Beyond the Scale: How Metabolic Context Reveals Hidden Genetic Risks

A change in weight or metabolic status is a dynamic process, yet most studies have focused on metabolically healthy obesity (MHO) and the transition between MHO and metabolically unhealthy obesity (MUO); therefore, they have not fully revealed the nature of all possible transitions among metabolism-weight phenotypes over the years. This was a longitudinal study based on a retrospective health check-up cohort. A total of 9,742 apparently healthy individuals aged 20-60 years at study entry were included and underwent at least two health check-ups. Six metabolism-weight phenotypes were cross-defined by body mass index (BMI) categories and metabolic status as follows: metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), MHO, metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW), and MUO. A multistate Markov model was used to analyse all possible transitions among these phenotypes and assess the effects of demographic and blood indicators on the transitions. The transition intensity from MUNW to MHNW was the highest (0.64), followed by the transition from MHO to MUO (0.56). The greatest sojourn time appeared in the MHNW state (3.84 years), followed by the MUO state (2.34 years), and the shortest sojourn time appeared in the MHO state (1.16 years). Transition intensities for metabolic improvement gradually decreased with BMI level as follows: 0.64 for MUNW to MHNW, 0.44 for MUOW to MHNW, and 0.27 for MUO to MHO; however, transition intensities for metabolic deterioration, including MHNW to MUNW, MHOW to MUOW, and MHO to MUO, were 0.15, 0.38, and 0.56, respectively. In the middle-aged male group, elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and uric acid (UA) increased the risk of deterioration in weight and metabolic status and decreased the possibility of improvement. Maintaining a normal and stable BMI is important for metabolic health. More attention should be given to males and elderly people to prevent their progression to an unhealthy metabolic and/or weight status. MHO is the most unstable phenotype and is prone to convert to the MUO state, and individuals with abnormal ALT, AST and UA are at an increased risk of transitioning to an unhealthy weight and/or metabolic status; therefore, we should be alert to abnormal indicators and MHO. Intervention measures should be taken early to maintain healthy weight and metabolic status.

There is conflicting evidence regarding the association between metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUNW) with incident hypertension and type 2 diabetes. The role of cardiorespiratory fitness on these associations has not been fully explored. We tested the hypothesis that obesity phenotypes predict incident hypertension and type 2 diabetes, but cardiorespiratory fitness modifies these associations in a prospective study of apparently healthy men. 3800 men (mean age 48±6 yrs, range 20-76 yrs) participated in two health examinations during 1998-2009. All subjects were free of hypertension and type 2 diabetes at baseline examination. MHO was defined as obesity (body mass index ≥ 25 kg/m2) with no more than one metabolic abnormality, and MUNW was defined as body mass index < 23 kg/m2) with two or more abnormalities. Cardiorespiratory fitness was directly measured by peak oxygen uptake during a treadmill test. Incident hypertension and type 2 diabetes were defined as blood pressure ≥140/90mmHg and as ≥6.5% of HbA1c or ≥126mg/dl of fasting glucose at second examination, respectively. During an average follow-up of 5 years (1-12 yrs), there were 371 (9.8%) men incident hypertension and 170 (4.5%) men incident type 2 diabetes. MHO and MUNW were present in 844 (22%) and 249 (6.6%) men. Compared with metabolically healthy normal weight men, MHO and MUNW men were at increased risk for hypertension (relative risk (RR) =1.82, 95% Confidence Interval (CI): 1.29-2.56 and 1.75, 1.11-2.74) and type 2 diabetes (RR=3.68, 1.92-7.07 and 5.35, 2.61-10.94), respectively. These risks in MHO and MUNW men were still persisted with adjustment for confounder variables and cardiorespiratory fitness (hypertension=1.57, 1.05-2.34 and 1.59, 1.01-2.51; type 2 diabetes=3.35, 1.63-6.89 and 4.76, 2.32-9.77). Metabolically healthy obese or metabolically unhealthy normal weight men were at increased risk of hypertension and type 2 diabetes compared with metabolically healthy normal weight men. However, these associations were not attenuated by cardiorespiratory fitness or other confounder factors.

Hypertension is a major public health concern. Although metabolic obesity phenotypes are key risk factors for cardiovascular disease, the association between their dynamic changes and hypertension incidence remains unclear. Based on the Guizhou Population Health Cohort Study (GPHCS), after excluding participants with hypertension at baseline or incomplete data, a total of 3399 subjects were included in the final analysis. Participants were classified into four phenotypes based on body mass index (BMI) and metabolic status: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). Cox proportional hazards models were applied to assess the associations between 16 phenotype transition patterns and the risk of hypertension, with robustness confirmed through multiple sensitivity analyses. Over a median follow-up of 6.42 years, 826 incident cases of hypertension were identified. After multivariable adjustment, compared with MHNW, baseline MHO (HR = 1.26, 95% CI: 1.02-1.55) and MUO (HR = 1.50, 95% CI: 1.22-1.82) were positively associated with hypertension risk, whereas MUNW was not (HR = 1.10, 95% CI: 0.91-1.33). Dynamic analysis showed that 48.75% of participants underwent phenotypic transitions during follow-up. The two most prominent changes were that 37.38% of individuals with MUNW transitioned to MHNW and 31.21% of those with MHO transitioned to MUO. Transitions from any baseline phenotype to MHNW were not associated with a statistically significant increase in hypertension risk (all P > 0.05). All other phenotypic transitions were positively associated. Even participants who remained MHO experienced increased hypertension risk (HR = 2.30, 95% CI: 1.45-3.64). Within the study population, MHO is an unstable state athat tended to progress to MUO, which carries the highest risk of hypertension. In contrast, the MUNW phenotype exhibits high reversibility and can revert to the MHNW phenotype. Future our studies require confirm whether early lifestyle interventions targeting metabolic health can effectively reduce the risk of hypertension.

Metabolically unhealthy individuals, either with obesity or not, have a higher risk of critical coronavirus disease 2019 outcomes than metabolically healthy individuals without obesity

P5294Metabolically healthy obese is associated with better left atrial function and lower risk of adverse cardiovascular events including atrial fibrillation

Obesity has become a global health challenge linked to morbidity and mortality associated with cardiovascular diseases. This study aimed to compare metabolic health indicators according to obesity phenotypes and examine prevalence according to physical activity (PA) and sedentary time in metabolically healthy obesity (MHO) and metabolically unhealthy normal weight (MUNW). Data were obtained from 3242 men participating in the 7th and 8th Korean National Health and Nutrition Examination Surveys. Participants were divided into four groups based on body phenotype and metabolic health status using obesity. Metabolic health was defined as metabolic syndrome. Representative statistical analyzes were one-way analysis of variance (ANOVA) and multiple logistic regression analysis. Compared with MUNW, the MHO had higher obesity, but systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose (FG), hemoglobin A1c (HbA1c), triglycerides (TG), low density lipoprotein cholesterol (LDLC), and total cholesterol (TC) were significantly lower. In comparison between MHO and metabolically healthy normal weight (MHNW), the same health group, there were no significant differences in SBP, FG, HbA1c, and LDLC. The odds ratio of MUNW in the normal weight group was 1.8 times higher than that of the high group in the low leisure PA group. The group with high sedentary time increased the MUNW odds ratio by 1.5 times compared to the low group. Meanwhile, in the obesity group, the high leisure PA group showed a 1.4-fold increase in the MHO odds ratio compared to the low group. In addition, the low sedentary group showed a 1.6-fold increase in the MHO odds ratio compared to the high sedentary group. In conclusion, MHO had higher adiposity than MUNW, but the metabolic health index was better. Low PA and high sedentary time increased the risk of MUNW even in normal weight. Conversely, high PA and low sedentary time increased the likelihood of MHO in the obesity group.

Association of metabolic health phenotypes, obesity, and hepatocellular carcinoma risk.

Metabolic abnormalities, but not obesity per se, associated with chronic kidney disease in a Taiwanese population

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD.

The reported effects of a metabolically healthy obese (MHO) phenotype on diabetes and cardiovascular disease (CVD) risk are contradictory. Within the context of a population-based cohort study, we aimed to investigate the long-term risk of an MHO status for the development of diabetes and CVD, and whether consistency of this phenotype or age affected cardiometabolic outcomes.We recruited 7588 subjects without diabetes or CVD, aged 40 to 69 years at baseline examination, from the Korean Genome and Epidemiology Study, and followed-up these subjects for 10 years biennially. Participants were divided into 4 groups based on the body mass index and the presence of metabolic syndrome: metabolically healthy normal weight (MHNW), MHO, metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). We defined persistent phenotypes if subjects maintained the same phenotype at every visit from baseline to their last visit. Incident diabetes and CVD morbidity or mortality were identified during 10 years of follow-up.Compared to MHNW controls, MUNW and MUO groups had increased risk for development of diabetes (hazard ratio [HR] 3.0 [95% CI: 2.5–3.6], and 4.0 [3.4–4.7], respectively) and CVD (HR 1.6 [1.3–2.0], and 1.9 [1.5–2.4], respectively). However, the MHO group showed only a marginal increase in risk for diabetes and CVD (HR 1.2 [0.99–1.6], 1.4 [0.99–1.8], respectively). The impact of MHO on the development of diabetes was more prominent in younger individuals (HR 1.9 [1.2–3.1] vs 1.1 [0.8–1.4], <45 years vs ≥45 years at baseline). Only 15.8% of MHO subjects maintained the MHO phenotype at every visit from baseline to the 5th biennial examination (persistent MHO). In subjects with persistent MHO, the risk for diabetes and CVD was significantly higher than those with persistent MHNW (1.9 [1.2–3.1], 2.1 [1.2–3.7], respectively).MHO phenotype, even if maintained for a long time, was associated with a significantly higher risk for the development of diabetes and CVD in Korean subjects.

Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. Here, we conducted genome-wide association studies (GWASs) to identify the MUHNW and MHO genetic indices. The study dataset comprised genome-wide single-nucleotide polymorphism genotypes and epidemiological data from 49,915 subjects categorised into four phenotypes—metabolically healthy normal weight (MHNW), MUHNW, MHO, and metabolically unhealthy obese (MUHO). We conducted two GWASs using logistic regression analyses and adjustments for confounding variables (model 1: MHNW versus MUHNW and model 2: MHO versus MUHO). GCKR, ABCB11, CDKAL1, LPL, CDKN2B, NT5C2, APOA5, CETP, and APOC1 were associated with metabolically unhealthy phenotypes among normal weight individuals (model 1). LPL, APOA5, and CETP were associated with metabolically unhealthy phenotypes among obese individuals (model 2). The genes common to both models are related to lipid metabolism (LPL, APOA5, and CETP), and those associated with model 1 are related to insulin or glucose metabolism (GCKR, CDKAL1, and CDKN2B). This study reveals the genetic architecture of the MUHNW and MHO phenotypes in a Korean population-based cohort. These findings could help identify individuals at a high metabolic risk in normal weight and obese populations and provide potential novel targets for the management of metabolically unhealthy phenotypes.

The risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) associated with obesity appears to be influenced by the coexistence of other metabolic abnormalities. We examined the risk of developing CVD and DM in metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUH-NW) individuals. We analyzed prospective data of the San Antonio Heart Study, a population-based study among Mexican Americans and non-Hispanic whites (median follow-up, 7.4 y). Incident DM and CVD were assessed in 2814 and 3700 participants aged 25 to 64 years, respectively. MHO was defined as obesity (body mass index ≥ 30 kg/m(2)) with no more than one metabolic abnormality, and MUH-NW was defined as body mass index <25 kg/m(2) with two or more abnormalities. In logistic regression models, BMI was associated with incident DM after controlling for demographics, family history of DM, and fasting glucose (odds ratio × 1 SD, 1.7 [95% CI, 1.5-2.0]). Both MUH-NW and MHO individuals had an increased DM risk (2.5 [1.1-5.6] and 3.9 [2.0-7.4], respectively). Similarly, BMI was related to incident CVD after adjusting for demographics and Framingham risk score (1.3 [1.1-1.6]). Incident CVD was also increased in MUH-NW and MHO individuals (2.9 [1.3-6.4] and 3.9 [1.9-7.8], respectively). Results were consistent across gender and ethnic categories. The risk of developing DM and CVD is increased in MUH-NW and MHO individuals. Screening for obesity and other metabolic abnormalities should be routinely performed in clinical practice to institute appropriate preventive measures.

BackgroundObesity is associated with an increased risk of reflux esophagitis (RE). Metabolic abnormalities have been implicated in the pathogenesis of RE. However, the role of metabolic status in the risk of RE among individuals with varying degrees of obesity remains unclear. Therefore, our study aimed to assess the association between metabolic obesity phenotypes and the risk of RE.MethodsThis study included a cohort of 24,368 participants aged 18 years and older who underwent upper gastrointestinal endoscopy at the First Affiliated Hospital of Dalian Medical University during health checkups between January 1, 2008, and December 31, 2021. Among these participants, a total of 9,947 individuals were classified into four groups based on their obesity phenotype: metabolically healthy normal weight (MHNW), metabolically healthy obesity (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obesity (MUO). To account for potential confounding factors, multivariate logistic regression analysis was applied to examine the association between metabolic obesity phenotypes and the risk of RE, with stratification by sex and age.ResultsAmong all participants, the MUNW, MHO, and MUO groups demonstrated a higher risk of RE when compared to the MHNW group. After controlling for all confounding factors, the MUO group exhibited the highest risk, with an odds ratio (OR) of 3.723 (95% CI: 2.751–5.040) in males and 5.482 (95% CI: 4.080–7.367) in females. The prevalence of RE increased in proportion to the number of metabolic risk factors. Subgroup analyses, which accounted for all confounders, revealed that the MHO, MUNW, and MUO phenotypes were associated with an elevated risk of RE in individuals under 60 years old as well as those over 60 years old. Interestingly, a more comprehensive analysis indicated that obesity may have a greater effect on the risk of RE than metabolic disorders.ConclusionsBoth metabolic disorders and obesity were associated with an increased risk of RE. The effect of obesity on RE prevalence may be stronger than that of metabolic disorders, emphasizing the significance of obesity regardless of metabolic health status. Clinical interventions should address not only obesity but also metabolic disorders in order to reduce the risk of RE.

BackgroundUrinary albumin‐creatinine ratio (UACR) is a sensitive marker of kidney injury. This study analyzed the prevalence of different metabolic phenotypes and investigated their relationship with UACR in Chinese community adults.MethodsThis study involved 33 303 participants over 40 years old from seven centers across China. They were stratified into six groups according to their body mass index (BMI) and metabolic status: metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), metabolically healthy obesity (MHO), metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW), and metabolically unhealthy obesity (MUO). Increased albuminuria was defined as a UACR ≥30 mg/g.ResultsThe percentages of MHNW, MHOW, MHO, MUNW, MUOW, and MUO were 27.6%, 15.9%, 4.1%, 19.8%, 22.5%, and 9.6%, respectively. Multiple logistic regression analysis showed that the MHO group (odds ratio [OR] 1.205; 95% CI, 1.081‐1.343), MUNW group (OR 1.232; 95% CI, 1.021‐1.486), MUOW group (OR 1.447; 95% CI, 1.303‐1.607), and MUO group (OR 1.912; 95% CI, 1.680‐2.176) were at higher risk of increased albuminuria compared to the MHNW group. Subgroup analysis indicated that the risk of increased albuminuria was further elevated among regular smokers in men aged 40 to 55 years old with abdominal obesity.ConclusionsAmong Chinese community adults, increased albuminuria was associated with increased BMI whether metabolism was normal or not, and those with abnormal metabolism were at greater risk of increased albuminuria than those with normal metabolism. These findings suggest that overweight or obesity or metabolic abnormalities are risk factors for chronic kidney disease.

Chronic kidney disease (CKD) risk is inconsistent in the normal-weight, overweight, and obese individuals due to the heterogeneity of metabolic status. This meta-analysis aimed to examine the combined effects of body mass index (BMI) and metabolic status on CKD risk. The MEDLINE, EMBASE, and Web of Knowledge databases were systematically searched up to March 2019 to identify all eligible studies investigating the CKD risk (defined as GFR < 60 mL/min per 1.73 m2 and/or microalbuminuria or proteinuria) associated with the body size phenotypes which are known as metabolically unhealthy normal-weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO). The classification of subjects in included studies as metabolically unhealthy was based on the presence of three components of metabolic syndrome. BMI categorization was based on the criteria of included studies. The risk estimates and 95% confidence intervals (CIs) were extracted and pooled using random effects analysis. A total of 9 prospective cohort studies with 128773 participants and 4797 incident cases were included in the meta-analysis. Compared with healthy normal-weight individuals as reference, MUNW and MHO subjects showed an increased risk for CKD events with a pooled RR of 1.58 (95% CI = 1.28-1.96) in MUNW and 1.55 (95% CI = 1.34-1.79) in MHO persons. Also, MHOW was at increased risk for CKD (RR = 1.34, 95% CI = 1.20-1.51). MUHO individuals were at the highest risk for the development of CKD (RR = 2.13, 95% CI = 1.66-2.72). Individuals with metabolic abnormality, although at normal-weight, have an increased risk for CKD. Healthy overweight and obese individuals had higher risk; refuting the notion that metabolically healthy overweight and obese phenotypes are benign conditions.