Obesity is not a single diagnosis, and the association of 'metabolically unhealthy' obesity with cardiovascular disease is well-described. However, the relationship between metabolically healthy obesity (MHO) and atrial fibrillation (AF) is still debated.

Our objective is to investigate the association between MHO and the risk of AF.

A comprehensive search of databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library regarding longitudinal studies of MHO and risk of AF was performed. Random effects were used to pool the effect estimates.

Nine cohort studies comprising 4,250,557 participants were included. The pooled results revealed that individuals with MHO were associated with a greater incidence of AF than those with a metabolically healthy normal weight (HR: 1.34, 95 % CI: 1.26 to 1.42) with moderate certainty according to the Grading of Recommendations Assessment, Development, and Evaluation assessment. Individuals with MHO were associated with a lower risk of AF compared with participants with metabolically unhealthy obesity (RR: 0.48, 95 % CI: 0.36 to 0.64). Individuals with MHO were not significantly associated with the risk of AF as compared to metabolically unhealthy normal weight (HR: 1.04, 95 % CI: 0.89 to 1.22).

MHO is associated with a greater incidence of AF, highlighting the importance of weight reduction in individuals without metabolic disorders in reducing the risk of AF.

PROSPERO - registration number CRD42023432195.

Background: Diabetes mellitus [DM) is a fast-increasing non-communicable disease in South Africa, with a prevalence of 11.3%. The present study aimed to longitudinally investigate the association of carotid intima-media thickness [CIMT) progression and cardiovascular risk factors in the T2DM and non-DM rural black population of South Africa. Methods: This population-based retrospective cohort study was conducted in the Dikgale Mamabolo Mothiba Surveillance area between 2014 and 2023 by the Africa Wits INDEPTH Partnership for Genomic Research (AWI-Gen). The IBM Statistical Package for the Social Sciences version 27 was used to analyze data. The paired T-test was used to determine the mean differences between baseline and follow-up. Longitudinal estimates of the association of CIMT with CVD risk factors in the T2DM and non-DM groups were analyzed using linear mixed models. Results: The baseline mean age was 51.64 years. There was a significant increase in CIMT (left and mean CIMT), low-density lipoprotein-cholesterol (LDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate in the T2DM and non-DM groups. In the T2DM group, there was a strong significant association between age (2.20 mm), LDL-C (4.30 mm), SBP (4.57 mm), and waist/hip ratio (0.24 mm) with CIMT progression. The non-DM group revealed a significant association between LDL-C (0.001 mm), SBP (1.41 mm), and CIMT progression. Conclusion: CIMT was associated with other main CVD-related risk factors (age, LDL-C, LDL-C/HDL-C ratio, TC/HDL-C ratio, waist/hip ratio, and SBP). CIMT progression was more pronounced in the T2DM group than non-DM, suggesting a higher risk of atherosclerosis and cardiovascular complications in T2DM individuals.

The concept of metabolic health, particularly in obesity, has attracted a lot of attention in the scientific community, and is being increasingly used to determine the risk of cardiovascular diseases and diabetes mellitus-related complications. This Review assesses the current understanding of metabolically healthy obesity (MHO). First, we present the historical evolution of the concept. Second, we discuss the evidence for and against its existence, the usage of different definitions of MHO over the years and the efforts made to provide novel definitions of MHO. Third, we highlight epidemiological data with regard to cardiovascular risk in MHO, which is estimated to be moderately elevated using widely used definitions of MHO when compared with individuals with metabolically healthy normal weight, but potentially not elevated using a novel definition of MHO. Fourth, we discuss novel findings about the physiological mechanisms involved in MHO and how such knowledge helps to identify and characterize both people with MHO and those with metabolically unhealthy normal weight. Finally, we address how the concept of MHO can be used for risk stratification and treatment in clinical practice.

Obesity represents a prevalent global health concern with significant implications for various diseases, including chronic kidney disease (CKD). Within this landscape, the phenomenon of metabolically healthy obesity has emerged, challenging traditional notions about the health risks associated with excess weight. While traditional CKD risk factors involve obesity, metabolic syndrome, diabetes, and hypertension, the metabolically healthy obese (MHO) subgroup disrupts these assumptions. Our main objective in this study is to integrate existing literature on CKD in MHO individuals. In this endeavor, we delve into the pathophysiological foundations, the transition between obesity phenotypes and their impact on renal health, examine the implications of their metabolic resilience on mortality within a renal context, and explore potential management strategies specifically designed for MHO individuals. Offering a comprehensive overview of the pathophysiology, we cover various factors contributing to the risk of CKD in the metabolically healthy obese setting, including inflammation, cytokines, hemodynamics, and the renin-angiotensin-aldosterone system, gastrointestinal microbiota, diet, exercise, adipose distribution, and lipotoxicity. Through this synthesis, we aim to provide a comprehensive understanding of the risk of CKD in those classified as MHO.

Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories.

In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories.

During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed.

MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

The proportion of heart failure patients with preserved ejection fraction has been rising over the past decades and has coincided with increases in the prevalence of obesity and metabolic syndrome. The relationship between these interconnected comorbidities and heart failure with preserved ejection fraction (HFpEF) is still poorly understood. This study characterized obesity and metabolic syndrome among real-world patients with HFpEF.

We identified adults with heart failure in the Veradigm Cardiology Registry, previously the PINNACLE Registry, with a left ventricular ejection fraction measurement ≥ 50% between 01/01/2016 and 12/31/2019. Patients were stratified by obesity diagnosis and presence of metabolic syndrome (≥ 3 of the following: diabetes, hypertension, hyperlipidemia, and obesity). We captured baseline demographic and clinical characteristics and used multivariable logistic regression to examine the odds of having cardiac (atrial fibrillation, coronary artery disease, coronary artery bypass surgery, myocardial infarction, and stroke/transient ischemic attack) and non-cardiac (chronic kidney disease, chronic liver disease, and peripheral artery disease) comorbidities of interest. The models adjusted for age and sex, and the main covariates of interest were obesity and metabolic burden score (0-3 based on the presence of diabetes, hypertension, and hyperlipidemia). The models were run with and without an obesity*metabolic burden score interaction term.

This study included 264,571 patients with HFpEF, of whom 55.7% had obesity, 52.5% had metabolic syndrome, 42.5% had both, and 34.3% had neither. After adjusting for age, sex, and burden of other metabolic syndrome-associated diagnoses, patients with HFpEF with obesity had lower odds of a diagnosis of other evaluated comorbidities relative to patients without obesity. The presence of metabolic syndrome in HFpEF appears to increase comorbidity burden as each additional metabolic syndrome-associated diagnosis was associated with higher odds of assessed comorbidities except atrial fibrillation.

Obesity was common among patients with HFpEF and not always co-occurring with metabolic syndrome. Multivariable analysis suggested that patients with obesity may develop HFpEF in the absence of other driving factors such as cardiovascular disease or metabolic syndrome.

This article briefly summarizes the results of existing research on metabolically healthy obesity in the context of health risks.

The PubMed database was searched for relevant meta-analyses addressing metabolically healthy obesity in the context of health risks.

We included a total of 17 relevant meta-analyses in this review. The results of the studied meta-analyses showed that metabolically healthy obesity may be only a transient condition associated with an increased risk of developing metabolic abnormalities in the future. People with obesity without metabolic abnormalities have an increased risk of type 2 diabetes, cardiovascular disease, cancer, chronic kidney disease, and depressive syndrome. In addition, all people with obesity are at risk of pathogenesis resulting from the mechanical stress caused by presence of abnormal adipose tissue, such as sleep apnoea syndrome or skin problems.

Based on the results of meta-analyses, we recommend motivating all obese patients to change their lifestyle regardless of the presence of metabolic defects.

Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality worldwide. Controversial views exist over the effects of metabolically unhealthy obesity phenotypes on CVDs. This study aimed to perform a meta-analysis to assess the association between metabolic syndrome and myocardial infarction (MI) among individuals with excess body weight (EBW).

We searched PubMed/Medline, Scopus, and Web of Science databases as of December 9, 2023. Cohort studies involving patients with overweight or obesity that reported the relevant effect measures for the association between metabolic syndrome and MI were included. We excluded studies with incomplete or unavailable original data, reanalysis of previously published data, and those that did not report the adjusted effect sizes. We used the Newcastle Ottawa Scale for quality assessment. Random-effect model meta-analysis was performed. Publication bias was assessed by Begg's test.

Overall, nine studies comprising a total of 61,104 participants were included. There was a significant positive association between metabolic syndrome and MI among those with obesity (hazard ratio (HR): 1.68; 95% confidence interval (CI): 1.27, 2.22). Subgroup analysis showed higher HRs for obesity (1.72; 1.03, 2.88) than overweight (1.58; 1.-13-2.21). Meta-regression revealed no significant association between nationality and risk of MI (p = 0.75). All studies had high qualities. There was no significant publication bias (p = 0.42).

Metabolic syndrome increased the risk of MI in those with EBW. Further studies are recommended to investigate other risk factors of CVDs in EBW, in order to implement preventive programs to reduce the burden of CVD in obesity.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Cardiovascular disease (CVD) is the most common non-communicable disease occurring globally. Although previous literature has provided useful insights into the important role that diet plays in CVD prevention and treatment, understanding the causal role of diets is a difficult task considering inherent and introduced weaknesses of observational (e.g. not properly addressing confounders and mediators) and experimental research designs (e.g. not appropriate or well designed). In this narrative review, we organised current evidence linking diet, as well as conventional and emerging physiological risk factors, with CVD risk, incidence and mortality in a series of diagrams. The diagrams presented can aid causal inference studies as they provide a visual representation of the types of studies underlying the associations between potential risk markers/factors for CVD. This may facilitate the selection of variables to be considered and the creation of analytical models. Evidence depicted in the diagrams was systematically collected from studies included in the British Nutrition Task Force report on diet and CVD and database searches, including Medline and Embase. Although several markers and disorders linked to conventional and emerging risk factors for CVD were identified, the causal link between many remains unknown. There is a need to address the multifactorial nature of CVD and the complex interplay between conventional and emerging risk factors with natural and built environments, while bringing the life course into the spotlight.

Current guidelines for obesity prevention and control focus on body mass index (BMI) and rarely address central obesity. Few studies have been conducted on the association between normal-weight central obesity and the risk of diabetes mellitus (DM).

26,825 participants from the National Health and Nutrition Examination Survey (NHANES) were included in our study. A weighted multivariate logistic regression model was used to analyze the relationship between different obesity patterns and the risk of DM.

Our results suggest that normal-weight central obesity is associated with an increased risk of DM (OR: 2.37, 95% CI: 1.75-3.23) compared with normal-weight participants without central obesity. When stratified by sex, men with normal-weight central obesity, obesity and central obesity were found to have a similar risk of DM (OR: 3.83, 95% CI: 2.10-5.97; OR: 4.20, 95% CI: 3.48-5.08, respectively) and a higher risk than all other types of obesity, including men who were overweight with no central obesity (OR: 1.21, 95% CI: 0.96-1.51) and obese with no central obesity (OR: 0.53, 95% CI: 0.30-0.91).

Our results highlight the need for more attention in people with central obesity, even if they have a normal BMI.

Obesity is an important risk factor for acute myocardial infarction (AMI), but the interplay between metabolic health and obesity on AMI mortality has been controversial. In this study, we aimed to elucidate the risk of short- and long-term all-cause mortality by obesity and metabolic health in AMI patients using data from a multi-ethnic national AMI registry.

A total of 73,382 AMI patients from the national Singapore Myocardial Infarction Registry (SMIR) were included. These patients were classified into four groups based on the presence or absence of metabolic diseases, diabetes mellitus, hyperlipidaemia, and hypertension, and obesity: (1) metabolically-healthy-normal-weight (MHN); (2) metabolically-healthy-obese (MHO); (3) metabolically-unhealthy-normal-weight (MUN); and (4) metabolically-unhealthy-obese (MUO).

MHO patients had reduced unadjusted risk of all-cause in-hospital, 30-day, 1-year, 2-year, and 5-year mortality following the initial MI event. However, after adjusting for potential confounders, the protective effect from MHO on post-AMI mortality was lost. Furthermore, there was no reduced risk of recurrent MI or stroke within 1-year from onset of AMI by the MHO status. However, the risk of 1-year mortality was higher in female and Malay AMI patients with MHO compared to MHN even after adjusting for confounders.

In AMI patients with or without metabolic diseases, the presence of obesity did not affect mortality. The exception to this finding were female and Malay MHO who had worse long-term AMI mortality outcomes when compared to MHN suggesting that the presence of obesity in female and Malay patients may confer worsened outcomes.

Among 20 leading global risk factors for years of life lost in 2040, reference forecasts point to three metabolic risks-high blood pressure, high BMI, and high fasting plasma glucose-as being the top risk variables. Building upon these and other risk factors, the concept of metabolic health is attracting much attention in the scientific community. It focuses on the aggregation of important risk factors, which allows the identification of subphenotypes, such as people with metabolically unhealthy normal weight or metabolically healthy obesity, who strongly differ in their risk of cardiometabolic diseases. Since 2018, studies that used anthropometrics, metabolic characteristics, and genetics in the setting of cluster analyses proposed novel metabolic subphenotypes among patients at high risk (eg, those with diabetes). The crucial point now is whether these subphenotyping strategies are superior to established cardiometabolic risk stratification methods regarding the prediction, prevention, and treatment of cardiometabolic diseases. In this Review, we carefully address this point and conclude, firstly, regarding cardiometabolic risk stratification, in the general population both the concept of metabolic health and the cluster approaches are not superior to established risk prediction models. However, both subphenotyping approaches might be informative to improve the prediction of cardiometabolic risk in subgroups of individuals, such as those in different BMI categories or people with diabetes. Secondly, the applicability of the concepts by treating physicians and communication of the cardiometabolic risk with patients is easiest using the concept of metabolic health. Finally, the approaches to identify cardiometabolic risk clusters in particular have provided some evidence that they could be used to allocate individuals to specific pathophysiological risk groups, but whether this allocation is helpful for prevention and treatment still needs to be determined.

The triglyceride-glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases.

Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression.

Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P < 0.001). In multivariable-adjusted analysis, both < 8.80 (adjusted hazard ratio [aHR] = 1.15, 95% confidence interval [CI] 1.02, 1.29) and > 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80-9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males.

A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence.

Obesity is a heterogenous condition with multiple different phenotypes. Among these a particular subtype exists named as metabolically healthy obesity (MHO). MHO has multiple definitions and its prevalence varies according to study. The potential mechanisms underlying the pathophysiology of MHO include the different types of adipose tissue and their distribution, the role of hormones, inflammation, diet, the intestinal microbiota and genetic factors. In contrast to the negative metabolic profile associated with metabolically unhealthy obesity (MUO), MHO has relatively favorable metabolic characteristics. Nevertheless, MHO is still associated with many important chronic diseases including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease as well as certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore, it should not be considered as a benign condition. The major therapeutic alternatives include dietary modifications, exercise, bariatric surgery and certain medications including glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. In this review, we discuss the significance of MHO while comparing this phenotype with MUO.

To estimate the risk of cardiovascular disease (CVD) in older adults with overweight or obesity without metabolic risk factors using a Bayesian survival analysis.

Prospective cohort study with median follow-up of 9.7 years.

Newcastle, New South Wales, Australia.

A total of 2313 community-dwelling older men and women.

Participants without known CVD and with a body mass index (BMI) ≥ 18.5 kg m² were stratified by BMI and metabolic risk to create six BMI-metabolic health categories. Metabolic risk was defined according to the International Diabetes Federation criteria for metabolic syndrome. 'Metabolically healthy' was defined as absence of metabolic risk factors. Bayesian survival analysis, incorporating prior information from a previously published meta-analysis was used to assess the effect of BMI-metabolic health categories on time from recruitment to CVD.

Incident physician-diagnosed CVD, defined as fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, angina, or coronary revascularisation procedure, was determined by linkage to hospital admissions records and Medicare Australia data. Secondary outcomes were cardiovascular mortality and all-cause mortality.

From 2313 adults with complete metabolic health data over a median follow-up of 9.7 years, 283 incident CVD events, 58 CVD related deaths and 277 deaths from any cause occurred. In an adjusted Bayesian survival model of complete cases with informative prior and metabolically healthy normal weight as the reference group, the risk of CVD was increased in metabolically healthy overweight (HR = 1.52, 95% credible interval 0.96-2.36), and in metabolically healthy obesity (HR = 1.86, 95% credible interval 1.14-3.08). Imputation of missing metabolic health and confounding data did not change the results.

There was increased risk of CVD in older adults with overweight or obesity, even in the absence of any metabolic abnormality. This argues against the notion of 'metabolically healthy' overweight or obesity.

The association between obesity severity and duration with the transition from metabolically healthy obese/overweight (MHO) phenotype to metabolically unhealthy obese (MUO) phenotype is not well understood.

This study includes the Tehran Lipid and Glucose Study participants who were initially classed as MHO. Cumulative excess weight (CEW) and cumulative excess waist circumference (CEWC) scores, which represent the accumulation of body mass index and waist circumference deviations from expected values over time (kg/m² ∗ y and cm ∗ y, respectively), were calculated until the transition from MHO to MUO or the end of follow-up. The sex-stratified association of CEW and CWEC with the transition from MHO to MUO was investigated by time-dependent Cox models, adjusting for confounders. Out of 2525 participants, 1732 (68.5%) were women. During 15 years of follow-up, 1886 (74.6%) participants transitioned from MHO to MUO. A significant association was found between CEW and CEWC quartiles with the development of MUO among women participants (fully adjusted hazard ratios in the fourth quartile of CEW and CEWC [95% (CI)]:1.65 [1.37-1.98] and [95% CI]: 1.83 [1.53-2.19]). There was no significant association between CEW and CEWC with the MHO transition to MUO among men participants.

Over 15 years of follow-up in TLGS, general and central obesity accumulation was associated with the increased transition from MHO to MUO among women participants. More research with a larger sample size is needed to confirm and explain why the results are different for men and women.

Excess weight is a major health problem. Aims of this study were to determine the prevalence rates of overweight and obesity, and to compare their associations with cardiometabolic and renal risk factors between obese and non-obese populations, and between overweight and non-overweight populations.

Cross-sectional observational study conducted in Primary Care. Population-based random sample: 6,588 study subjects between 18 and 102 years of age (response rate: 66%). Crude and sex- and age-adjusted prevalence rates of overweight and obesity were calculated, and their associations with cardiometabolic and renal variables were assessed by bivariate and multivariate analysis.

The age- and sex-adjusted prevalence rates of overweight and obesity were 36.0% (42.1% in men; 33.1% in women) and 25.0% (26.2% in men; 24.5% in women), respectively. These prevalences increased with age, and were higher in men than in women. Fifty-two percent (95%CI: 50.0-53.9) of the overweight population and 62.3% (95%CI: 60.1-64.5) of the obese population had a high or very high cardiovascular risk. Abdominal obesity, physical inactivity, prediabetes, hypertension, hypertriglyceridemia, and low HDL-C were independently associated with both entities. Furthermore, diabetes was independently associated with overweight and hypercholesterolemia with obesity.

The prevalence of overweight and obesity was 61.0% (68.4% in men and 59.0% in women). More than half of the overweight population and nearly two-thirds of the obese population had a high cardiovascular risk. Hyperglycemia, physical inactivity, hypertension, hypercholesterolemia, low HDL-C, and hypertriglyceridemia were independently associated with overweight and obesity.

Discrepant results have been demonstrated regarding the cardiovascular (CV) risk of populations with metabolically healthy overweight/obesity (MHO) who were transitioned into metabolically unhealthy states. So, the objective of this systematic review and meta-analysis was to estimate the risk of cardiovascular diseases (CVD) incidence in individuals with transitional MHO phenotype.

A literature review was done in PubMed, Scopus, EMBASE, and google scholar databases. Pooled HRs for all fatal and nonfatal CV events were computed using random-effect models for transitional MHOs in general as well as for each sex subgroup separately. This systematic review and meta-analysis included a total of 7 prospective observational studies with a total of 7,720,165 participants, published between 2018 and 2020. The mean follow-up duration of participants was 11.7 (5.5) years. Overall, the transitional MHO individuals had a significant risk of CVD incidence [HR = 1.42, 95% CI (1.24-1.60)]. In addition, in both male and female subgroups, unstable MHO phenotype demonstrated a significant CVD risk and HRs for incident CVD in males and females were 1.51 (1.07-1.96) and 1.71 (1.08-2.34), respectively.

Transition from MHO to unhealthy state throughout follow-up elevated the risk of CVD in both male and female groups. This can explain the association between MHO and incidence of CV events especially with longer follow up period.

CRD42021270225.

There is robust evidence that in midlife, higher body mass index (BMI) and metabolic syndrome (MetS), which often co-exist, are associated with increased mortality risk. However, late-life findings are inconclusive, and few studies have examined how metabolic health status (MHS) affects the BMI-mortality association in different age categories. We, therefore, aimed to investigate how mid- and late-life BMI and MHS interact to affect the risk of mortality.

This cohort study included 12,467 participants from the Swedish Twin Registry, with height, weight, and MHS measures from 1958-2008 and mortality data linked through 2020. We applied Cox proportional hazard regression with age as a timescale to examine how BMI categories (normal weight, overweight, obesity) and MHS (identification of MetS determined by presence/absence of hypertension, hyperglycemia, low HDL, hypertriglyceridemia), independently and in interaction, are associated with the risk of all-cause mortality. Models were adjusted for sex, education, smoking, and cardiovascular disease.

The midlife group included 6,252 participants with a mean age of 59.6 years (range = 44.9-65.0) and 44.1% women. The late-life group included 6,215 participants with mean age 73.1 years (65.1-95.3) and 46.6% women. In independent effect models, metabolically unhealthy status in midlife increased mortality risks by 31% [hazard ratio 1.31; 95% confidence interval 1.12-1.53] and in late-life, by 18% (1.18;1.10-1.26) relative to metabolically healthy individuals. Midlife obesity increased the mortality risks by 30% (1.30;1.06-1.60) and late-life obesity by 15% (1.15; 1.04-1.27) relative to normal weight. In joint models, the BMI estimates were attenuated while those of MHS were less affected. Models including BMI-MHS categories revealed that, compared to metabolically healthy normal weight, the metabolically unhealthy obesity group had increased mortality risks by 53% (1.53;1.19-1.96) in midlife, and across all BMI categories in late-life (normal weight 1.12; 1.01-1.25, overweight 1.10;1.01-1.21, obesity 1.31;1.15-1.49). Mortality risk was decreased by 9% (0.91; 0.83-0.99) among those with metabolically healthy overweight in late-life.

MHS strongly influenced the BMI-mortality association, such that individuals who were metabolically healthy with overweight or obesity in mid- or late-life did not carry excess risks of mortality. Being metabolically unhealthy had a higher risk of mortality independent of their BMI.

Metabolically healthy obese (MHO) individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome. However, the association between MHO and type 2 diabetes (T2DM) is still controversial. Some studies indicated that MHO is a favorable phenotype for T2DM, but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normal-weight individuals, especially among those who would acquire metabolically unhealthy obesity. This has been supported by finding insulin resistance and low-grade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction. Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO. Here, we reviewed current literature on the relationship between MHO and T2DM, discussed the determinants for the development of diabetes in MHO, and summarized the measures for the prevention of T2DM in MHO.

Contested evidence suggests that obesity confers no risk to health in people who have a healthy lifestyle, particularly if there are no metabolic complications of obesity. The aim was to examine the association between adherence to lifestyle recommendations and the absence of metabolic complications on the incident or fatal cardiovascular disease and all-cause mortality across different categories of body mass index (BMI).

This contemporary prospective cohort study included 339,902 adults without cardiovascular disease at baseline, recruited between 2006 and 2010 from the UK Biobank and followed until 2018-2020. The main exposures were four healthy lifestyle behaviours: never smoker, alcohol intake ≤ 112g/ week, 150 min moderate physical activity or 75 min vigorous activity/week, ≥ 5 servings of fruit or vegetables/day, and we assessed these overall and across the BMI groups. Metabolic complications of excess adiposity were hypertension, diabetes and hyperlipidaemia, and we examined whether obesity was associated with increased risk in the absence of these complications. The outcomes were all-cause mortality, death from, and incident cardiovascular disease (CVD).

Individuals who met four lifestyle recommendations but had excess weight had higher all-cause mortality; for BMI 30-34.9 kg/m2, the hazard ratio (HR) was 1.42 (95% confidence interval 1.20 to 1.68), and for BMI ≥ 35 kg/m2, HR was 2.17 (95% CI 1.71 to 2.76). The risk was lower, but still increased for people with no metabolic complications; for all-cause mortality, BMI 30-34.9 kg/m2 had an HR of 1.09 (95% CI 0.99 to 1.21), and BMI ≥ 35 kg/m2 had an HR of 1.44 (95% CI 1.19 to 1.74) for all-cause mortality. Similar patterns were found for incident and fatal CVD.

Meeting healthy lifestyle recommendations, or the absence of metabolic complications of obesity offsets some, but not all, of the risk of subsequent CVD, and premature mortality in people with overweight or obesity. Offering support to achieve and maintain a healthy weight and to adopt healthy behaviours are likely to be important components in effective preventative healthcare.

Obesity, a major risk factor for acute coronary syndrome (ACS), is a multifaceted disease with different metabolic phenotypes and sex-specific features. Here, we evaluated the long-term cardiovascular risk by different obesity/metabolic phenotypes and by sex in ACS patients. The occurrence of the composite outcome of death, nonfatal reinfarction with or without PCI and/or stroke was evaluated in 674 patients (504 men; 170 women), consecutively hospitalized for ACS and followed-up for 7 years, who were stratified in metabolically healthy (MHNW) and unhealthy normal weight (MUNW), and in metabolically healthy (MHO) and unhealthy obese (MUO) groups. At baseline, 54.6% of patients were included in the MHNW group, 26.4% in the MUNW, 5.9% in the MHO and 13.1% in the MUO, with no sex-differences in the distribution of phenotypes. The overall rate of major outcome (100 person-years) in the reference group (MHNW) was higher in men than in women (RR: 1.19 vs. 0.6). The Kaplan-Meier curves for cumulative survival free from cardiovascular events according to obesity/metabolic status diverged significantly according to sex (log rank test, p = 0.006), this effect being more prominent in men (log 11.20; p = 0.011), than in women (log 7.98; p = 0.047). Compared to MHNW, the risk increased in obese men (RR: 2.2; 95% 1.11-1.54 in MUO group), whereas in women the risk was confined to metabolically unhealthy subjects (RR: 3.2; 95% CI 1.23-9.98, MUNW group). Our data show a sex-specific impact of obesity phenotypes on long-term cardiovascular risk in patients hospitalized for ACS.

Cardiovascular disease (CVD) continues to be the leading cause of death in adults, highlighting the need to develop novel strategies to mitigate cardiovascular risk. The advancing obesity epidemic is now threatening the gains in CVD risk reduction brought about by contemporary pharmaceutical and surgical interventions. There are sex differences in the development and outcomes of CVD; premenopausal women have significantly lower CVD risk than men of the same age, but women lose this advantage as they transition to menopause, an observation suggesting potential role of sex hormones in determining CVD risk. Clear differences in obesity and regional fat distribution among men and women also exist. While men have relatively high fat in the abdominal area, women tend to distribute a larger proportion of their fat in the lower body. Considering that regional body fat distribution is an important CVD risk factor, differences in how men and women store their body fat may partly contribute to sex-based alterations in CVD risk as well. This article presents findings related to the role of obesity and sex hormones in determining CVD risk. Evidence for the role of sex hormones in determining body composition in men and women is also presented. Lastly, the clinical potential for using sex hormones to alter body composition and reduce CVD risk is outlined. © 2022 American Physiological Society. Compr Physiol 12:1-45, 2022.

We propose a weight-neutral strategy for obesity treatment on the following grounds: (1) the mortality risk associated with obesity is largely attenuated or eliminated by moderate-to-high levels of cardiorespiratory fitness (CRF) or physical activity (PA), (2) most cardiometabolic risk markers associated with obesity can be improved with exercise training independent of weight loss and by a magnitude similar to that observed with weight-loss programs, (3) weight loss, even if intentional, is not consistently associated with lower mortality risk, (4) increases in CRF or PA are consistently associated with greater reductions in mortality risk than is intentional weight loss, and (5) weight cycling is associated with numerous adverse health outcomes including increased mortality. Adherence to PA may improve if health care professionals consider PA and CRF as essential vital signs and consistently emphasize to their patients the myriad benefits of PA and CRF in the absence of weight loss.

To assess serum vitamin D trend from baseline to 12 months after one anastomosis gastric bypass (OAGB).

In this observational cohort analysis of longitudinal data, we assessed the trend of serum vitamin D, and its associations with anthropometric, and biochemical measurements in 98 patients undergoing OAGB in a bariatric surgery center. All participants were on >800 IU/day vitamin D supplementation.

Vitamin D, lipid profile, creatinine, and albumin levels significantly improved at 12 months post-surgery. Vitamin D concentrations significantly increased from 26.52 ± 12.32 to 54.52 ± 27.90 ng/mL at 12 months. The correlations between vitamin D concentrations and weight, body mass index, lipid profile, ferritin, glycemic indices, and albumin were not significant. In addition, the correlations between vitamin D and parathormone, vitamin D receptor, calcium, phosphorus, body composition, and basal metabolic rate (BMR) did not reach the threshold of statistical significance at 12 months following bariatric surgery. Although there was a significant correlation between body weight and body composition (P < 0.001) and basal metabolic rate (BMR) (r = 0.762, P < 0.001) at 12 months, there were no significant correlations between weight change percent and body composition (P > 0.05), BMR (r = -0.101, P = 0.350), and vitamin D (r = 0.120, P = 0.271) at 12 months.

Our results showed that supplementation of vitamin D with dosage of >800 IU/day is sufficient for prevention of vitamin D deficiency within 12 months after OAGB surgery. Note: This data is mandatory.

Research investigating the efficacy of workplace wellness programmes to promote exercise, and by extension, reduce obesity and increase productivity has proliferated in recent years. Although preliminary work is encouraging, more work is needed.

To evaluate the effects and overall cost of a workplace exercise programme on multiple physical outcomes, including body mass index, aerobic fitness and muscular fitness.

Data from the Bruin Health Improvement Programme .5 (BHIP) between August 2013 and July 2018 were analysed. BHIP is a 12-week workplace wellness programme that assesses multiple areas of physical and mental health. For this study, changes in weight, waist-to-hip ratio, aerobic fitness and muscular endurance were analysed using paired samples t-tests and chi-squared tests. Using results from a prior analysis of Medical Expenditure Panel Survey, the estimated medical expenditure savings associated with weight loss were also analysed.

A total of 518 participants (84% female) took part in the BHIP programme (mean age = 41 years, SD = 1.17). There were significant decreases in all anthropometric indices and significant increases in all fitness outcomes (P < 0.01) from baseline to follow-up. Estimated programme cost per participant, per session was $473 US Dollars (USD), and weight loss is estimated to reduce annual medical care costs by ~$2200 USD.

Results showed significant improvements in all physical outcomes of interest. Additionally, there appears to be an inverse relationship between improvements in employee health and employer healthcare costs. Strengths, limitations and future directions are discussed.

Debate over the cardio-cerebrovascular risk associated with metabolically healthy obesity (MHO) continues. In this study we investigated the association of MHO with the risk of stroke among 221,114 individuals aged 40 years or older based on data from the China National Stroke Screening and Prevention Project (CNSSPP), a nationally representative cross-sectional study, during 2014 to 2015. Different metabolic health and obesity phenotypes were defined according to the Adult Treatment Panel III (ATP III) criteria, where obesity was defined as a body mass index (BMI) ≥28 kg/m². Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for stroke risk associated with different metabolically healthy phenotypes. BMI was used to estimate the mediation effect for metabolic abnormalities to stroke. Compared with the metabolically healthy non-obesity (MHNO) group, individuals with MHO (adjusted OR: 1.21, 95% CI: 1.10,1.33), metabolically unhealthy non-obesity (MUNO) (adjusted OR:1.41, 95% CI: 1.36,1.46), or metabolically unhealthy obesity (MUO) (adjusted OR: 1.70, 95% CI: 1.61,1.80) were found to have an increased risk of stroke. The findings were confirmed robustly by various sensitivity analyses and subgroup analyses. Furthermore, obesity and metabolic abnormalities had an additive interaction for stroke risk with an attributable proportion (AP) of 14.0% in females. BMI played a partial mediating role with the proportion of the effect (PE) at 11.1% in the relationship between metabolic abnormalities and stroke. This study strengthens the evidence that management and interventions in the MHO population may contribute to the primary prevention of stroke.

To obtain a set of reference values for the intake of different types of dietary fibre in a healthy UK population.

This descriptive cross-sectional study used the UK Biobank data to estimate the dietary patterns of healthy individuals. Data on fibre content in different foods were used to calculate the reference values which were then calibrated using real-world data on total fibre intake.

UK Biobank is a prospective cohort study of over 500 000 individuals from across the United Kingdom with the participants aged between 40 and 69 years.

UK Biobank contains information on over 500 000 participants. This study was performed using the data on 19 990 individuals (6941 men, 13 049 women) who passed stringent quality control and filtering procedures and had reported above-zero intake of the analysed foods.

A set of reference values for the intake of six different types of soluble and insoluble fibres (cellulose, hemicelluloses, pectin and lignin), including the corresponding totals, was developed and calibrated using real-world data.

To our knowledge, this is the first study to establish specific reference values for the intake of different types of dietary fibre. It is well known that effects exerted by different types of fibre both directly and through modulation of microbiota are numerous. Conceivably, a deficit or excess intake of specific types of dietary fibre may detrimentally affect human health. Filling this knowledge gap opens new avenues for research in discussion in studies of nutrition and microbiota and offers valuable tools for practitioners worldwide.

The aim of this study was to identify the health risk factors associated with flavonoid intake in cohort studies investigating the association between dietary polyphenols and the risk of cardiovascular disease (CVD). A systematic search of the PubMed and EMBASE databases was performed. Prospective studies with the background characteristics given for categories of flavonoid intake were eligible to inclusion. A bivariate meta-analysis summarising the intercepts and slopes of the linear regression and a dose-response meta-analysis of differences in means were used to analyse the relationships. The intake of total flavonoids was inversely associated with BMI, alcohol consumption, saturated fat intake, and current smoking, and positively associated with vitamin E, folate, fibre, beta-carotene intake, multivitamin supplement use, and high physical activity. The results of this study underline the importance of considering the association between dietary flavonoid consumption and CVD risk in the context of a healthy lifestyle.

The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.

Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Coffee can regulate glucose homeostasis but the underlying mechanism is unclear. This study investigated the preventive and therapeutic effects of chlorogenic acid (CGA), a polyphenol that is found in coffee, on obesity and obesity-related metabolic endotoxemia.

Male 4-week-old C57BL/6 mice were fed either normal chow or a high-fat diet or 20 weeks and half the mice in each group were gavaged with CGA. Oral glucose tolerance tests (OGTTs) and insulin tolerance tests (ITTs) were performed. Markers of inflammation and intestinal barrier function were assayed. The composition of the gut microbiota was analyzed by 16S rRNA high-throughput pyrosequencing. The role of CGA-altered microbiota in metabolic endotoxemia was verified by fecal microbiota transplantation.

CGA protected against HFD-induced weight gain, decreased the relative weight of subcutaneous and visceral adipose, improved intestinal barrier integrity, and prevented glucose metabolic disorders and endotoxemia (P <0.05). CGA significantly changed the composition of the gut microbiota and increased the abundance of short chain fatty acid (SCFA)-producers (e.g., Dubosiella, Romboutsia, Mucispirillum, and Faecalibaculum) and Akkermansia, which can protect the intestinal barrier. In addition, mice with the CGA-altered microbiota had decreased body weight and fat content and inhibited metabolic endotoxemia.

CGA-induced changes in the gut microbiota played an important role in the inhibition of metabolic endotoxemia in HFD-fed mice.

Associations between different biomarkers (proteomics, lipidomics, and metabolomics) coupled to either MHO or metabolically unhealthy obese (MUO) individuals were analyzed through principal component analysis (PCA). Subjects were identified from a subsample of 416 obese individuals, selected from the Malmö Diet and Cancer study-Cardiovascular arm (MDCS-CV, n = 3,443). They were further divided into MHO (n = 143) and MUO (n = 273) defined by a history of hospitalization, or not, at baseline inclusion, and nonobese subjects (NOC, n = 3,027). Two distinctive principle components (PL2, PP5) were discovered with a significant difference and thus further investigated through their main loadings.

MHO individuals had a more metabolically favorable lipid and glucose profile than MUO subjects, that is, lower levels of traditional blood glucose and triglycerides, as well as a trend of lower metabolically unfavorable lipid biomarkers. PL2 (lipidomics, p=0.02) showed stronger associations of triacylglycerides with MUO, whereas phospholipids correlated with MHO. PP5 (proteomics, p=0.01) included interleukin-1 receptor antagonist (IL-1ra) and leptin with positive relations to MUO and galanin that correlated positively to MHO. The group differences in metabolite profiles were to a large extent explained by factors included in the metabolic syndrome.

Compared to MUO individuals, corresponding MHO individuals present with a more favorable lipid metabolic profile, accompanied by a downregulation of potentially harmful proteomic biomarkers. This unique and extensive biomarker profiling presents novel data on potentially differentiating traits between these two obese phenotypes.

Brown adipose tissue (BAT), consisted of brown adipocytes and stromal vascular fraction, which includes endothelial cells, lymphocytes, fibroblasts and stem cells, plays a vital role in regulating cardiovascular health and diseases. As a thermogenic organ, BAT can influence body through strengthening energy expenditure by promoting glucose and lipid metabolism. In addition, BAT is also an endocrine organ which is able to secret adipokines in an autocrine and/or paracrine fashion. BAT plays a protective role in cardiovascular system through attenuating cardiac remodeling and suppressing inflammatory response. In this review, we summarize the advances from the discovery of BAT to the present and provide an overview on the role of BAT dysfunction in cardiovascular diseases.

Obesity and metabolic syndrome have been reported to exert an impact on the male reproductive system with decreasing levels of serum total testosterone (TT); however, the effect of different metabolic obesity phenotypes on testosterone has been poorly studied. We aimed to evaluate the association of metabolic obesity phenotypes and total testosterone levels in a Chinese male population.

We performed a retrospective study based on an epidemiological investigation, a total of 4,081 male individuals aged from 40-75 years old were recruited. The population was classified as metabolically healthy normal weight (MHNW), metabolically healthy overweight/obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy overweight/obese (MUO) according to normal weight (BMI<25.0) and overweight/obesity (BMI≥25.0) with or without metabolic syndrome.

We collected 563 hypotestosteronemia among 4,081 male individuals. The odds ratios (ORs) (95% CIs) of hypotestosteronemia in obesity and metabolic syndrome were 3.072 (2.414-3.911) and 3.294 (2.631-4.125), respectively, after adjusting for age, luteinizing hormone, smoking status, and alcohol consumption. Compared to the MHNW group, male subjects in MHO, MUNW, and MUO groups had decreased serum TT levels. Additionally, the MUO group had a lowest concentration of serum TT and a highest proportion of hypotestosteronemia. There was no significant difference of TT levels between the MHO and MUNW groups.

Obesity and metabolic syndrome are independent risk factors of hypotestosteronemia in Chinese male populations. Our study also suggested that individuals with MHO, MUNW, and MUO have a higher risk of developing hypotestosteronemia.

This review examined the risk of cardiovascular disease in adults with metabolically healthy overweight/obesity. A systematic review and meta-analysis using data from Medline, EMBASE, SCOPUS and Cochrane Library searched from inception up to 31st October 2019. We included prospective cohort studies of adults who are metabolically healthy or unhealthy. Outcomes were fatal and nonfatal cardiovascular events, all-cause mortality. Pooled relative risk was calculated for each outcome in populations with metabolically healthy overweight and metabolically healthy obesity using metabolically healthy normal weight as reference. A random-effects model was used for meta-analysis, and risk of bias assessment tool for nonrandomized studies assessed risk of bias within each study. Twenty-three prospective cohort studies with 4,492,723 participants were included. Cardiovascular disease risk was increased in metabolically healthy groups with overweight (RR = 1.34, CI: 1.23-1.46, n = 20, I2 = 90.3%) and obesity (RR = 1.58, CI: 1.34-1.85, n = 21, I2 = 92.2) compared with a reference group with metabolically healthy normal weight. Cardiovascular disease risk was similar irrespective of the number of risk factors used to define metabolically healthy and the risk remained in the group with no metabolic risk factors. Cardiovascular disease risk is increased in populations with overweight and obesity classified as metabolically healthy even when there were no metabolic risk factors.

Body mass index (BMI) is closely associated with bone mineral density (BMD) in both men and women. However, the relationship between BMI and BMD varies according to different studies. Using SNPs strongly associated with BMI in 336,107 individuals, we conducted a two-sample Mendelian randomization study to identify whether and to what extent BMD at different skeletal sites was affected by BMI. A power calculation was also performed. We found that BMI may causally increase lumbar BMD (β 0.087; 95% CI 0.025 to 0.149; P = 0.006) and heel calcaneus BMD (β 0.120; 95% CI 0.082 to 0.157; P = 1 × 10-7). The associations of BMI with forearm and femoral neck BMD were not statistically significant. Our study suggested that higher BMI plays a causal role in increasing BMD and the effects are similar across the skeleton. BMI was causally and positively associated with lumbar and heel calcaneus BMD. However, no statistically significant effects were observed for BMI on femoral neck or forearm BMD.