Association of serum calcium and metabolically healthy obese in US adults: a cross-sectional study.

OBJECTIVES: The relationship between serum calcium and occurrence of MHO (metabolically healthy obesity) and MUNO (metabolically unhealthy non-obesity) remains unclear, and distinguishing these two phenotypes is difficult within primary healthcare units. This study explores that relationship. METHODS: This survey included 28590 adults from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Obesity phenotypes were categorized based on BMI and presence or absence of metabolic syndrome components. Weighted multivariate logistic regression analyses were used to assess the association between serum calcium levels and the obesity phenotype. Restricted cubic spline analysis characterized dose-response relationships, and stratified analyses explored these relationships across sociodemographic and lifestyle factors. RESULTS: The overall prevalence of MHO and MUNO were 2.6% and 46.6%, respectively. After adjusting for covariates, serum calcium exhibited a negative association with MHO [OR (95%): 0.49 (0.36,0.67), p < 0.001], while exhibiting a positive association with MUNO [OR (95%): 1.48 (1.26,1.84), p < 0.001]. Additionally, we found a non-linear association between serum calcium levels and the incidences of MHO and MUNO. Stratified analyses demonstrated a strong negative correlation between serum calcium levels and MHO occurrence across various subgroups. There was no significant interaction between calcium and stratified variables except sex; the association between calcium and the occurrence of MHO was remarkable in female patients. Meanwhile, the predictive ability of serum calcium level for the occurrence of MUNO among all patients was consistent across various subgroups. There was a significant interaction between calcium level and stratified variables based on age, sex, race, and smoking status; the association was remarkable in older (≥ 40 years old), white, none or less smoking, and female patients. CONCLUSIONS: A significant correlation was identified between serum calcium levels and MHO or MUNO. The findings suggest that serum calcium levels may serve as an indicator for more accurate assessment and diagnosis of MUNO and MHO, especially among individuals with abdominal obesity.

Serum calcium levels exhibited an inverse relationship with metabolically healthy obesity (MHO) and a positive relationship with metabolically unhealthy non-obese (MUNO).A nonlinear association exists between serum calcium levels and the incidence of both MHO and MUNO.Serum calcium has the potential to enhance evaluation and screening for MUNO or MHO in the general US adult population.

Serum selenium accelerates the development of metabolic disorders in a metabolically healthy obese U.S. population: a retrospective cross-sectional analysis of a population-based study from the NHANES (2011-2018).

Background: Obesity represents a significant risk factor for the development of metabolic abnormalities. However, it is not inevitable that all individuals with obesity will develop these disorders. Selenium has been demonstrated to play a role in maintaining metabolic homeostasis in vivo, with the ability to regulate relevant signaling pathways involved in glucose and lipid metabolism processes. Previous studies have indicated that selenium concentrations in obese individuals are higher than those reported in the general population. These findings the question of whether altered selenium concentrations may act as important triggers for accelerating metabolic imbalances in the obese population. The aim of this study was to examine the potential correlation between serum selenium concentrations and the risk of developing metabolic abnormalities in individuals with obesity. Methods: The present study included 6,125 participants from the 2011-2018 National Health and Nutrition Examination Survey (NHANES) who were aged between 20 and 80 years, with a body mass index (BMI) of 30 kg/m2 or greater, and met the inclusion and exclusion criteria. Weighted generalized linear regression analyses were conducted to evaluate the associations between serum selenium concentrations and the conversion of metabolically healthy obesity (MHO) to metabolically unhealthy obesity (MUO). A generalized additive model (GAM) and a two-piecewise linear regression model were employed to investigate the saturation threshold effect between selenium and MUO. The correlation between different selenium concentration intervals and metabolic diseases was evaluated by categorizing selenium concentrations according to the saturation threshold. Furthermore, this study investigated the correlation between serum selenium and lipid concentrations in obese females and between serum selenium and blood pressure in obese males. Results: The weighted prevalence of MUO in the study population was 48.35%. After rigorous adjustment for sociodemographic, physical, and laboratory test covariates, the weighted odds ratio (OR) of MUO increased by 44% for every 1 µM increase (approximately 78.74 µg) in the serum selenium concentration (weighted OR=1.44; 95% CI=1.09 - 1.91; P=0.018). Second, GAM analysis and saturation threshold analyses revealed an inverted U-shaped relationship between serum selenium and metabolic abnormalities in males, with a corresponding inflection point (K) of 2.82 µM. When the serum selenium concentration was below the K-value, the effects of serum selenium were mainly on blood pressure, especially diastolic blood pressure (DBP) (weighted ß: 3.34; 95% CI= 0.25 - 6.44; P=0.038). Conversely, the correlation between the serum selenium concentrations and metabolic homeostasis imbalance in females was linear. When the selenium concentration exceeded 2.12 µM, the increase in selenium content was accompanied by increases in total cholesterol (TC, weighted ß=0.54, 95% CI=0.32 - 0.76; P=0.000) and triglyceride (TG, weighted ß=0.51, 95% CI=0.27 - 0.75; P=0.000) concentrations. Conclusions: The findings of our study indicate that selenium supplementation strategies for individuals with obesity should be tailored to the sex of the individual. In females, serum selenium concentration above the saturation threshold primarily facilitates the transition from MHO to MUO by influencing alterations in serum lipid metabolism. Maintaining selenium concentrations below the threshold levels is highly important for preventing the conversion of MHO to MUO. In males, serum selenium concentrations above the threshold were found to be effective in preventing an elevation in blood pressure, particularly in improving systolic blood pressure (SBP). Nevertheless, serum selenium concentrations below the threshold are linked to an increased risk of hypertension in obese individuals, particularly those with elevated diastolic blood pressure (DBP). Further research is needed to elucidate the optimal serum selenium concentration that exerts deleterious effects on blood pressure.

Metabolically healthy obesity in adults with X-linked hypophosphatemia.

OBJECTIVES: X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH. METHODS: We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls. RESULTS: Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls. CONCLUSION: The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.

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.

Neurological-related proteomic profiling in plasma of children with metabolic healthy and unhealthy overweight/obesity.

OBJECTIVE: Children with overweight/obesity (OW/OB) exhibit poor cardiometabolic health, yet mechanisms influencing brain health remain unclear. We examined the differences in neurological-related circulating proteins in plasma among children with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and the association with metabolic syndrome markers. METHODS: In this cross-sectional study, we included 84 Caucasian children (39% girls), aged 10.1 ± 1.1 years, from the ActiveBrains project (NCT02295072). A ninety-two-protein targeted approach using Olink's® technology was used. RESULTS: We identified distinct concentrations of CD38, LAIR2, MANF and NRP2 proteins in MHO compared with MUO. Moreover, individual metabolic syndrome (MS) markers were linked to nine proteins (CD38, CPM, EDA2R, IL12, JAMB, KYNU, LAYN, MSR1 and SMOC2) in children with OW/OB. These proteins play crucial roles in diverse biological processes (e.g., angiogenesis, cholesterol transport, nicotinamide adenine dinucleotide (NAD+) catalysis and maintenance of blood-brain barrier) related to brain health. CONCLUSION: Our proteomics study suggests that cardiometabolic health (represented by MHO/MUO or individual MS markers) is associated with the concentration in plasma of several proteins involved in brain health. Larger-scale studies are needed to contrast/confirm these findings, with CD38 standing out as a particularly noteworthy and robust discovery.

Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity.

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid-lipoprotein profile, inflammation, and glucose-insulin homeostasis in 51 postmenopausal women versus 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3 × 10 repetitions at 80% one repetition maximum (1-RM)). Percent fat marginally decreased and lean body mass increased (0.01 < p < 0.05) while CRF and muscular strength improved in all women, after RT (effect size (ES): 0.11-1.21 (trivial to large effects), p ˂ 0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased, respectively, in participants with MHO using the A/L ratio approach (ES: -0.47 to 1.07 (small to large effects), p ˂ 0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: -0.42 to -0.84 (small to large effects), p ˂ 0.05). Glucose-insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.

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.

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.

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.

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.

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.

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.