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Primary hypertension is the dominant form of arterial hypertension in adolescents. Disturbed body composition with, among other things, increased visceral fat deposition, accelerated biological maturation, metabolic abnormalities typical for metabolic syndrome, and increased adrenergic drive constitutes the intermediary phenotype of primary hypertension. Metabolic syndrome is observed in 15–20% of adolescents with primary hypertension. These features are also typical of obesity-related hypertension. Metabolic abnormalities and metabolic syndrome are closely associated with both the severity of hypertension and the risk of target organ damage. However, even though increased body mass index is the main determinant of blood pressure in the general population, not every hypertensive adolescent is obese and not every obese patient suffers from hypertension or metabolic abnormalities typical for metabolic syndrome. Thus, the concepts of metabolically healthy obesity, normal weight metabolically unhealthy, and metabolically unhealthy obese phenotypes have been developed. The risk of hypertension and hypertensive target organ damage increases with exposure to metabolic risk factors which are determined by disturbed body composition and visceral obesity. Due to the fact that both primary hypertension and obesity-related hypertension present similar pathogenesis, the principles of treatment are the same and are focused not only on lowering blood pressure, but also on normalizing body composition and metabolic abnormalities.

Summary Objective ANGPTL4 inhibits lipoprotein lipase in adipose tissue, regulating plasma triglycerides levels. In persons with obesity plasma ANGPTL4 levels have been positively correlated with body fat mass, TG levels and low HDL. A loss‐of‐function E40K mutation in ANGPTL4 prevents LPL inhibition, resulting in lower TGs and higher HDLc in the general population. Since obesity determines metabolic alterations and consequently is a major risk factor for cardiovascular disease, the aim was to explore if obesity‐related metabolic abnormalities are modified by the ANGPTL4‐E40K mutation. Methods ANGPTL4‐E40K was screened in 1206 Italian participants, of which 863 (71.5%) with obesity. All subjects without diabetes underwent OGTT with calculation of indices of insulin‐sensitivity. Results Participants with obesity carrying the E40K variant had significantly lower TG (p = 0.001) and higher HDLc levels (p = 0.024). Also in the whole population low TGs and high HDLc were confirmed in E40K carriers. In the obese subpopulation it was observed that almost all E40K carriers were within the lowest quartile of TGs (p = 1.1 × 10−9). E40K had no substantial effect of on glucose metabolism. Finally, none of the obese E40K carriers had T2D, and together with the favourable lipid profile, they resemble a metabolically healthy obese (MHO) phenotype, compared to 38% of E40E wild‐type obese that had diabetes and/or dyslipidaemia (p = 0.0106). Conclusions In participants with obesity the ANGPTL4‐E40K variant protects against dyslipidemia. The phenotype of obese E40K carriers is that of a patient with obesity without metabolic alterations, similar to the phenotype described as metabolic healthy obesity.

Aims/hypothesisPeople with obesity and a normal metabolic profile are sometimes referred to as having ‘metabolically healthy obesity’ (MHO). However, whether this group of individuals are actually ‘healthy’ is uncertain. This study aims to examine the associations of MHO with a wide range of obesity-related outcomes.MethodsThis is a population-based prospective cohort study of 381,363 UK Biobank participants with a median follow-up of 11.2 years. MHO was defined as having a BMI ≥ 30 kg/m2 and at least four of the six metabolically healthy criteria. Outcomes included incident diabetes and incident and fatal atherosclerotic CVD (ASCVD), heart failure (HF) and respiratory diseases.ResultsCompared with people who were not obese at baseline, those with MHO had higher incident HF (HR 1.60; 95% CI 1.45, 1.75) and respiratory disease (HR 1.20; 95% CI 1.16, 1.25) rates, but not higher ASCVD. The associations of MHO were generally weaker for fatal outcomes and only significant for all-cause (HR 1.12; 95% CI 1.04, 1.21) and HF mortality rates (HR 1.44; 95% CI 1.09, 1.89). However, when compared with people who were metabolically healthy without obesity, participants with MHO had higher rates of incident diabetes (HR 4.32; 95% CI 3.83, 4.89), ASCVD (HR 1.18; 95% CI 1.10, 1.27), HF (HR 1.76; 95% CI 1.61, 1.92), respiratory diseases (HR 1.28; 95% CI 1.24, 1.33) and all-cause mortality (HR 1.22; 95% CI 1.14, 1.31). The results with a 5 year landmark analysis were similar.Conclusions/interpretationWeight management should be recommended to all people with obesity, irrespective of their metabolic status, to lower risk of diabetes, ASCVD, HF and respiratory diseases. The term ‘MHO’ should be avoided as it is misleading and different strategies for risk stratification should be explored.

Richard Christophorus Kurniawan,1,* Frederick Suhamdy,1,* Muhammad Makarimal Akhlaq,1 Eko Fuji Ariyanto2,3 1Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia; 2Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia; 3Study Center for Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, 40161, Indonesia*These authors contributed equally to this workCorrespondence: Richard Christophorus Kurniawan, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia, Email richard24002@mail.unpad.ac.idBackground and Objectives: Childhood obesity is associated with both short-term and long-term health complications, yet a new obesity phenotype called metabolically healthy obesity (MHO) has emerged. While MHO is often perceived as a “benign” form of obesity, research specifically examining health disorders risks in children with MHO remains limited. This systematic review and meta-analysis aimed to evaluate health disorders in children with MHO.Methods: Following PRISMA 2020 guidelines, we systematically searched five databases (PubMed, Scopus, Google Scholar, EBSCO, and ScienceDirect) for observational studies examining MHO children aged 0– 18 years. The studies were analyzed using R and R Studio software, with study quality assessed using the Newcastle Ottawa Scale.Results: Ten studies with a total of 19,119 children were included in this review. Children with MHO demonstrated significantly higher overall health disorders risk compared to MHNW children (pooled OR 2.88, 95% CI [1.64; 5.06]). This trend aligns with the subgroups analysis of left ventricle hypertrophy, hypertension, and kidney damage. However, some of the subgroup analyses showed insignificant results. Additionally, MHO children showed lower risks of experiencing health disorders compared to MUO children (pooled OR 0.56, 95% CI [0.23; 1.34]). The underlying mechanism of the increased health risk is excess adipokines causing systemic inflammation and leading to increased various health risks.Conclusion: Despite metabolically “healthy” status, children with MHO remain at increased risk for health disorders compared to normal-weight peers. This systematic review and meta-analysis is the first one discussing the health disorders in children with MHO. More studies are required in the future to reinforce these findings in order to produce much more comprehensive insights.Keywords: children, disorders, metabolically healthy obesity, obesity

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.

Obesity now stands as a paramount public health challenge globally. The classification of individuals with obesity extends into two categories: those with metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUO), differentiated by the presence or absence of metabolic irregularities. This study aimed to explore the independent correlates of MHO or MUO in children and adolescents with depressive disorders. In a study conducted at the Third People’s Hospital of Fuyang throughout 2021, 515 pediatric adolescent in-patient patients diagnosed with depressive disorders according to the ICD-10 criteria were examined. Comprehensive demographic and clinical data were gathered for these individuals. Using regression analysis, the research delved into the distinct impacts of MHO and MUO on these patients. This approach aimed to discern the varying contributions of metabolic health statuses to depressive symptoms in this demographic group. The detection rates of MHO and MUO were 3.7% (19/515) and 8.0% (41/515), respectively. Compared with the MHO group, patients in the MUO group showed older age, older ages of onset and first hospitalization of depressive disorders, higher systolic and diastolic blood pressure, higher levels of TG, TC/HDL, TG/HDL, TyG index and AST, and lower levels of HDL. Binary regression analysis showed that a high level of LDL ( OR  = 2.76, P  = 0.007) was an independent risk factor for MHO, whereas older age at the onset of the disorders ( OR  = 0.69, P  = 0.002) was a protective factor for MHO. In addition, high levels of TC/HDL ( OR  = 2.66, P  = 0.003), TG/HDL ( OR  = 1.81, P  = 0.034), AST ( OR  = 1.03, P  < 0.001), and uric acid ( OR  = 1.004, P  = 0.018) were independent risk factors for MUO. Children and adolescents suffering from depressive disorders exhibit increased rates of both MHO and MUO. It is imperative in clinical settings to monitor these conditions closely. Proactive measures are essential to address the underlying risk factors, thereby mitigating the progression from MHO to MUO and enhancing patient outcomes.

The mechanisms underlying metabolically healthy obesity (MHO) in pediatrics remain poorly understood. This study aims to evaluate the plasma metabolome of MHO versus metabolically unhealthy obesity (MUO) in Asian children and adolescents, to identify key metabolic drivers that undergird the MUO phenotype. MHO and MUO were defined by the absence or presence of metabolic syndrome criteria, respectively. We conducted untargeted metabolomics analysis on plasma samples from children and adolescents without obesity (n = 24), with MHO (n = 65) and with MUO (n = 222). Multivariate data analyses identified key metabolites differentiating the groups. Logistic regression assessed metabolite associations with metabolic conditions, while Spearman’s correlation evaluated their links to cardiometabolic parameters. Metabolites such as plasma fatty acids, amino acids and 1,5-anhydroglucitol differentiated MHO from MUO, correlating significantly with parameters of glucose homeostasis. Plasma branched-chain amino acids and 3-hydroxyisobutyric acid were elevated while 1,5-anhydroglucitol was reduced in pediatrics with obesity and abnormal glucose tolerance compared to those with obesity and normal glucose tolerance. Our study revealed distinct metabolome alterations between MHO and MUO in Asian children and adolescents. Notably, we identified that these metabolomic differences between MHO and MUO are primarily linked to abnormal glucose homeostasis, highlighting potential metabolic targets for improving health outcomes in pediatric obesity.

Obesity is associated with increased risk of developing metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) leading to higher all-cause mortality. However accumulating evidence suggests that not all obese subjects are at increased cardiometabolic risk and that the “metabolically healthy obese” (MHO) phenotype may exist in the absence of metabolic abnormalities. Despite the knowledge of the existence of obese metabolic phenotypes for some time now there is no standard set of criteria to define metabolic health, thus impacting on the accurate estimation of the prevalence of the MHO phenotype and making comparability between studies difficult. Furthermore prospective studies tracking the development of cardiometabolic disease and mortality in MHO have also produced conflicting results. Limited data regards the determinants of the MHO phenotype exist, particularly in relation to dietary and lifestyle behaviours. In light of the current obesity epidemic it is clear that current “one size fits all” approaches to tackle obesity are largely unsuccessful. Whether dietary, lifestyle and/or therapeutic interventions based on stratification of obese individuals according to their metabolic health phenotype are more effective remains to be seen, with limited and conflicting data available so far. This review will present the current state of the art including the epidemiology of MHO and its definitions, what factors may be important in determining metabolic health status and finally, some potential implications of the MHO phenotype in the context of obesity diagnosis, interventions and treatment.

PurposeCardiorespiratory fitness (CRF) is critical for cardiovascular health. Normal-weight obesity (NWO) and metabolically healthy obesity (MHO) may be at increased risk for cardiovascular disease, but a comparison of CRF and submaximal exercise dynamics against rigorously defined low- and high-risk groups is lacking.MethodsFour groups (N = 40; 10/group) based on body mass index (BMI), body fat %, and metabolic syndrome (MetS) risk factors were recruited: healthy controls (CON; BMI 18.5–24.9 kg/m2, body fat < 25% [M] or < 35% [F], 0–1 risk factors), NWO (BMI 18.5–24.9 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F]), MHO (BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 0–1 risk factors), or metabolically unhealthy obesity (MUO; BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 2 + risk factors). All participants completed a V˙O2peak test on a cycle ergometer.ResultsV˙O2peak was similarly low in NWO (27.0 ± 4.8 mL/kg/min), MHO (25.4 ± 6.7 mL/kg/min) and MUO (24.6 ± 10.0 mL/kg/min) relative to CON (44.2 ± 11.0 mL/kg/min) when normalized to total body mass (p’s < 0.01), and adjusting for fat mass or lean mass did not alter these results. This same differential V˙O2 pattern was apparent beginning at 25% of the exercise test (PGroup*Time < 0.01).ConclusionsNWO and MHO had similar peak and submaximal CRF to MUO, despite some favorable health traits. Our work adds clarity to the notion that excess adiposity hinders CRF across BMI categories.Clinicaltrials.gov registration: NCT05008952.

The obesity epidemic has contributed to an escalating prevalence of metabolic diseases in children. Overnutrition leads to increased tryptophan uptake and availability. An association between the induction of the tryptophan catabolic pathway via indoleamine 2,3-dioxygenase (IDO) activity and obesity-related inflammation has been observed. This study aimed to investigate the impact of pediatric obesity on tryptophan metabolism and the potential relationship with metabolic disease. In this prospective cohort study, plasma kynurenine, tryptophan, and serotonin levels were measured by ELISA, and IDO activity was estimated by calculating the kynurenine/tryptophan ratio in a clinically characterized population with severe obesity (BMI ≥ 97th percentile) aged 9 to 19 (n = 125). IDO activity and its product kynurenine correlated with BMI z-score and body fat mass, whereas concentrations of serotonin, the alternative tryptophan metabolite, negatively correlated with these measures of adiposity. Kynurenine and tryptophan, but not serotonin levels, were associated with disturbed glucose metabolism. Tryptophan concentrations negatively correlated with adiponectin and were significantly higher in prediabetes and metabolically unhealthy obesity. In conclusion, BMI and body fat mass were associated with increased tryptophan catabolism via the kynurenine pathway and decreased serotonin production in children and adolescents with severe obesity. The resulting elevated kynurenine levels may contribute to metabolic disease in obesity.