Metabolically healthy obesity and left ventricular geometric remodelling in Chinese children.

AIM: To investigate the association between metabolically healthy obesity (MHO) and left ventricular geometric remodelling in Chinese children. MATERIALS AND METHODS: This cross-sectional study used data from two population-based samples in China, including 2871 children aged 6-11 years. Weight status was defined based on body mass index according to the World Health Organization growth chart. Metabolic status was defined based on the 2018 consensus-based criteria proposed by Damanhoury et al. Obes Rev 2018;19:1476-1491 (blood pressure, lipids and glucose). Left ventricular geometric remodelling was determined as concentric remodelling, eccentric hypertrophy, and concentric hypertrophy. Multinomial logistic regression analysis was used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for the association between categories of weight and metabolic status and left ventricular geometric remodelling. RESULTS: Compared with children with metabolically healthy normal weight, those with MHO had higher odds of left ventricular geometric remodelling, with adjusted ORs (95% CIs) of 2.01 (1.23-3.28) for concentric remodelling, 6.36 (4.03-10.04) for eccentric hypertrophy, and 17.07 (7.97-36.58) for concentric hypertrophy. Corresponding ORs (95% CIs) were 2.35 (1.47-3.75), 10.85 (7.11-16.55), and 18.56 (8.63-39.94), respectively, for children with metabolically unhealthy obesity. In contrast, metabolically unhealthy normal weight was not associated with higher odds of left ventricular geometric remodelling. Findings were consistent in sensitivity analyses that used different definitions of weight and metabolic status and left ventricular geometric remodelling. CONCLUSIONS: Children with MHO had higher odds of left ventricular geometric remodelling than their metabolically healthy normal weight counterparts. Our findings suggest MHO may not be a benign condition for cardiac health in children.

Physical activity in relation to metabolic health and obesity: The Feel4Diabetes study.

AIM: To examine physical activity levels in association with metabolic health and estimate the stability of metabolically healthy obese (MHO) phenotypes over a 2-year period. METHODS: In total, 2848 men and women from families at risk of the development of diabetes were recruited. Participants were classified as obese or non-obese and metabolic health was defined using five existing definitions. Physical activity was estimated with the International Physical Activity Questionnaire and pedometers. RESULTS: Prevalence of the MHO phenotype varied among definitions (0% to 20.2%). Overall, the MHO were more active than the metabolically unhealthy obese (MUO). Daily sitting hours (odds ratio [OR] = 1.055, 95% confidence interval [CI]: 1.009-1.104) and daily steps (per 500; OR = 0.934, 95% CI: 0.896-0.973) were remarkable predictors of metabolic health in individuals with obesity; and likewise, in individuals without obesity. After 2 years, 44.1% of baseline MHO adults transitioned to MUO, while 84.0% of the MUO at baseline remained at the same phenotype. Although physical activity was not a major determinant in phenotype transitioning, daily steps were associated with the maintenance of metabolic health over time in the non-obese group. CONCLUSION: A universally accepted definition for MHO is needed. Being physically active can contribute to a metabolically healthy profile even in the presence of obesity; still, MHO is a transient condition and physical activity alone may not be an adequate factor for its maintenance.

Association between metabolic phenotypes of overweight/obesity and cardiovascular diseases in postmenopausal women.

BACKGROUND AND AIM: Obesity and metabolic abnormalities were associated with an increased risk of cardiovascular disease. However, it is unclear how metabolic weight phenotypes relate to cardiovascular diseases in postmenopausal women. This study aimed to explore the relationships in postmenopausal women. METHODS AND RESULTS: We included 15,575 postmenopausal women aged 35-75 years (median age, 60.6) without cardiovascular disease at baseline from a subcohort of the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project. Metabolically unhealthy phenotype was defined as having ≥2 risk factors of metabolic syndrome: blood pressure ≥130/85 mm Hg or current use of antihypertensive drugs, fasting glucose ≥5.6 mmol/L or current use of antidiabetic agents, triglycerides ≥1.7 mmol/L, and high-density lipoprotein cholesterol <1.3 mmol/L. Cox regression analysis was used to evaluate the risks of cardiovascular diseases. Over a median follow-up period of 3.55 (interquartile range, 2.59-4.44) years, a total of 1354 cardiovascular events occurred. Compared to metabolically healthy normal weight, the multivariate-adjusted hazard ratios and their 95% confidence intervals were 1.41 (1.16-1.72) for metabolically unhealthy normal weight, 1.42 (1.16-1.73) for metabolically healthy overweight/obesity, and 1.75 (1.48-2.08) for metabolically unhealthy overweight/obesity. Subdividing overweight/obesity into separate groups revealed higher total cardiovascular disease risk only in metabolically unhealthy individuals across body mass index categories. CONCLUSION: In postmenopausal women, both metabolically healthy overweight/obesity and metabolically unhealthy normal weight were associated with a higher risk of cardiovascular disease compared to metabolically healthy normal weight, and the greatest risk was observed in the metabolically unhealthy overweight/obesity category.

Influence of dietary patterns on the metabolically healthy obesity phenotype: A systematic review.

AIMS: In many individuals (35%) obesity is not accompanied by cardiometabolic disorders, a condition referred to as metabolically healthy obesity. Since the effectiveness of dietary interventions for this condition is not well established, this study reviews the influence of dietary patterns on the phenotype of metabolically healthy obesity in adults and elderly. DATA SYNTHESIS: The review was carried out following the PRISMA guidelines and registered in the PROSPERO. The search was conducted in the MEDLINE, SCOPUS, Web of Science, Science Direct, LILACS, and SciELO databases. A total of 236 articles were identified, seven of which were selected for synthesis after application of the eligibility criteria. CONCLUSIONS: The overall result found out in this synthesis was that the greater adherence to healthy eating patterns was considered a preventive to the transition from metabolically healthy obesity to metabolic unhealthy obese phenotypes, by improving metabolic health, and reducing the risk of cardiovascular disease and mortality from all causes. In contrast, unhealthy eating patterns resulted in increased inflammation and risks of developing noncommunicable diseases. This review indicates that adherence to healthy eating patterns may interfere with metabolic phenotypes of obesity and positively affect metabolically healthy obesity. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42020159783.

Contribution of 20-year body mass index and waist circumference history to poor cardiometabolic health in overweight/obese and normal weight adults: A cohort study.

BACKGROUND AND AIMS: We investigated the associations of 20-year body mass index (BMI) and waist circumference (WC) histories with risk of being 1) metabolically unhealthy overweight/obese (MUOO) vs metabolically healthy overweight/obese (MHOO) and 2) metabolically unhealthy normal weight (MUNW) vs metabolically healthy normal weight (MHNW). METHODS AND RESULTS: Participants comprised 3018 adults (2280 males; 738 females) with BMI and WC measured, every ~5 years, in 1991-1994, 1997-1999, 2002-2004, 2007-2009, and 2012-2013. Mean age in 2012-2013 was 69.3 years, with a range of 59.7-82.2 years. Duration was defined as the number of times a person was overweight/obese (or centrally obese) across the 5 visits, severity as each person's mean BMI (or WC), and variability as the within-person standard deviation of BMI (or WC). At the 2013-2013 visit, participants were categorised based on their weight (overweight/obese or normal weight; body mass index (BMI) ≥25 kg/m2) and health status (healthy or unhealthy; two or more of hypertension, low high-density lipoprotein cholesterol, high triglycerides, high glucose, and high homeostatic model assessment of insulin resistance). Logistic regression was used to estimate associations with the risk of being MUNW (reference MHNW) and MUOO (reference MHOO) at the last visit. BMI and WC severity were each related to increased risk of being unhealthy, with estimates being stronger among normal weight than overweight/obese adults. The estimates for variability exposures became null upon adjustment for severity. Individuals who were overweight/obese at all 5 time points had a 1.60 (0.96-2.67) times higher risk of being MUOO than MHOO compared to those who were only overweight/obese at one (i.e., the last) time point. The corresponding estimate for central obesity was 4.20 (2.88-6.12). Greater duration was also related to higher risk of MUNW than MHNW. CONCLUSION: Being overweight/obese yet healthy seems to be partially attributable to lower exposure to adiposity across 20 years of adulthood. The results highlight the importance of maintaining optimum and stable BMI and WC, both in adults who become and do not become overweight/obese.

Lifestyle factors associated with the transition from healthy to unhealthy adiposity among black South African adults over 10 years.

BACKGROUND AND AIMS: Obesity is associated with an increasing prevalence of cardiovascular diseases in Africa, but some obese individuals maintain cardiometabolic health. The aims were to track metabolically healthy overweight or obesity (MHO) over 10 years in African adults and to identify factors associated with a transition to metabolically unhealthy overweight or obesity (MUO). METHODS AND RESULTS: The participants were the South African cohort of the international Prospective Urban and Rural Epidemiological study. From the baseline data of 1937 adults, 649 women and 274 men were followed for 10 years. The combined overweight and obesity prevalence of men (19.2%-23.8%, p = .02) and women (58%-64.7%, p < .001), and the prevalence of the metabolic syndrome in all participants (25.4%-40.2%, p < .001) increased significantly. More than a quarter (26.2%) of the women and 10.9% of men were MHO at baseline, 11.4% of women and 5.1% of men maintained MHO over 10 years, while similar proportions (12.3% of women, 4.7% of men) transitioned to MUO. Female sex, age, and total fat intake were positively associated with a transition to MUO over 10 years, while physical activity was negatively associated with the transition. HIV positive participants were more likely to be MHO at follow-up than their HIV negative counterparts. CONCLUSIONS: One in two black adults with BMI ≥25 kg/m2 maintained MHO over 10 years, while a similar proportion transitioned into MUO. Interventions should focus on lower fat intakes and higher physical activity to prevent the transition to MUO.

Metabolically healthy overweight in young adulthood: is it a matter of duration and degree of overweight?

BACKGROUND AND AIM: Given the controversy regarding metabolically healthy obesity, we studied the association between duration and degree of body mass index (BMI) from adolescence to early adulthood and metabolic status of both overweight/obese and under/normal weight subjects. METHODS AND RESULTS: Participants of the EPITeen cohort were evaluated at 13, 17, 21 and 24 years (n = 1040). Duration and degree of BMI in the 11-year period was summarized through the area under the curve of BMI (BMIAUC). Metabolic health at 24 y was defined as optimal levels of lipids, blood pressure and glucose. The association between BMIAUC per year and metabolic health was estimated through binary logistic regression models, adjusted for confounders and stratified by BMI. The proportion of metabolically healthy overweight/obesity at 24 y was 13.4%. After adjustment for sociodemographic and behavioural factors, the increase of one kg/m2 in BMI on average per year during the period between 13 and 24 y was associated with 14% lower odds of being metabolically healthy among under/normal weight participants (OR = 0.86, 95% CI 0.78-0.94); and 8% lower odds of metabolic health among obese/overweight participants (OR = 0.92, 95% CI 0.85-1.00). After additional adjustment for waist circumference, the association was attenuated, especially in the obese/overweight group (OR = 1.03, 95% CI 0.93-1.14). About 20% of the metabolically healthy obese/overweight at 13 y transitioned to metabolically unhealthy obesity/overweight at 24 y. CONCLUSION: The results support the hypothesis that the healthy obesity phenotype could be explained by a lower exposure to adiposity, either by shorter time or lower quantity, and a more favourable body fat distribution.

Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.

BACKGROUND: We aimed to investigate the hazard of hospitalization for heart failure (hHF) according to the transitions in metabolic health and obesity status. METHODS: The Korean National Health Insurance Service datasets from 2002 to 2017 were used for this nationwide, longitudinal, population-based study. The hazard of hHF was analyzed according to the eight groups stratified by stability in metabolic health and transition in obesity status among initially metabolically healthy adults who underwent two cycles of health examinations in 2009-2010 and 2013-2014 (N = 7,148,763). RESULTS: During two examinations, 48.43% of the initially metabolically healthy obese (MHO) individuals and 20.94% of the initially metabolically healthy non-obese (MHNO) individuals showed changes in their metabolic health and obesity status. During a mean follow-up of 3.70 years, 3151 individuals were hospitalized for HF. When stable MHNO individuals were set as the reference, transition to metabolically unhealthy phenotype was associated with an increased hazard of hHF; the hazard ratio (HR) and 95% confidence interval (CI) in the individuals who transformed from MHO to metabolically unhealthy non-obese was 2.033 (1.579-2.616). The constant MHO group had a 17.3% increased hazard of hHF compared with the stable MHNO group [HR (95% CI) 1.173 (1.039-1.325)]. Individuals who shifted from MHO to MHNO showed a 34.3% lower hazard of hHF compared with those who maintained the MHO category [HR (95% CI) 0.657 (0.508-0.849)]. CONCLUSION: Dynamic changes in metabolic health and obesity status were observed during a relatively short interval of 3-5 years. Loss of metabolic health was significantly associated with an increased hazard of hHF. Even if metabolic health was maintained, persistent obesity remained as a risk factor for hHF, and transition from MHO to MHNO had a protective effect against hHF. Therefore, the prevention and control of obesity while maintaining metabolic health would be crucial in preventing hHF.

Metabolically healthy obesity increased diabetes incidence in a middle-aged and elderly Chinese population.

BACKGROUND: We examined the association between metabolically healthy obese (MHO) and diabetes incidence in a middle-aged and elderly population and whether the association differed by the presence of nonalcoholic fatty liver disease (NAFLD). METHODS: We examined 17 801 participants without diabetes at study entry (7980 males and 9821 females with a mean age of 63.2 years) derived from the Dongfeng-Tongji cohort study (median follow-up: 4.6 years). Participants were divided into six groups based on BMI (normal weight, overweight, or obese) and metabolic health (healthy/unhealthy) defined by the Adult Treatment Panel III criteria. The MHO was defined as BMI greater than 28.0 kg/m2 with 0 or 1 of four metabolic abnormalities (elevated blood pressure, triglyceridaemia, hyperglycaemia, low HDL cholesterol). The hazard ratio (HR) and 95% confidence interval (CI) for incident diabetes were derived from the Cox proportional hazard regression model. RESULTS: During 79 843 person-years of follow-up, 1453 individuals developed diabetes. Compared with metabolically healthy normal weight (MH-NW) individuals, the multivariable-adjusted HRs (95% CI) were 1.74 (1.16-2.59) for MHO and 2.15 (1.65-2.81) for metabolically unhealthy obese subjects after adjusting for age, sex, smoking, alcohol drinking, physical activity, fruit and vegetable consumption, family history of diabetes, fasting glucose, waist circumference, and NAFLD. Among those without NAFLD, MHO individuals showed higher incidence of diabetes (multivariate-adjusted HR = 2.71, 95% CI: 1.47-5.00) than MH-NW individuals. CONCLUSIONS: The MHO phenotype was associated with increased incidence of diabetes in a middle-aged and elderly population, and the association did not differ by the presence or absence of NAFLD.

Metabolically healthy general and abdominal obesity are associated with increased risk of hypertension.

Metabolically healthy obesity refers to a subset of obese people with a normal metabolic profile. We aimed to explore the association between metabolically healthy and obesity status and risk of hypertension among Chinese adults from The Rural Chinese Cohort Study. This prospective cohort study enrolled 9137 Chinese adults without hypertension, type 2 diabetes or treatment for lipid abnormality at baseline (2007-2008) and followed up during 2013-2014. Modified Poisson regression models were used to examine the risk of hypertension by different metabolically healthy and obesity status, estimating relative risks (RR) and 95 % CI. During 6 years of follow-up, we identified 1734 new hypertension cases (721 men). After adjusting for age, sex, smoking and other confounding factors, risk of hypertension was increased with metabolically healthy general obesity (MHGO) defined by BMI (RR 1·75, 95 % CI 1·02, 3·00) and metabolically healthy abdominal obesity (MHAO) defined by waist circumference (RR 1·51, 95 % CI 1·12, 2·04) as compared with metabolically healthy non-obesity. The associations between metabolically healthy and obesity status and hypertension outcome were consistent after stratifying by sex, age, smoking, alcohol drinking and physical activity. Both MHGO and MHAO were associated with increased risk of hypertension. Obesity control programmes should be implemented to prevent or delay the development of hypertension in rural China.

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.

Does healthy obesity exist in the elderly? Findings from the Northern Shanghai Study.

BACKGROUND AND AIMS: Metabolic unhealthiness and obesity are both associated with an increased risk of cardiovascular disease. We aimed to investigate the significance of metabolic unhealthiness and obesity in organ damages in a community-based elderly cohort. METHODS AND RESULTS: A total of 3325 elderly participants (>65 years old) were recruited in northern Shanghai. Associations of metabolic status and obesity with organ damages were investigated. In all, 1317 (39.6%) participants were metabolically unhealthy and 481 (14.5%) were obese. Compared with metabolically healthy nonobese (MH-nonobese) individuals, metabolically healthy obese subjects had a greater left ventricular mass index (LVMI) and pulse wave velocity (PWV). Metabolically unhealthy subjects, regardless of their obesity status, had greater organ damage parameters including E/Ea, LVMI, PWV, and urine albumin-creatinine ratio (UACR) than MH-nonobese subjects (all P < 0.05). After multivariate adjustments, both metabolic unhealthiness and obesity increased the risk of left ventricular hypertrophy (LVH) (OR 1.31, 95% CI 1.10-1.57 and OR 1.63, 95% CI 1.30-2.04), diastolic dysfunction (OR 1.33, 95% CI 1.06-1.67 and OR 1.51, 95% CI 1.14-1.99), and lower extremity atherosclerosis (OR 1.44, 95% CI 1.11-1.85 and OR 2.01, 95% CI 1.49-2.70). Metabolic unhealthiness was also associated with arterial stiffness, microalbuminuria and chronic kidney disease (all P < 0.05). In a subgroup analysis, metabolic unhealthiness was associated with more organ damages in nonobese subjects, and obesity was associated with LVH and lower extremity atherosclerosis regardless of metabolic status. CONCLUSION: Both obesity and metabolic unhealthiness were associated with organ damages. Metabolic unhealthiness was associated with more organ damages, especially in nonobese individuals. Even healthy obesity was significantly associated with cardiac and vascular impairment. REGISTRATION NUMBER FOR CLINICAL TRIALS: NCT02368938.

A systematic review and quantitative analysis of resting energy expenditure prediction equations in healthy overweight and obese children and adolescents.

BACKGROUND: Resting energy expenditure (REE) estimates are often needed in young people and can be predicted using prediction equations based on body weight. However, these equations may perform poorly in those who are obese and overweight. The aim of this systematic review was to identify equations based on simple anthropometric and demographic variables that provide the most accurate and precise estimates of REE in healthy obese and overweight young people. METHODS: Systematic searches for relevant studies in healthy obese and overweight young people aged ≤18 years were undertaken using PubMed, Scopus, Cinahl, OpenGrey and Cochrane Library (completed January 2018). Search terms included metabolism, calorimetry, obesity and prediction equation. Data extraction, study appraisal and synthesis followed PRISMA guidelines. RESULTS: From 390 screened titles, 13 studies met inclusion criteria. The most accurate REE predictions (least biased) were provided by Schofield equations [+0.8% (3-18 years); 0% (11-18 years); +1.1% (3-10 years)]. The most precise REE estimations (percentage of predictions ± 10% of measured) for 11-18 years were provided by Mifflin equations (62%) and, for 7-18 years, by the equations of Schmelzle (57%), Henry (56%) and Harris Benedict (54%). Precision of Schofield predictions was 43% in both age groups. No accuracy data were available for those <3 years or for precision for those <7 years. CONCLUSIONS: No single equation provided accurate and precise REE estimations in this population. Schofield equations provided the most accurate REE predictions so are useful for groups. Mifflin equations provided the most precise estimates for individuals aged 11-18 years but tended to underestimate REE.

Metabolic health in normal-weight and obese individuals.

Cardiovascular complications are commonly associated with obesity. However, a subgroup of obese individuals may not be at an increased risk for cardiovascular complications; these individuals are said to have metabolically healthy obesity (MHO). In contrast, metabolically unhealthy individuals are at high risk of cardiovascular disease (CVD), irrespective of BMI; thus, this group can include individuals within the normal weight category (BMI 18.5-24.9 kg/m2). This review provides a summary of prospective studies on MHO and metabolically unhealthy normal-weight (MUHNW) phenotypes. Notably, there is ongoing dispute surrounding the concept of MHO, including the lack of a uniform definition and the potentially transient nature of metabolic health status. This review highlights the relevance of alternative measures of body fatness, specifically measures of fat distribution, for determining MHO and MUHNW. It also highlights alternative approaches of risk stratification, which account for the continuum of risk in relation to CVD, which is observable for most risk factors. Moreover, studies evaluating the transition from metabolically healthy to unhealthy phenotypes and potential determinants for such conversions are discussed. Finally, the review proposes several strategies for the use of epidemiological research to further inform the current debate on metabolic health and its determination across different stages of body fatness.

Fate of the metabolically healthy obese-is this term a misnomer? A study from the Clinical Practice Research Datalink.

INTRODUCTION: The metabolically healthy obese (MHO) phenotype may express typical characteristics on long-term follow-up. Little is known about the initiation of this phenotypes and its future stability. AIM: The Clinical Practice Research Datalink (CPRD) is a large-scale primary care database. The aim of this study was to assess the stability of, and evaluate the factors associated with a transition into an unhealthy outcome in, a MHO population in the UK. METHODS: The CPRD was interrogated for a diagnosis of 'obesity' and cross-referenced with a body mass index (BMI) ≥35 kg/m2; participants were further classified as MH using a clinical diagnostic code or a relative therapeutic code. A hazard cox regression univariate and multivariate analysis evaluated the time to transition for independent variables. RESULTS: There were 231,399 patients with a recorded BMI of 35 kg/m2 or greater. Incomplete records were eliminated and follow-up limited to 300 months, the cohort was reduced to 180,560 patients. The prevalence of MHO within the obese population from the CPRD was 128,191/180,560 (71%). MHO individuals, who were of male gender (hazard ratio (HR) 1.23 (1.21-1.25), p = < 0.01), older age group (HR 3.93 (3.82-4.04), p = < 0.01), BMI of 50-60 kg/m2 at baseline (HR 1.32(1.26-1.38), p = 0.01), smokers (HR 1.07(1.05-1.09), p = < 0.01) and regionally from North West England (HR 1.15(1.09-1.21), p = < 0.01) were more prone to an unhealthy transition (to develop comorbidities). Overall, of those MH at baseline, 71,485/128,191(55.8%) remained healthy on follow-up, with a mean follow-up of 113.5 (standard deviations (SD) 78.6) months or 9.4 (SD 6.6) years. CONCLUSIONS: From this unique large data set, there is a greater prevalence of MHO individuals in the UK population than in published literature elsewhere. Female gender, younger age group, and lower initial weight and BMI were found to be significant predictors of sustained metabolic health in this cohort. However, there remains a steady progressive transition from a healthy baseline over the years.

Duration and stability of metabolically healthy obesity over 30 years.

BACKGROUND: Obese adults who are free from metabolic risk factors may develop risk factors over time. Our objective was to characterize development of obesity and duration of metabolically healthy obese (MHO) over 30 years. METHODS: Participants in CARDIA who developed obesity (BMI ≥ 30 kg/m2) at follow-up exams during years 7, 10, 15, 20, 25, and 30 were analyzed. MHO was defined as obese and having 0 or 1 risk factor: ≥SBP/DBP 130/85 mmHg; fasting glucose ≥100 mg/dL/5.55 mmol/L; fasting triglycerides (≥150 mg/dL/1.69 mmol/L); and HDL-C (men <40 mg/dL/1.036 mmol/L, women <50 mg/dL/1.295 mmol/L) or on any medication(s) for these conditions. MHO duration (years) and obesity duration (years) were estimated for each subsequent time-point; and an overall cumulative duration was also calculated over available follow-up. MHO duration (%) was approximated as MHO duration ÷ obesity duration. Stable MHO was defined as 100% MHO duration over follow-up, while transient MHO was defined as <1-99%. Chi-squared tests were used to compare proportions by sex and race across obesity phenotypes. Multivariable-adjusted ANCOVA, adjusting for baseline BMI, age, race, and sex, was used to analyze obesity duration in all individuals who developed obesity, and also compare MHO duration (%) across race and sex in transient MHO individuals. RESULTS: Of the 987 eligible participants who developed obesity, 51% were African American (AA), 56% were women. Higher percentages of AA were classified as transient MHO, and higher proportions of females were MHO (both p < 0.0001). Obesity duration (years) was higher in transient MHO compared with stable MHO (mean difference: 6.2 ± 0.5 years, p < 0.0001). Of those with transient MHO, African Americans (51.4 ± 1.6%) were more likely to have longer MHO duration compared to Caucasians (44.4 ± 1.9%, p = 0.005). CONCLUSION: MHO status can be a transient phenotype which differs by sex and race. Future studies are needed to explore modifiable lifestyle/behavioral predictors associated with longer MHO duration.

Metabolically healthy and unhealthy obesity phenotypes and risk of renal stone: a cohort study.

BACKGROUND/OBJECTIVES: Although obesity is considered an independent risk factor of nephrolithiasis, little is known about the effect of obesity on nephrolithiasis according to metabolic health status. We investigated the association between body mass index (BMI) category and the incidence of nephrolithiasis in metabolically healthy and unhealthy individuals. SUBJECTS/METHODS: The cohort consisted of 270,190 Korean adults free of nephrolithiasis at baseline, who were followed-up annually or biennially for a median of 4.1 years. Nephrolithiasis were determined based on ultrasonographic findings. Being metabolically healthy was defined as not having any metabolic syndrome component. A parametric Cox model was used to estimate the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During 1,415,523.0 person-years of follow-up, 13,450 participants developed nephrolithiasis (incidence rate, 9.5 per 1000 person-years). Obesity was positively associated with an increased risk of incident nephrolithiasis in dose-response manner, but the association was stronger in metabolically healthy individuals. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CIs) for incident nephrolithiasis comparing BMIs 23-24.9, 25-29.9, and ≥30 with a BMI of 18.5-22.9 kg/m2 as the reference were 1.02 (0.95-1.10), 1.12 (1.03-1.22), and 1.72 (1.21-2.44), respectively, whereas corresponding HRs (95% CIs) in metabolically unhealthy individuals were 1.10 (1.04-1.17), 1.27 (1.20-1.34), and 1.36 (1.22-1.51), respectively. The association between obesity and incident nephrolithiasis was stronger in men and current smokers. CONCLUSIONS: Obesity was associated with a higher incidence of nephrolithiasis in both metabolically healthy and unhealthy individuals, indicating obesity per se as an independent risk factor for nephrolithiasis.

Effectiveness of vitamin D therapy in improving metabolomic biomarkers in obesity phenotypes: Two randomized clinical trials.

BACKGROUND: Uncertainty remains about the effect of vitamin D therapy on biomarkers of health status in obesity. The molecular basis underlying this controversy is largely unknown. OBJECTIVE: To address the existing gap, our study sought to compare changes in metabolomic profiles of obesity phenotypes (metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO)) patients with sub-optimal levels of vitamin D following vitamin D supplementation. METHODS: We conducted two randomized double-blind clinical trials on participants with either of the two obesity phenotypes from Tehran province. These phenotypes were determined by the Adult Treatment Panel-III criteria. Patients in each of the MHO (n = 110) and MUHO (n = 105) groups were separately assigned to receive either vitamin D (4000 IU/d) or placebo for 4 months. Pre- and post-supplementation plasma metabolomic profiling were performed using Liquid chromatography coupled to a triple quadrupole mass spectrometry. Multivariable linear regression was used to explore the association of change in each metabolite with the trial assignment (vitamin D/placebo) across obesity phenotypes. RESULTS: Metabolites (n = 104) were profiled in 82 MHO and 78 MUHO patients. After correction for multiple comparisons, acyl-lysophosphatidylcholines C16:0, C18:0, and C18:1, diacyl-phosphatidylcholines C32:0, C34:1, C38:3, and C38:4, and sphingomyelin C40:4 changed significantly in response to vitamin D supplementation only in MUHO phenotype. The interaction analysis revealed that vitamin D therapy was different between the two obesity phenotypes based on acyl-lysophosphatidylcholines C16:0 and C16:1 and citrulline which were altered significantly after supplementation. Changes in metabolites were associated with changes in cardiometabolic biomarkers after the intervention. CONCLUSIONS: Vitamin D treatment influenced the obesity-related plasma metabolites only in adults with obesity and metabolically unhealthy phenotype. Therefore, not all patients with obesity may benefit from an identical strategy for vitamin D therapy. These findings provide mechanistic basis highlighting the potential of precision medicine to mitigate diseases in health-care settings.

Early determinants of metabolically healthy obesity in young adults: study of the Northern Finland Birth Cohort 1966.

BACKGROUND: A body of literature suggests a metabolically healthy phenotype in individuals with obesity. Despite important clinical implications, the early origins of metabolically healthy obesity (MHO) have received little attention. OBJECTIVE: To assess the prevalence of MHO among the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years of age, examine its determinants in early life taking into account the sex specificity. METHODS: We studied 3205 term-born cohort participants with data available for cardio-metabolic health outcomes at 31 years, and longitudinal height and weight data. After stratifying the population by sex, adult BMI and a strict definition of metabolic health (i.e., no risk factors meaning metabolic health), we obtained six groups. Repeated childhood height and weight measures were used to model early growth and early adiposity phenotypes. We employed marginal means adjusted for mother and child covariates including socio-economic status, birth weight and gestational-age, to compare differences between the groups. RESULTS: The prevalence of adult MHO was 6% in men and 13.5% in women. Differences in adult metabolic status were linked to alterations in BMI and age at adiposity peak in infancy (p < 0.0003 in men and p = 0.027 in women), and BMI and age at adiposity rebound (AR) (p < 0.0001 irrespective of sex). Compared to MHO, metabolically unhealthy obese (MUO) women were five and a half months younger at AR (p = 0.007) with a higher BMI while MUO men were four months older (p = 0.036) with no difference in BMI at AR. CONCLUSION: At the time of AR, MHO women appeared to be older than their MUO counterparts while MHO men were younger. These original results support potential risk factors at the time of adiposity rebound linked to metabolic health in adulthood. These variations by sex warrant independent replication.

Impact of respiratory function on the progression from metabolically healthy non-overweight to metabolically abnormal phenotype.

BACKGROUND AND AIMS: Recent studies identified that metabolically abnormal non-overweight phenotype is a risk factor for cardiovascular diseases. However, only little is known about risk factors for the progression from metabolically healthy non-overweight (MHNO) to metabolically abnormal phenotype. In this study, we investigated the impact of respiratory function on the progression from MHNO to metabolically abnormal phenotype. METHODS AND RESULTS: In this retrospective cohort study, 8949 (3872 men and 5077 women) individuals with MHNO, who participated in a health-checkup program from 2004 to 2015, were enrolled. Four metabolic factors (high-normal blood pressure or hypertension, impaired fasting glucose or diabetes, hypertriglyceridemia, and low HDL cholesterol concentration) were used to define metabolically healthy (less than two factors) or metabolically abnormal (two or more factors) phenotypes. Respiratory function was measured by spirometry. Over a median 4.0 years of follow-up, 927 participants progressed to metabolically abnormal phenotype. The percentage of FVC for predicted values (HR 0.98, 95% CI 0.93-1.03, p = 0.418) was not associated with the progression to metabolically abnormal phenotype after adjusting for covariates, including age, sex, alcohol consumption, exercise, smoking status, and body mass index, whereas the percentage of FEV1 for predicted values (%FEV1) (HR 0.87, 95% CI 0.84-0.91, p < 0.001) and the FEV1/FVC ratio (HR 0.86, 95% CI 0.78-0.95, p = 0.004) were associated with the progression to metabolically abnormal phenotype. CONCLUSION: Decrease in respiratory function in terms of %FEV1 and the FEV1/FVC ratio is associated with the progression to metabolically abnormal phenotype in individuals with MHNO.