Ramadan Intermittent Fasting Is Associated with Changes in Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Metabolically Healthy Obese Subjects.

Background and Objectives: Dietary modification is the principal approach to the management of hyperlipidemia in adults. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of plasma cholesterol and a target for novel lipid-lowering pharmacotherapies. This study aimed to explore how circulating levels of PCSK9 changed during Ramadan intermittent fasting in metabolically healthy obese subjects. Materials and Methods: This cross-sectional study used convenience sampling to recruit 55 overweight and obese participants (22 females and 33 males) who observed Ramadan fasting. Body weight and composition, glucoregulatory factors, serum PCSK9 concentration, dietary intake, and physical activity were assessed 1 week before and at the end of Ramadan fasting. Results: The median (interquartile range) age was 35 (22) years, and body mass index was 30.2 (5.4). We found significant (p < 0.05) increases in serum levels of PCSK9, serum insulin, insulin resistance, and leptin at the end of Ramadan compared with pre-fasting levels. Significant (p < 0.05) reductions in body weight, waist circumference, systolic and diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and adiponectin were also observed at the end of Ramadan. Conclusions: Observing Ramadan fasting was associated with increased PCSK9 levels in metabolically healthy obese subjects. The complex relationships between PCSK9 and insulin resistance and dysregulation of adipokine secretion in relation to dietary and lifestyle modifications during Ramadan warrant further research.

Multi-Vessel Disease in Metabolically Healthy Obese Patients Presenting with ST-Elevation Myocardial Infarction.

BACKGROUND: The extent and impact of obesity as an isolated risk factor for coronary artery disease is not clear since co-morbidities serve as confounders and may mask this association. OBJECTIVES: To examine whether obesity is associated with extensive coronary artery disease among metabolically healthy patients presenting with ST-elevation myocardial infarction (STEMI) and to explore the outcomes according to body mass index (BMI). METHODS: We stratified STEMI patients who had a metabolically healthy phenotype and available weight and height data according to BMI: 18.5-25 kg/m² (lean), 25.01-30 kg/m² (overweight), and > 30 kg/m² (obese). RESULTS: Overall 381 patients were included, 42% lean, 41% overweight, and 17% obese. Patients with increased BMIs had higher levels of low-density proteins and triglycerides (P < 0.05). Obese patients presented with the lowest rates of multi-vessel disease (12.9% vs. 22.9% for overweight and 28% for lean). In a univariable analysis, obese patients were 60% less likely to be diagnosed with multi-vessel disease (odds ratio 0.4, 95% confidence interval 0.2-0.9, P = 0.021) compared to lean patients. The association remained significant in a multivariable model adjusted for baseline characteristics (P = 0.029). There were no differences in 30-day or long-term mortality (median follow-up 3.2 years) among the groups (P > 0.1 for all comparisons). CONCLUSIONS: Metabolically healthy phenotype obesity was associated with lower rates of multi-vessel disease despite higher levels of triglycerides. However, this association did not translate into increased mortality.

Metabolically Healthy Obesity (MHO) vs. Metabolically Unhealthy Obesity (MUO) Phenotypes in PCOS: Association with Endocrine-Metabolic Profile, Adherence to the Mediterranean Diet, and Body Composition.

Obesity and obesity-related low-grade inflammation are common findings in polycystic ovary syndrome (PCOS), the most common endocrine-metabolic disorder-affecting women in reproductive age. The terms metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) have been introduced to define individuals with obesity in whom cardio-metabolic risk factors are absent or present, respectively. To date, evidence investigating differences in body composition and adherence to the Mediterranean diet (MD) between MHO and MUO-PCOS women are lacking. Aim of this study was to better characterize the determinants of the metabolic health status in PCOS patients with obesity according to MHO and MUO phenotypes by evaluating endocrine-metabolic profile, inflammatory status, adherence to the MD, and body composition. The study population consisted of 94 treatment-naïve women with PCOS and obesity (BMI = 38.23 ± 6.62 kg/m2 and age = 24.12 ± 3.68 years). Compared PCOS MHO with PCOS MUO patients, the latter had higher levels of high-sensitivity C-reactive protein (hs-CRP) (p < 0.001), testosterone (p < 0.001), and insulin (p < 0.001), worse metabolic parameters, and higher Homeostatic Model Assessment of Insulin Resistance (HoMA-IR), Visceral Adiposity Index (VAI), and Fatty liver Index (FLI) (p < 0.001). Furthermore, PCOS MUO patients had lower adherence to the MD (p < 0.001) in spite of the same total energy intake (p = 0.102) as compared to PCOS MHO. The presence of MUO was associated with highest hs-CRP levels (OR = 1.49, p < 0.001), more severe hyperandrogenism and cardio-metabolic indices (p < 0.001). On the contrary, being PCOS MUO was associated with lower adherence to the MD (OR = 0.28, p < 0.001), and smaller PhAs (OR = 0.04, p < 0.001). Using a regression linear analysis model PREDIMED score entered at the first step (p < 0.001), followed by VAI (p < 0.001), and FLI (p = 0.032) in this analysis. At ROC analysis, a PREDIMED score of ≤4 (p < 0.001, AUC 0.926) could serve as a threshold for a significantly increased risk of presence the MUO-PCOS phenotype. To the best of our knowledge, this is the first study that characterized MHO and MUO-PCOS women on the basis of their adherence to the MD, body composition, and cardio-metabolic indices, providing evidence of the usefulness of adjunctive diagnostic parameters to better differentiate the MHO/MHO phenotypes in this cohort of PCOS patients with obesity.

Do Temporal Eating Patterns Differ in Healthy versus Unhealthy Overweight/Obese Individuals?

This study examined whether the temporal patterns of energy and macronutrient intake in early and late eating windows were associated with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) among non-shift workers. A total of 299 overweight/obese non-shift workers (Age: 40.3 ± 6.9 years; 73.6% women; BMI: 31.7 ± 5.0 kg/m2) were recruited in the Klang Valley area of Malaysia. The biochemical parameters were determined from fasting blood samples, whereas information on dietary intake and timing was obtained from a 7-day diet history questionnaire. The midpoint of eating was used to determine the early and late windows. Compared to MHO non-shift workers (n = 173), MUO non-shift workers (n = 126) had lower energy intake from carbohydrates and protein during the early window. In contrast, MUO participants had greater energy intake from carbohydrates and fat during the late window. Participants with unhealthy metabolic status (regardless of their chronotypes) had similar temporal patterns of energy intake characterized by smaller energy intake during the early window and greater energy intake during the late window compared with participants with healthier metabolic status. Overall, the lowest percentile of energy intake during the early window was associated with an increased risk of MUO, after adjustment for potential confounders [odds ratio (OR) = 4.30, 95% confidence interval (CI) 1.41-13.11]. The greater the energy intake during the late window, the greater the risk of MUO (OR = 2.38, 95% CI 1.11-5.13) (OR = 2.33, 95% CI 1.03-5.32) (OR = 4.45, 95% CI 1.71-11.56). In summary, consuming less energy earlier in the day and more energy and carbohydrate later in the day was associated with a greater risk of MUO. Thus, a prospective study is needed to explore the potential role of chrono-nutrition practices in modifying risk factors to delay the transition of MHO to MUO.

Leukocyte related parameters in older adults with metabolically healthy and unhealthy overweight or obesity.

It remains unclear whether leukocyte-related parameters could be used as biomarkers to differentiate metabolically unhealthy overweight/obesity (MUO) from metabolically healthy overweight/obesity (MHO). We aimed to examine the differences in the distribution of leukocyte-related parameters between older adults with MHO and MUO and the correlations of leukocyte-related parameters with individual components of metabolic abnormality. In the Weitang Geriatric Diseases Study on older Chinese adults aged 60 years or above, 404 individuals with MHO and 480 with MUO contributed to the analysis. Overweight/obesity was defined as body mass index (BMI) of 25 kg/m2 or more. MHO and MUO were discriminated based on the Adult Treatment Panel III (ATP III) criteria. Leukocyte-related parameters were assessed using an automated hematology analyzer. All leukocyte-related parameters except monocytes were elevated in MUO group compared with MHO group (all P < 0.05). The prevalence of MUO increased by 24% with each 109/L increase of leukocytes after adjusting for confounders in the multiple-adjusted model (P < 0.01) and each unit elevation of other parameters except lymphocytes and monocytes were significantly associated with the presence of MUO (all P < 0.01). Trend tests revealed a linear trend for the association between MUO and all the leukocyte-related parameters (all P for trend < 0.05). Significant interactions between leukocyte-related parameters and sex on the presence of MUO were observed (all P value for interaction < 0.05). Higher leukocyte-related parameters were found in patients with MUO than those with MHO and were associated with higher prevalence of MUO which seems to be sex-dependent. Further studies are needed to see whether these parameters could be used as biomarkers for the screening or diagnosis for MUO in clinical or public health practice.

Circulating cell adhesion molecules in metabolically healthy obesity.

BACKGROUND/OBJECTIVES: People with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals. SUBJECTS/METHODS: Serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (n = 32), MHO categorized into BMI-matched insulin sensitive (IS, n = 32) or insulin resistant (IR) obesity (n = 32) and people with metabolically unhealthy obesity (MUO, n = 32). RESULTS: Indeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO. CONCLUSIONS: These findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored.

Metabolically healthy obesity: is there a link with polyunsaturated fatty acid intake and status?

The aim of this study was to compare dietary intake and status of polyunsaturated fatty acids (PUFA) in plasma and erythrocyte phospholipids metabolically healthy and unhealthy, and obese and nonobese persons. Metabolic health status in 171 participants was defined according to criteria for metabolic syndrome. Obese and nonobese metabolically unhealthy persons (MUHO and MUHNO) had higher energy intake of n-6 PUFA (7.82 ± 1.03 and 7.49 ± 0.86) and lower intake of n-3 PUFA (0.60 ± 0.12 and 0.62 ± 0.11) compared to obese and nonobese metabolically healthy persons (MHO and MHNO) (5.92 ± 0.63 and 5.72 ± 0.67; 1.20 ± 0.07 and 1.22 ± 0.09, respectively) and a higher n-6/n-3 PUFA ratio. The plasma level of n-6 PUFA was lower in the MUHO and MUHNO groups (38.49 ± 3.71 and 38.53 ± 2.19) compared to MHNO (40.90 ± 2.43), while n-3 PUFA status was lower in obese than in nonobese persons (3.58 ± 0.79 and 3.50 ± 1.02 vs. 4.21 ± 0.80 and 4.06 ± 1.15). The MHO group had a higher eicosapentaenoic/arachidonic acid ratio and estimated desaturase (SCD16, D6D) and elongase activity in plasma phospholipids compared to MHNO. The low intake of n-3 PUFA is directly associated with metabolic risk factors. These results indicated that obesity is closely associated with low levels of n-3 PUFA in plasma phospholipids, suggesting that dietary modifications including n-3 PUFA supplementation appear to be suitable therapeutic strategy in obese persons.

Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity.

BACKGROUND: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes. The underlying mechanisms for those differences are still unclear. This study aimed to analyze the whole-blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. METHODS: Twenty-seven children with OW/OB (10.1 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein-cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers were additionally determined. Total blood RNA was analyzed by 5'-end RNA-sequencing. RESULTS: Whole-blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. Thirty-two genes differentially expressed were linked to metabolism, mitochondrial, and immune functions. CONCLUSIONS: The identified gene expression patterns related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity. IMPACT: A distinct pattern of whole-blood transcriptome profile (RNA-seq) was identified in children with metabolic healthy overweight/obesity (MHO) compared to metabolic unhealthy overweight/obesity (MUO) phenotype. The most relevant genes in understanding the molecular basis underlying the MHO/MUO phenotypes in children could be: RREB1, FAM83E, SLC44A1, NRG1, TMC5, CYP3A5, TRIM11, and ADAMTSL2. The identified whole-blood transcriptome profile related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity.

Metabolic health is a determining factor for incident colorectal cancer in the obese population: A nationwide population-based cohort study.

BACKGROUND: The association of the risk of colorectal cancer (CRC) with obesity or obesity-induced metabolic disturbances remains controversial. We assessed the association of metabolic health status with incident CRC among subjects with obesity. METHODS: This study included 319,397 subjects from the Korean National Health Insurance Service-National Health Screening Cohort. Transitions in metabolic health status and obesity were examined during 2009-2010 and 2011-2012. We categorized subjects with obesity into four separate groups according to their dynamic metabolic health status: metabolically healthy obesity (MHO), MHO to metabolically unhealthy obesity (MUO), MUO to MHO, and stable MUO. Subjects were followed up from 2009 to 2015 for incident CRC. RESULTS: The stable MHO group showed no increased risk of incident CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.83-1.14). However, the MHO to MUO group had a higher risk of incident CRC than the stable metabolically healthy nonobese (MHNO) group (HR, 1.34; 95% CI, 1.15-1.57). Among patients with MUO at baseline, those in the subgroup who transitioned to MHO group were not at increased risk of CRC (HR, 1.06; 95% CI, 0.91-1.25), whereas those who remained in the stable MUO group had a higher risk of incident CRC than those in the stable MHNO group (HR, 1.29; 95% CI, 1.19-1.41). CONCLUSIONS: The transition of metabolic health was a determining factor for CRC among subjects with obesity. Hence, maintenance or recovery of metabolic health should be addressed to prevent CRC in individuals with obesity.

Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: A cohort study.

BACKGROUND: Metabolically healthy obesity (MHO) and its transition to unhealthy metabolic status have been associated with risk of cardiovascular disease (CVD) in Western populations. However, it is unclear to what extent metabolic health changes over time and whether such transition affects risks of subtypes of CVD in Chinese adults. We aimed to examine the association of metabolic health status and its transition with risks of subtypes of vascular disease across body mass index (BMI) categories. METHODS AND FINDINGS: The China Kadoorie Biobank was conducted during 25 June 2004 to 15 July 2008 in 5 urban (Harbin, Qingdao, Suzhou, Liuzhou, and Haikou) and 5 rural (Henan, Gansu, Sichuan, Zhejiang, and Hunan) regions across China. BMI and metabolic health information were collected. We classified participants into BMI categories: normal weight (BMI 18.5-23.9 kg/m²), overweight (BMI 24.0-27.9 kg/m²), and obese (BMI ≥ 28 kg/m²). Metabolic health was defined as meeting less than 2 of the following 4 criteria (elevated waist circumference, hypertension, elevated plasma glucose level, and dyslipidemia). The changes in obesity and metabolic health status were defined from baseline to the second resurvey with combination of overweight and obesity. Among the 458,246 participants with complete information and no history of CVD and cancer, the mean age at baseline was 50.9 (SD 10.4) years, and 40.8% were men, and 29.0% were current smokers. During a median 10.0 years of follow-up, 52,251 major vascular events (MVEs), including 7,326 major coronary events (MCEs), 37,992 ischemic heart disease (IHD), and 42,951 strokes were recorded. Compared with metabolically healthy normal weight (MHN), baseline MHO was associated with higher hazard ratios (HRs) for all types of CVD; however, almost 40% of those participants transitioned to metabolically unhealthy status. Stable metabolically unhealthy overweight or obesity (MUOO) (HR 2.22, 95% confidence interval [CI] 2.00-2.47, p < 0.001) and transition from metabolically healthy to unhealthy status (HR 1.53, 1.34-1.75, p < 0.001) were associated with higher risk for MVE, compared with stable healthy normal weight. Similar patterns were observed for MCE, IHD, and stroke. Limitations of the analysis included lack of measurement of lipid components, fasting plasma glucose, and visceral fat, and there might be possible misclassification. CONCLUSIONS: Among Chinese adults, MHO individuals have increased risks of MVE. Obesity remains a risk factor for CVD independent of major metabolic factors. Our data further suggest that metabolic health is a transient state for a large proportion of Chinese adults, with the highest vascular risk among those remained MUOO.

The association between transition from metabolically healthy obesity to metabolic syndrome, and incidence of cardiovascular disease: Tehran lipid and glucose study.

Considering that the data available on the cardiovascular (CV) risk of metabolically healthy obesity phenotype, and the effect of transition to an unhealthy status are inconsistent, the aim of this study was to investigate the possible role of transition to unhealthy status among metabolically healthy overweight/obese (MHO) subjects on CVD incidence over a median follow-up of 15.9 years. In this large population-based cohort, 6758 participants (41.6% men) aged ≥ 20 years, were enrolled. Participants were divided into 4 groups based on their obesity phenotypes and follow-up results, including persistent metabolically healthy normal weight (MHNW), persistent MHO, transitional MHO and metabolically unhealthy overweight/obese (MUO). Metabolic health was defined as not having metabolic syndrome based on the Joint Interim Statement (JIS) criteria. Multivariable adjusted hazard ratios (HRs) were calculated for cardiovascular events. During follow-up, rate of CVD Incidence per 1000 person-years were 12 and 7 in males and females, respectively. Multivariable adjusted HRs (CI 95%) of CVD incidence among males and females were 1.37 (.78-2.41) and .85 (.34-2.15) in persistent MHO group, 1.55 (1.02-2.37) and .93 (.41-2.12) in transitional MHO group and 2.64 (1.89-3.70) and 2.65 (1.24-5.68) in MUO group. Our findings showed that CVD risk did not increase in the persistent MHO phenotype over a 15.9-year follow-up in both sexes. However, transition from MHO to MUO status during follow-up increased the CVD risk just in male individuals. Further studies are needed to provide conclusive evidence in favor of benign nature of transitional MHO phenotype in females.

Increased AHR Transcripts Correlate With Pro-inflammatory T-Helper Lymphocytes Polarization in Both Metabolically Healthy Obesity and Type 2 Diabetic Patients.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose transcription activity is regulated by small compounds provided by diet, xenobiotics, and metabolism. It has been proven to be involved in energy homeostasis and inflammation in most recent years. Epidemiologically, exposure to xenobiotic AHR ligands contributes to obesity and type 2 diabetes (T2D). AHR is also the critical transcription factor determining the lineage commitment of pro-inflammatory Th17 and Th22 cells from naïve CD4+ T lymphocytes. It has been well-illustrated in animal models that IL-22, the major effector cytokine of Th17 and Th22 cells, played a major role in the interaction of metabolism and gut microbiota. But there were still missing links between gut microbiota, IL-22, and metabolism in humans. Our previous findings indicated that elevated circulating levels of IL-22 and frequencies of Th22 cells were associated with insulin resistance in both patients with obesity and T2D. Additionally, the hyperactive Th17 and Th22 cells phenotype also correlate with islets ß-cell dysfunction in T2D. In this study, we made efforts to determine AHR expressions in peripheral blood mononuclear cells (PBMCs) from patients with T2D and metabolically healthy obesity (MHO). Correlation analyses were conducted to assess the possible link between AHR and the metabolic and inflammatory context. We revealed that mRNA expression of AHR was up-regulated and correlated with the percentage of Th17, Th22 as well as Th1 cells. Elevated plasma levels of IL-22 and IL-17 also correlated with increased AHR transcripts in PBMCs from both MHO and T2D patients. The transcription factor AHR may thus have a plausible role in the interaction between metabolism and pro-inflammatory status of patients in the development of obesity and T2D.

Higher Serum Neuropeptide Y Levels Are Associated with Metabolically Unhealthy Obesity in Obese Chinese Adults: A Cross-Sectional Study.

OBJECTIVE: Neuropeptide Y (NPY), an orexigenic peptide known to cause hyperphagia, has been involved in the occurrence and development of obesity. However, differences in the distribution of serum NPY levels in obese phenotypes (including metabolically unhealthy obesity (MUO) phenotype and metabolically healthy obesity (MHO) phenotype) and the association of NPY with MUO phenotype have not been unequivocally established. We therefore determined associations of serum NPY levels with MUO phenotype in obese Chinese adults. METHODS: A cross-sectional study was conducted from 400 obese adults in Hunan province, who underwent a health examination in the Second Xiangya Hospital, and 164 participants were finally enrolled in the study and divided into MHO and MUO groups. Serum NPY levels were examined; univariate and multivariate analyses as well as smooth curve fitting analyses were conducted to measure the association of NPY serum levels with the MUO phenotype. RESULTS: Serum NPY levels were significantly elevated in the MUO group compared with the MHO group ((667.69 ± 292.90) pg/mL vs. (478.89 ± 145.53) pg/mL, p < 0.001). A threshold and nonlinear association between serum NPY levels and MUO was found (p = 0.001). When serum NPY levels exceeded the turning point (471.5 pg/mL), each 10 pg/mL increment in the NPY serum level was significantly associated with an 18% increased odds ratio of MUO phenotype (OR: 1.18, 95% CI: 1.07-1.29, p = 0.0007) after adjusted for confounders. CONCLUSIONS: Higher NPY serum levels were positively correlated with MUO phenotype in obese Chinese adults.

Association Metabolic Obesity Phenotypes with Cardiometabolic Index, Atherogenic Index of Plasma and Novel Anthropometric Indices: A Link of FTO-rs9939609 Polymorphism.

BACKGROUND: The role of metabolic states in cardiovascular risks among individuals with varying degrees of obesity is unknown. The study aimed to compare cardiometabolic index (CMI), atherogenic index of plasma (AIP), lipid accumulation product (LAP) and novel anthropometric indices in metabolic and non-metabolically obese individual with regard to the role of FTO gene in Iranian adults. METHODS: In total, 165 individuals were recruited into this cross-sectional study. Individuals grouped into four groups: metabolic healthy normal-weight (MHNW) individuals, metabolically unhealthy normal-weight (MUNW) individuals, metabolically healthy obese (MHO) individuals and metabolic unhealthy obese (MUO) individuals. The dietary intake was evaluated by food frequency questionnaire (FFQ). The cardiovascular indices (CMI, AIP and LAP) were calculated. A variety of anthropometric indices were calculated, including body adiposity Index (BAI), weight-adjusted-waist index (WWI), A body shape index (ABSI) and waist-height ratio (WHR). The genotypes of FTO-rs9939609 subjects were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The individuals with metabolically unhealthy phenotypes (MUO, MUNW) have higher levels of triglyceride and cardiovascular indices (AIP, LAP and CMI) than the individuals with metabolic healthy phenotypes (MHO, MHNW). With a similar degree of obesity, the anthropometric indices (BAI, WWI and WHR) levels were higher in metabolic unhealthy groups than metabolically healthy groups. The highest frequency of obesity-risk allele AA of FTO gene was observed in MUO, MHO, MUNW and MHNW, respectively. CONCLUSION: Normal-weight individuals with metabolic unhealthy status are at higher risk for cardiovascular diseases than obese individuals with metabolically healthy status. The genotype frequencies of obesity-risk allele AA of FTO gene were higher in obesity phenotypes than metabolic phenotypes.

Functional pasta consumption in healthy volunteers modulates ABCG1-mediated cholesterol efflux capacity of HDL.

BACKGROUNDS AND AIMS: Prevention of cardiovascular (CV) disease is considered a central issue in public health and great attention is payed to nutritional approaches, including consumption of functional foods to reduce CV risk in individuals without indications for anti-atherosclerotic drugs. Cholesterol efflux capacity (CEC) is an important anti-atherogenic property of HDL and a marker of CV risk. We evaluated the effect of a daily consumption of an innovative whole-wheat synbiotic pasta, compared to a control whole-wheat pasta, on serum ATP binding cassette G1 (ABCG1)-mediated CEC in healthy overweight or obese individuals. METHODS AND RESULTS: Study participants (n = 41) were randomly allocated to either innovative or control pasta, consumed daily for twelve weeks. Serum CEC was measured before and after the dietary intervention, by a well-established radioisotopic technique on Chinese Hamster Ovary Cells transfected with human ABCG1. The innovative synbiotic pasta consumption was associated to a significantly higher post treatment/baseline ratio of ABCG1-mediated CEC values with respect to control pasta (mean ratio 1.05 ± 0.037 and 0.95 ± 0.042 respectively, p < 0.05). Analysis of the relationship between ABCG1-mediated CEC and glycemia, homocysteine, total folates and interleukin-6 showed specific changes in the correlations between HDL function and glycemia, oxidative and inflammatory markers only after synbiotic pasta consumption. CONCLUSION: This is the first report on serum CEC improvement obtained by a new synbiotic functional pasta consumption, in absence of lipid profile modifications, in overweight/obese participants. This pilot study suggests that a simple dietary intervention can be a promising approach to CV preservation through improving of athero-protective HDL function.

Semaphorin 3 C is a Novel Adipokine Representing Exercise-Induced Improvements of Metabolism in Metabolically Healthy Obese Young Males.

This study investigated the endurance exercise-induced changes in lesser known adipokines (visfatin, chemerin, apelin, semaphorin 3 C) related to obesity and metabolism, and their correlations with the changes in the parameters of obesity and glucose homeostasis. Forty metabolically healthy obese young males were randomly assigned to control group (C, n = 12) or exercise group (Ex, n = 28). The subjects in Ex participated in a 8-week supervised endurance exercise training program, comprised of four sessions of treadmill running at 65-70% of VO2max per week. Serum levels of visfatin, chemerin, apelin, and semaphorin 3 C were significantly decreased in Ex. At baseline, apelin and semaphorin 3 C appeared to be correlated with obesity measures, including body mass index, % total fat and trunk fat, and waist circumference. Exercise-induced changes in these obesity measures significantly correlated with the changes in chemerin and semaphorin 3 C. Basal chemerin, apelin and semaphorin 3 C correlated with glucose homeostasis parameters, including fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance and ß-cell function, and quantitative insulin-sensitivity check index to different extents. Furthermore, the changes in apelin and semaphorin 3 C well predicted the improvements in glycemic parameters. We suggest that semaphorin 3 C is a novel adipokine involved in pathophysiology of obesity and metabolism, and that it is a biomarker representing an exercise-induced improvement in metabolically healthy obese young males.

A comprehensive metabolic profiling of the metabolically healthy obesity phenotype.

BACKGROUND: The ever-increasing prevalence of obesity constitutes a major health problem worldwide. A subgroup of obese individuals has been described as "metabolically healthy obese" (MHO). In contrast to metabolically unhealthy obese (MUO), the MHO phenotype has a favorable risk profile. Despite this, the MHO phenotype is still sub-optimally characterized with respect to a comprehensive risk assessment. Our aim was to increase the understanding of metabolic alterations associated with healthy and unhealthy obesity. METHODS: In this cross-sectional study, men and women (18-70 years) with obesity (body mass index (BMI) ≥ 30 kg/m2) or normal weight (NW) (BMI ≤ 25 kg/m2) were classified with MHO (n = 9), MUO (n = 10) or NW (n = 11) according to weight, lipid profile and glycemic regulation. We characterized individuals by comprehensive metabolic profiling using a commercial available high-throughput proton NMR metabolomics platform. Plasma fatty acid profile, including short chain fatty acids, was measured using gas chromatography. RESULTS: The concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) subclasses were overall significantly higher, and high density lipoprotein (HDL) subclasses lower in MUO compared with MHO. VLDL and IDL subclasses were significantly lower and HDL subclasses were higher in NW compared with MHO. The concentration of isoleucine, leucine and valine was significantly higher in MUO compared with MHO, and the concentration phenylalanine was lower in NW subjects compared with MHO. The fatty acid profile in MHO was overall more favorable compared with MUO. CONCLUSIONS: Comprehensive metabolic profiling supports that MHO subjects have intermediate-stage cardiovascular disease risk marker profile compared with NW and MUO subjects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01034436, Fatty acid quality and overweight (FO-study).

Cardiovascular Risk Factors Associated With the Metabolically Healthy Obese (MHO) Phenotype Compared to the Metabolically Unhealthy Obese (MUO) Phenotype in Children.

Background: In pediatric age the prevalence of obesity is high. Obese children who do not have other risk factors than excess weight have been defined as "metabolically healthy obese" (MHO). Aim: The aim of this study is to evaluate, in a population of obese children, the prevalence of the MHO and "metabolically unhealthy obese" (MUO) phenotype. Furthermore, we evaluated the distribution of Uric Acid, HOMA index and Waist-Height ratio (W-Hr) in the MHO and MUO sub-groups and the impact of these non-traditional risk factors on the probability to be MUO. Methods: In 1201 obese children and adolescents [54% males, age (±SD) 11.9 (±3.0) years] weight, height, waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, pubertal status, glucose, insulin, HDL cholesterol, triglycerides and Uric Acid serum values were assessed. MUO phenotype was defined as the presence of at least one of the following risk factors: SBP or DBP ≥ 90th percentile, glycaemia ≥ 100 mg/dl, HDL cholesterol <40 mg/dl, triglycerides ≥100 mg/dl (children <10 years) or ≥130 mg/dl (children ≥10 years). A multivariate logistic regression analysis was used to estimate the association between MUO phenotype and non-traditional cardiovascular risk factors. Results: The prevalence of the MUO status was high (61%). MUO subjects were more often male, older and pubertal (p < 0.001). The levels of the three non-traditional risk factors were significantly higher in MUO children compared to MHO children (p < 0.001) and all of them were independent predictors of the fact of being MUO [OR 1.41 (95% CI 1.24-1.69); 1.15 (95% CI 1.06-1.23) and 1.03 (95% CI1.01-1.05) for Uric Acid, HOMA index and W-Hr, respectively]. About 15% of MHO subjects had serum Uric Acid, HOMA index and W-Hr values within the highest quartile of the study population. Conclusion: The prevalence of MUO subjects in a large pediatric population is high and serum Uric Acid, HOMA index and W-Hr values are independent predictors of the probability of being MUO. A non-negligible percentage of subjects MHO has high values of all three non-traditional risk factors.

Effects of a long-term lifestyle intervention on metabolically healthy women with obesity: Metabolite profiles according to weight loss response.

BACKGROUND & AIMS: The benefits of weight loss in subjects with metabolically healthy obesity (MHO) are still a matter of controversy. We aimed to identify metabolic fingerprints and their associated pathways that discriminate women with MHO with high or low weight loss response after a lifestyle intervention, based on a hypocaloric Mediterranean diet (MedDiet) and physical activity. METHODS: A UPLC-Q-Exactive-MS/MS metabolomics workflow was applied to plasma samples from 27 women with MHO before and after 12 months of a hypocaloric weight loss intervention with a MedDiet and increased physical activity. The subjects were stratified into two age-matched groups according to weight loss: <10% (low weight loss group, LWL) and >10% (high weight loss group, HWL). Random forest analysis was performed to identify metabolites discriminating between the LWL and the HWL as well as within-status effects. Modulated pathways and associations between metabolites and anthropometric and biochemical variables were also investigated. RESULTS: Thirteen metabolites discriminated between the LWL and the HWL, including 1,5-anhydroglucitol, carotenediol, 3-(4-hydroxyphenyl)lactic acid, N-acetylaspartate and several lipid species (steroids, a plasmalogen, sphingomyelins, a bile acid and long-chain acylcarnitines). 1,5-anhydroglucitol, 3-(4-hydroxyphenyl)lactic acid and sphingomyelins were positively associated with weight variables whereas N-acetylaspartate and the plasmalogen correlated negatively with them. Changes in very long-chain acylcarnitines and hydroxyphenyllactic levels were observed in the HWL and positively correlated with fasting glucose, and changes in levels of the plasmalogen negatively correlated with insulin resistance. Additionally, the cholesterol profile was positively associated with changes in acid hydroxyphenyllactic, sphingolipids and 1,5-AG. CONCLUSIONS: Higher weight loss after a hypocaloric MedDiet and increased physical activity for 12 months is associated with changes in the plasma metabolome in women with MHO. These findings are associated with changes in biochemical variables and may suggest an improvement of the cardiometabolic risk profile in those patients that lose greater weight. Further studies are needed to investigate whether the response of those subjects with MHO to this intervention differs from those with unhealthy obesity.