.8 kg/m2), aged 43.21 ± 13.6 years. Serum 25OHD, calcemia, phosphatemia, PTH, plasma lipids, fasting plasma glucose, insulin levels, and body composition were measured. Participants were classified as MHO (n = 65) or IRO (n = 93) based on homeostatic model assessment insulin-resistance value. IRO patients had a higher BMI (p = 0.001), waist circumference (p = 0.03), and trunk fat mass (p = 0.007) than MHO patients. Mean HbA1c (p = 0.03), triglycerides (p = 0.02), and hsCRP (p = 0.04) plasmatic levels were increased in the IRO group. No between-group difference was found on 25OHD, PTH, calcium, or phosphorus plasmatic levels. Only age-predicted 25OHD levels were identified among IRO participants, whereas no factors were identified in MHO. No predictive factors of PTH plasmatic level were identified in the IRO and MHO groups. Although MHO and IRO patients have different metabolic profiles, we did not detect any difference regarding either 25OHD or PTH. Insulin resistance was not a predictive factor of vitamin D status. Our results confirm the absence of link between vitamin D status and insulin resistance in moderate obesity.

Abstract 44: Cardiometabolic Responses to Weight Change are Different between Obese and Normal Weight Adults Who are Metabolically Healthy: The Atherosclerosis Risk in Communities Study

Introduction: The 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults recommended weight loss for obese adults in order to reduce their cardiovascular disease (CVD) risk. However, not all obese adults develop CVD and approximately 17% of obese Americans in the 1999-2004 NHANES were metabolically healthy. The absence of abnormal CVD risk factors in this subgroup of obese adults indicates that some individuals are resistant to excess adiposity and positive energy balance, and raises the question of whether all obese adults should be recommended for weight loss treatment. We know of no study that has examined whether metabolically healthy obese (MHO) adults respond to weight changes the same way as metabolically healthy normal weight adults (MHNW). Also, no study has compared the effects of weight loss, weight maintenance and weight gain on CVD risk factors in MHO adults. Hypothesis: We hypothesized that the effects of weight change would be different in MHNW and MHO adults, with MHO adults having less stable risk factors, and that weight loss has a protective effect on CVD risk factors in the MHO compared to weight maintenance and weight gain. Methods: Data were from 2,710 MHO and MHNW participants in the Atherosclerosis Risk in Communities (ARIC) study. Four examinations yielded 4,541 observations over sequential 3-year intervals. Metabolically healthy was defined as absence of all components of metabolic syndrome, excluding waist circumference, at the beginning of a 3-year interval. Mixed effect models were applied to individually compare changes in five CVD risk factors (systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol and glucose) in MHO and MHNW adults within 3 weight change categories (&lt;3% weight loss, weight maintenance (±3%) and &gt;3% weight gain). Results: Weight loss was associated with small or no changes in the five CVD risk factors in both MHO and MHNW adults. Weight maintenance was associated with larger increases in MHO compared to MHNW adults in triglycerides (mean ± standard error: 10.0±1.7 vs. 6.5±1.0 mg/dL) and glucose (1.7±0.4 vs. 0.9±0.2 mg/dL). Weight gain was associated with larger increases in systolic (8.6±0.6 vs. 6.2±0.4 mmHg) and diastolic (3.9±0.4 vs. 2.5±0.3 mmHg) blood pressure, triglycerides (22.0±1.8 vs. 16.0±1.1 mg/dL) and glucose (4.9±0.4 vs. 1.9±0.3 mg/dL) among the MHO compared to the MHNW. MHO weight losers experienced more favorable changes in the five CVD risk factors compared to MHO weight maintainers (p&lt;0.04) or gainers (p&lt;0.0001). Conclusions: We showed that compared to MHNW, MHO adults experienced similar changes in CVD risk factors with weight loss and larger increases with weight maintenance and gain. Our study supports the 2013 Guideline that primary health care providers should recommend weight loss treatment for MHO patients.

Prevalence, Risk Factors, and Genetic Traits in Metabolically Healthy and Unhealthy Obese Individuals.

Objective. To assess prevalence of metabolically healthy individuals among patients with abdominal obesity (AO) and to determine phenotype and potential genetic traits associated with a benign metabolic status. Methods. 503 AO patients without cardiovascular diseases were examined. Waist circumference (WC), BMI, blood pressure, plasma glucose and serum insulin levels, HOMA-IR, lipid profile, and adiponectin (AN) and leptin (LEP) concentrations in serum were measured. Polymorphisms A19G and Q223R of the LEP and LEP receptor gene, and G276T and T45G of the AN gene were investigated. Results. 91.3% of patients were metabolically unhealthy obese (MUO), and 8.7% metabolically healthy obese (MHO). MHO patients were younger, and had lesser BMI and WC, while duration of obesity, frequency, and duration of physical training were greater than MUO patients (p < 0.05). In MHO and MUO patients distribution of the G19G, G19A, and A19A genotypes of the LEP gene and G276G, G276T, and T276T genotypes of AN gene did not differ. The Т45Т genotype was associated with increase of metabolic disorders' risk for patients with АО (OR = 2.331; 95% CI = 1.121 ÷ 5.132). Conclusions. Prevalence of MHO individuals among patients with AO is low. Benign metabolic status was associated with younger age, lower waist circumference, and higher physical activity, shorter duration of obesity, and G45G adiponectin genotype carriage.

Preclinical effects of healthy obesity on inappropriate left ventricular mass and systolic function

Increased cardiometabolic risk is associated with a preclinical im-pairment of cardiac function [1]. Patients with metabolic syndrome(MetS) display myocardial inflammation with early consequences onleft ventricular mass, cardiac geometry and systo-diastolic proper-ties [2,3]. Indeed, increase in cardiovascular mortality begins witheven one MetS component [4]. Interestingly, recent studies haveshownthatmetabolicdisordersratherthanobesityperseareresponsi-ble for increased risk of heart failure overtime [5,6]. Indeed,obese indi-viduals with a favourable metabolic profile had a lower cardiovascularrisk as compared with unhealthy obese and, more surprisingly, withnormal weight individuals matching MetS criteria [7]. In a recentstudy, risk of heart failure was significantly decreased in metabolicallyhealthy obese patients after 6-year follow-up [5]. In this study bodymass index (BMI) was not associated with HF while the presence ofMetS conferred a 2.5-fold higher HF risk. In contrast, overweight andobese individuals without MetS criteria had the lowest HF risk [5].These findings suggest that individual contribution of obesity may bescarce and that metabolic disorders drive most of structural and func-tional changes occurring in the heart of metabolically unhealthy sub-jects. However, obesity-induced cardiomyopathy is a well establishedpathophysiological condition leading to impaired cardiac performancebeyondthepresenceofotherriskfactors[8].Thisscenarioraisesthefol-lowingquestion:whatistheindividualcontributionofobesityoncardi-ac structure and function? Is healthy obesity beneficial for the heart?Tothisend,weinvestigatedtheprevalenceofinappropriateleftven-tricular mass (ILVM) and cardiac function in obese and normal weightindividuals, in the presence or in the absence of metabolic disorders. Atotal of 173 hypertensive subjects were recruited at the CardiologyUnit of Sant'Andrea Hospital and every participant signed an informedconsent before entering the study. According to ATP III criteria [9] andthe presence of obesity (BMI>30 kg/m

High Leptin/Adiponectin Ratio and Serum Triglycerides Are Associated With an “At‐Risk” Phenotype in Young Severely Obese Patients

"At-risk" severely obese subjects are characterized by insulin resistance, and higher visceral fat and plasma lipid levels compared with metabolically healthy obese (MHO) subjects, although both groups have a high BMI and fat mass. The aim of this study was to measure several serum adipokines and gastrointestinal hormones in a young severely obese population from Southern Italy to identify biochemical markers of the "at-risk" insulin-resistant obese profile. We studied 160 unrelated white young adults (mean age = 25.2 years, mean BMI = 44.9 kg/m(2), 65% women) affected by obesity for at least 5 years. Serum concentrations of glucagon, ghrelin, gastric inhibitory peptide, glucagon like peptide-1, interleukin-6, tumor necrosis factor α, leptin, adiponectin, adipsin, and visfatin were measured. The leptin/adiponectin (L/A) ratio and fatty liver index (FLI) were calculated. We found a prevalence of 21.3% of MHO patients in our young severely obese patients. At univariate analysis, the "at-risk" group had higher mean levels of BMI (P < 0.0001), leptin (P = 0.039, men) and the L/A ratio (P = 0.003), and lower mean levels of visfatin (P = 0.026) than the MHO group. The L/A ratio, serum triglycerides, and male sex were significantly associated with "at-risk" obesity and accounted for 19.5% of insulin resistance at multivariate analysis. In conclusion, we demonstrate that a high serum L/A ratio and high levels of serum triglycerides may be markers of "at-risk" obesity, independent of waist circumference (WC) and BMI, in young severely obese population.