Healthy obesity as an intermediate state of risk: A critical review

Introduction: Obesity is a top public health priority but interventions to reverse the condition have had limited success. About 1-in-3 obese adults are free of metabolic risk factor clustering and are considered ‘healthy', and much attention has focused on the implications of this state for obesity management. Areas covered: We searched for individual studies, systematic reviews, and meta-analyses which examined correlates and outcomes of metabolically healthy obesity. We discuss the key roles of fat distribution and physical activity in determining healthy vs. unhealthy obesity and report a greatly increased risk of incident type 2 diabetes associated with healthy obesity vs. healthy normal-weight, among other outcomes. We argue that despite inconsistencies in the definition, patterns across studies clearly show that healthy obesity is a state of intermediate disease risk. Expert commentary: Given the current state of population-level evidence, we conclude that obesity and metabolic dysfunction are inseparable and that healthy obesity is best viewed only as a state of relative health but not of absolute health. We recommend that weight loss through energy restriction be a stand-alone target in addition to increased physical activity for minimising risk of future disease

Improving risk estimates for metabolically healthy obesity and mortality using a refined healthy reference group

Objective: We aimed to re-examine mortality risk estimates for metabolically healthy obesity by using a ‘stable’ healthy non-obese referent group. Design: prospective cohort study. Methods: Participants were 5,427 men and women (aged 65.9 ± 9.4 years, 45.9% men) from the English Longitudinal Study of Ageing. Obesity was defined as body mass index ≥ 30 kg/m2 (vs. non-obese as below this threshold). Based on blood pressure, HDL-cholesterol, triglycerides, glycated haemoglobin, and C-reactive protein, participants were classified as ‘healthy’ (0 or 1 metabolic abnormality) or ‘unhealthy’ (≥ 2 metabolic abnormalities). Results: 671 deaths were observed over an average follow up of 8 years. When defining the referent group based on 1 clinical assessment, the unhealthy non-obese (Hazard ratio = 1.22; 95% CI, 1.01, 1.45) and unhealthy obese (1.29; 1.05, 1.60) were at greater risk of all-cause mortality compared to the healthy non-obese, yet no excess risk was seen in the healthy obese (1.14; 0.83, 1.52). When we re-defined the referent group based on 2 clinical assessments, effect estimates were accentuated and healthy obesity was at increased risk of mortality (2.67; 1.64, 4.34). Conclusion: An unstable healthy referent group may make ‘healthy obesity’ appear less harmful by obscuring the benefits of remaining never obese without metabolic dysfunction

Metabolically healthy obesity and risk of incident type 2 diabetes: a meta-analysis of prospective cohort studies

The risk of type 2 diabetes among obese adults who are metabolically healthy has not been established. We systematically searched Medline (1946–August 2013) and Embase (1947–August 2013) for prospective studies of type 2 diabetes incidence (defined by blood glucose levels or self-report) among metabolically healthy obese adults (defined by body mass index [BMI] and normal cardiometabolic clustering, insulin profile or risk score) aged ≥18 years at baseline. We supplemented the analysis with an original effect estimate from the English Longitudinal Study of Ageing (ELSA), with metabolically healthy obesity defined as BMI ≥ 30 kg m−2 and <2 of hypertension, impaired glycaemic control, systemic inflammation, adverse high-density lipoprotein cholesterol and adverse triglycerides. Estimates from seven published studies and ELSA were pooled using random effects meta-analyses (1,770 healthy obese participants; 98 type 2 diabetes cases). The pooled adjusted relative risk (RR) for incident type 2 diabetes was 4.03 (95% confidence interval = 2.66–6.09) in healthy obese adults and 8.93 (6.86–11.62) in unhealthy obese compared with healthy normal-weight adults. Although there was between-study heterogeneity in the size of effects (I2 = 49.8%; P = 0.03), RR for healthy obesity exceeded one in every study, indicating a consistently increased risk across study populations. Metabolically healthy obese adults show a substantially increased risk of developing type 2 diabetes compared with metabolically healthy normal-weight adults. Prospective evidence does not indicate that healthy obesity is a harmless condition

Examining associations between physical activity and cardiovascular mortality using negative control outcomes

Background: The purpose of a negative control is to reproduce a condition that cannot involve the hypothesized causal mechanism, but does involve the same sources of bias and confounding that may distort the primary association of interest. Observational studies suggest physical inactivity is a major risk factor for cardiovascular disease (CVD) although potential sources of bias, including reverse causation and residual confounding, make it difficult to infer causality. The aim was to employ a negative control outcome to explore the extent to which the association between physical activity and CVD mortality is explained by confounding. Methods: The sample comprised 104,851 participants (aged 47 ± 17 yrs; 45.4% male) followed up over mean [SD] 9.4±4.5 years, recruited from The Health Survey for England and the Scottish Health Surveys. Results: There were 10,309 deaths, of which 3,109 were attributed to CVD, and 157 to accidents (negative control outcome). Accidental death was related to age, male sex, smoking, longstanding illness and psychological distress, with some evidence of social patterning. This confounding structure was similar to that seen with CVD mortality, suggesting that our negative control outcome was appropriate. Physical activity (per SD unit increase in MET-hr-wk) was inversely associated with CVD (HR=0.75; 95% CI, 0.70, 0.80); the point estimate between physical activity and accidental death was in the same direction but of lesser magnitude (HR=0.86; 0.69, 1.07). A linear dose-response pattern was observed for physical activity and CVD but not with the negative control. Conclusions: Inverse associations between physical activity and risk of CVD mortality are likely causal but of a smaller magnitude than commonly observed. Negative control studies have potential to improve causal inference within the physical activity field

Stability of metabolically healthy obesity over 8 years: the English Longitudinal Study of Ageing.

Objective Metabolically healthy obesity possibly reflects a transitional stage before the onset of metabolic dysfunction, but few studies have characterised this transition. We examined the behavioural and biological characteristics of healthy obese adults that progressed to an unhealthy state over 8 years follow-up. Methods Participants were 2422 men and women (aged 63.3±7.7 years, 44.2% men) from the English Longitudinal Study of Ageing. Obesity was defined as BMI ≥30 kg/m2. Based on blood pressure (BP), HDL-cholesterol, triglycerides, HbA1c and C-reactive protein (CRP) participants were classified as ‘healthy’ (0 or 1 metabolic abnormality) or ‘unhealthy’ (≥2 metabolic abnormalities). Results Over 8 years follow-up, 44.5% of healthy obese subjects had transitioned into an unhealthy state, compared to only 16.6 and 26.2% of healthy normal-weight and overweight adults respectively. Compared with healthy obese adults who remained stable, those who progressed to an unhealthy state were more likely to have high BP (75.0% vs 37.0%, age- and sex-adjusted odds ratio (OR) 8.9, 95% CI 4.7–17.0), high CRP (53.7% vs 17.0%, OR=8.6, 95% CI 4.1–18.0), high HbA1c (46.3% vs 5.9%, OR=13.8, 95% CI 6.1–31.2) and high triglycerides (45.4% vs 11.9%, OR=5.9, 95% CI 2.9–12.0) at follow-up, with excess risk remaining independent of lifestyle factors including self-reported physical activity. Progression to an unhealthy state was also linked with significant gains in waist circumference (B=2.7, 95% CI, 0.5–4.9 cm). Conclusion These data show that a healthy obesity phenotype is relatively unstable. Transition to an unhealthy state is characterised by multiple biological changes that are not fully explained by lifestyle risk factors

Combined effect of physical activity and leisure time sitting on long-term risk of incident obesity and metabolic risk factor clustering

Aims/hypothesis Our study aimed to investigate the combined effects of moderate-to-vigorous physical activity and leisure time sitting on the long-term risk of obesity and clustering of metabolic risk factors. Methods The duration of moderate and vigorous physical activity and of leisure time sitting was assessed by questionnaire between 1997 and 1999 among 3,670 participants from the Whitehall II cohort study (73% male; mean age 56 years). Multivariable-adjusted logistic regression models examined associations of physical activity and leisure time sitting tertiles with odds of incident obesity (BMI ≥ 30 kg/m2) and incident metabolic risk factor clustering (two or more of the following: low HDL-cholesterol, high triacylglycerol, hypertension, hyperglycaemia, insulin resistance) at 5 and 10 year follow-ups. Results Physical activity, but not leisure time sitting, was associated with incident obesity. The lowest odds of incident obesity after 5 years were observed for individuals reporting both high physical activity and low leisure time sitting (OR = 0.26; 95% CI 0.11, 0.64), with weaker effects after 10 years. Compared with individuals in the low physical activity/high leisure time sitting group, those with intermediate levels of both physical activity and leisure time sitting had lower odds of incident metabolic risk factor clustering after 5 years (OR 0.53; 95% CI 0.36, 0.78), with similar odds after 10 years. Conclusions/interpretation Both high levels of physical activity and low levels of leisure time sitting may be required to substantially reduce the risk of obesity. Associations with developing metabolic risk factor clustering were less clear

Dynapenic obesity and the risk of incident type 2 diabetes: the English Longitudinal Study of Ageing

Aim Obesity is a well-established risk factor for developing Type 2 diabetes. Evidence suggests that sarcopenia, the age-related decline in muscle mass and strength, may exacerbate diabetes risk in obese individuals. The aim of this study was to determine the combined effect of obesity and low muscle strength, dynapenia, on the risk of incident Type 2 diabetes in older adults. Methods Participants were 5953 (1670 obese) men and women from the English Longitudinal Study of Ageing without known Type 2 diabetes at baseline and for whom handgrip strength, biochemical and other clinical data were collected. A diagnosis of Type 2 diabetes was recorded from self-reported physician diagnosis over 6 years. Results For each unit increase in grip strength, there was a reduction in diabetes risk (age and sex, BMI adjusted HR; 0.98; 95% CI 0.96–0.99). The risk of Type 2 diabetes was elevated in all obese participants, but was greatest in those with low handgrip strength (HR = 4.93, 95% CI 2.85, 8.53) compared with non-obese individuals with high handgrip strength. Eleven per cent of the sample met the threshold for weakness (handgrip strength: men < 26 kg; women < 16 kg) that was associated with elevated Type 2 diabetes risk in obese (HR = 3.57, 95% CI 2.04, 6.24) but not in non-obese (HR = 0.86, 95% CI, 0.44, 1.68) compared with normal/non-obese participants. Conclusion Dynapenic obesity, determined by high BMI and low handgrip strength, is associated with increased risk of incident Type 2 diabetes in older people

Associations of device-measured physical activity across adolescence with metabolic traits: prospective cohort study

Background: Multiple occasions of device-measured physical activity have not been previously examined in relation to metabolic traits. We described associations of total activity, moderate-tovigorous physical activity (MVPA), and sedentary time from three accelerometry measures taken across adolescence with detailed traits related to systemic metabolism. Methods and Findings: 1826 male and female participants recruited at birth in 1991-92 via mothers into the Avon Longitudinal Study of Parents and Children offspring cohort who attended clinics in 2003-05, 2005-06, and 2006-08 were included in ≥ 1 analysis. Waist-worn uniaxial accelerometers measured total activity (counts/min), MVPA (min/day), and sedentary time (min/day) over ≥ 3 days at age 12y, 14y, and 15y. Current activity (at age 15y), mean activity across occasions, interaction by previous activity, and change in activity were examined in relation to systolic and diastolic blood pressure, insulin, C-reactive protein, and 230 traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) including lipoprotein cholesterol and triglycerides, amino and fatty acids, glycoprotein acetyls, and others, at age 15y. Mean current total activity was 477.5 counts/min (SD=164.0) while mean MVPA and sedentary time durations were 23.6 min/day (SD=17.9) and 434.5 min/day (SD=64.7), respectively. Mean body mass index at age 15y was 21.4 kg/m2 (SD=3.5). Withinmeasure correlations between first and last activity measurement occasions were low (e.g. r=0.40 for counts/min). Current activity was most strongly associated with cholesterol and triglycerides in HDL and VLDL particles (e.g. -0.002 mmol/l or -0.18 SD-units; 95% CI=-0.24, -0.11 for triglycerides in chylomicrons and XL-VLDL) and with glycoprotein acetyls (-0.02 mmol/l or -0.16 SD-units; 95% CI=-0.22, -0.10), among others. Associations were similar for mean activity across 3 occasions. Attenuations were modest with adjustment for fat mass index based on dual-energy x-ray absorptiometry. In mutually adjusted models, higher MVPA and sedentary time were oppositely associated with cholesterol and triglycerides in VLDL and HDL particles; MVPA more strongly with glycoprotein acetyls and sedentary time more strongly with amino acids. Associations appeared less consistent for sedentary time than for MVPA based on longer-term measures and were weak for change in all activity types from age 12-15y. Evidence was also weak for interaction between activity types at age 15y and previous activity measures in relation to most traits (minimum P=0.003; median P=0.26 for counts/min) with interaction coefficients mostly positive. Study limitations include modest sample sizes and relatively short durations of accelerometry measurement on each occasion (3-7 days) and of time lengths between first and last accelerometry occasions (< 4 years) which can obscure patterns from chance variation and limit description of activity trajectories. Activity was also recorded using uniaxial accelerometers which predated more sensitive triaxial devices. Conclusions: Our results support associations of physical activity with metabolic traits that are small in magnitude and more robust for higher MVPA than lower sedentary time. Activity fluctuates over time, but associations of current activity with most metabolic traits do not differ by previous activity. This suggests that the metabolic effects of physical activity, if causal, depend on most recent engagement

Healthy obesity and objective physical activity

Background: Disease risk is lower in metabolically healthy obese adults than in their unhealthy obese counterparts. Studies considering physical activity as a modifiable determinant of healthy obesity have relied on self-reported measures, which are prone to inaccuracies and do not capture all movements that contribute to health. Objective: We aimed to examine differences in total and moderate-to-vigorous physical activity between healthy and unhealthy obese groups by using both self-report and wrist-worn accelerometer assessments. Design: Cross-sectional analyses were based on 3457 adults aged 60–82 y (77% male) participating in the British Whitehall II cohort study in 2012–2013. Normal-weight, overweight, and obese adults were considered “healthy” if they had <2 of the following risk factors: low HDL cholesterol, hypertension, high blood glucose, high triacylglycerol, and insulin resistance. Differences across groups in total physical activity, based on questionnaire and wrist-worn triaxial accelerometer assessments (GENEActiv), were examined by using linear regression. The likelihood of meeting 2010 World Health Organization recommendations for moderate-to-vigorous activity (≥2.5 h/wk) was compared by using prevalence ratios. Results: Of 3457 adults, 616 were obese [body mass index (in kg/m2) ≥30]; 161 (26%) of those were healthy obese. Obese adults were less physically active than were normal-weight adults, regardless of metabolic health status or method of physical activity assessment. Healthy obese adults had higher total physical activity than did unhealthy obese adults only when assessed by accelerometer (P = 0.002). Healthy obese adults were less likely to meet recommendations for moderate-to-vigorous physical activity than were healthy normal-weight adults based on accelerometer assessment (prevalence ratio: 0.59; 95% CI: 0.43, 0.79) but were not more likely to meet these recommendations than were unhealthy obese adults (prevalence ratio: 1.26; 95% CI: 0.89, 1.80). Conclusions: Higher total physical activity in healthy than in unhealthy obese adults is evident only when measured objectively, which suggests that physical activity has a greater role in promoting health among obese populations than previously thought

Associations of body mass and fat indexes with cardiometabolic traits

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects