Metabolic health in normal-weight and obese individuals

Obesity is a worldwide epidemic that poses considerable problems for an individual’s health and has large cost implications associated with its prevention and the treatment of its complications [1, 2]. More specifically, cardiovascular complications are particularly common with obesity. However, a subgroup of obese individuals may not be at an increased risk for cardiovascular complications; these individuals are said to have metabolically healthy obesity (MHO) [3, 4]. Distinguishing MHO from obesity with substantially elevated risk of cardiovascular complications would allow us to focus interventions, such as weight loss, on those likely to benefit most. This may be a practical and important step towards personalised medicine for obesity [4]. Yet, the concept of MHO has been disputed for several reasons, including the lack of a uniform definition of the condition and risks associated with obesity other than cardiovascular disease (CVD) [3, 5].

On the other hand, metabolically unhealthy subgroups of individuals are at high risk of CVD irrespective of BMI; this group may include individuals within the normal weight category, with a BMI of 18.5–24.9 kg/m² (the metabolically unhealthy normal-weight [MUHNW] phenotype) [6, 7]. Importantly, individuals in the MUHNW group have not been focused on with regards to the prevention of diseases more commonly related to obesity, such as CVD.

This review discusses several aspects of metabolic health in obese and normal-weight individuals, including: (1) the evidence from prospective studies on MHO and MUHNW phenotypes; (2) the role of body-fat distribution patterns in MHO and MUHNW; (3) prospective studies on the transition from metabolically healthy to unhealthy phenotypes and its consequences; and (4) potential determinants for such conversions in metabolic health status.

Individuals within specific BMI groups can be further stratified for the absence or presence of cardiometabolic risk factors (other than BMI). The term ‘MHO’ thus applies to obese individuals in whom cardiometabolic risk factors are (largely) absent. The use of the term ‘healthy’ implies here that individuals who fall into the MHO category are not at an increased risk of cardiometabolic complications compared with individuals with a normal weight. Several studies have evaluated subgroups of individuals categorised by BMI and cardiometabolic risk factors (determined at baseline) to assess their subsequent risk of CVD and/or mortality [8‐11]. In addition to BMI, the criteria used to define subgroups in the context of metabolic health is frequently based on: (1) the absence/presence of the metabolic syndrome; and (2) insulin sensitivity. Interestingly, findings from several meta-analyses [8‐11] and recent large-scale cohort studies [12‐14] do not clearly support the notion that MHO subgroups, as currently defined, are protected from cardiometabolic complications (Table 1).

The absence of the metabolic syndrome in obesity has most commonly been used to define MHO. Although various definitions have been considered, most studies include measures of blood pressure, triacylglycerols, HDL-cholesterol and plasma glucose [8‐11]. Importantly, the mere absence of the metabolic syndrome alone does not mean that individual risk factors will not be present. However, more rigorous definitions of metabolic health, e.g. absence of all individual components of the metabolic syndrome, have rarely been investigated [8, 11]. Importantly, the proportion of obese individuals considered to be metabolically healthy varies largely depending on the definition of MHO used. To illustrate this point, Fig. 1 shows prevalence estimates of MHO using different definitions, using data from the Third National Health and Nutrition Examination Survey (NHANES III), which has formed the basis for several prospective studies on MHO [3, 8]. The prevalence of MHO in this survey varied between 47% when classified based on the absence of the metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III [15], 32% if based on insulin sensitivity (using a HOMA-IR cut-off of 2.5, similar to several previous studies [3]) and 10% if based on all components of the metabolic syndrome being simultaneously absent (Fig. 1). Moreover, the different definitions of MHO in Fig. 1 only partly overlap in terms of identifying those with MHO; for example, only approximately one-third of those identified as having MHO based on insulin sensitivity are also identified as having MHO based on absence of the metabolic syndrome. This becomes even more complicated when considering that individual metabolic risk factors are defined differently between studies, ranging from the presence/absence of manifest diagnosed conditions (e.g. type 2 diabetes) [12, 13] to risk factor levels prior to disease onset [8‐11], the latter identifying a smaller proportion of individuals with MHO. For example, if only excluding individuals with manifest diagnosed conditions from the MHO group, this group would have higher cardiovascular risk than if individuals with pre-clinical risk factors were also excluded. However, the same exclusions should be applied to the normal-weight metabolic healthy reference group, for comparison. Whether the choice of risk factor-thresholds actually affects the associations between MHO and risk of cardiometabolic complications observable in studies has not yet been evaluated. Overall, the heterogeneity of the methods used to define metabolic health across studies poses as a major limitation of this line of research.

In studies related to metabolic health, the highest risk for cardiometabolic complications has been found among the group considered to be metabolically unhealthy, irrespective of BMI. This includes individuals within the normal-weight category according to BMI [16]. For example, according to prospective studies [8‐10, 13, 14], risk for CVD among MUHNW individuals is about 1.5–3-fold higher than among metabolically healthy individuals with normal weight (Table 1); this risk was higher than the relative risk in those with MHO. In prospective studies, characteristics that were used to define metabolically unhealthy subgroups were similar between individuals with a normal BMI and those who fell within BMI categories of overweight and obesity. Thus, as with obese individuals, the presence of the metabolic syndrome has primarily been used to reflect an unhealthy phenotype in individuals with normal weight [8‐10]. However, among individuals with CVD events, the metabolic syndrome has been found to be present in a much smaller fraction of individuals with normal weight as compared with overweight and obese individuals. As an example, in the European Prospective Investigation into Cancer and Nutrition (EPIC-CVD) study, only 20% of incident CVD cases among normal-weight participants were observed in those with the metabolic syndrome at baseline; this is a considerably smaller proportion than in overweight (52%) and obese (76%) individuals [14]. This clearly points towards variation in the sensitivity of the metabolic syndrome to predict future CVD cases across the BMI range; its absence is unlikely to rule out CVD risk in normal-weight individuals. Still, the risk factors used to define the metabolic syndrome might be useful for quantifying risk in those with a normal weight since there is limited evidence to show that risk factors are overall different for those with normal weight compared with those in the overweight and obese BMI subgroups. According to the results of the Emerging Risk Factor Collaboration, the associations between blood lipids [17] and hyperglycaemia [18] with CVD risk are generally not modified by BMI. The same has been reported for waist circumference and waist-to-hip ratio, although the risk gradients appear to be more pronounced for individuals with normal weight compared with those who are obese [1].

In the context of MHO and MUHNW phenotypes, the clear-cut classification of individuals according to BMI and metabolic risk factors ignores the fact that the associations between cardiometabolic disease and its risk factors are a continuum. This applies to BMI as well as other factors determining metabolic health. For example, the risk of coronary heart disease associated with BMI increases continuously with increasing BMI within the overweight and obese range [1]. Similarly, there is a stepwise increase in risk of coronary heart disease with increasing fasting glucose values within the prediabetes range (5.6–6.9 mmol/l) [18] and a more linear association with increasing HbA_1c (even within the normal range) [19]. In addition, CVD risk increases with increasing blood pressure [17, 18], with risk gradients already observed within the blood pressure range considered to be normal [20]. An alternative approach would be to use risk factor information on a continuous scale, as is already done, for example, in the context of global cardiovascular risk estimation. For example, the Pooled Cohort Equation [21] considers total cholesterol, HDL-cholesterol and systolic blood pressure levels on a continuous scale to estimate absolute risk of major cardiovascular events.

A central problem of research related to the MHO and MUHNW phenotypes is that BMI is the anthropometric measure used to classify individuals. Although BMI is widely used in clinical practice and shows reasonable correlation with body fatness, it may result in misclassification on an individual level because of the varying contributions of bone mass, muscle mass and fluid to body weight [22]. Also, BMI does not reflect body-fat distribution. Waist circumference and waist-to-hip ratio better predict cardiovascular events than BMI, although this may differ across populations [1]. While this suggests that measures of body fat distribution would more accurately allow identification of individuals at cardiometabolic risk, as compared with BMI, their relative contribution to overall risk prediction is only moderate and substantially smaller than information on metabolic risk factor levels [1].

Noteworthy in this context is that few studies have used measures of body-fat distribution, such as waist circumference, to define MHO, despite these being an integral part of classification of the metabolic syndrome [8]. This may be explained by the high correlation between BMI and waist circumference: the vast majority of individuals with a BMI in the obese range also have a large waist circumference (>88 cm for women and >102 cm for men), according to the National Cholesterol Education Program Adult Treatment Panel III [15]. Individuals with obesity can be assumed to have an abnormal waist circumference, as defined by the International Diabetes Federation (≥80 cm for women and ≥94 cm for men) [23]. Similarly, abdominal obesity is rare among individuals with normal weight according to their BMI (Fig. 2a). Still, for a given BMI there is considerable heterogeneity in waist circumference across the range of BMI, including within the normal weight category. Instead of categorising normal weight and obesity using established cut-offs for waist circumference, stratification by measures of relative fat distribution for a given degree of overall body fatness might be more informative (Fig. 2b). This approach is strongly supported by the observation that differences in waist circumference are related to increased metabolic risk in individuals with normal weight, even if waist circumference measures are within a range that is considered normal [24]. A strong linear increase in risk for cardiovascular mortality has been described for waist circumference adjusted for BMI [25], which is different from the rather J-shaped association of BMI and waist circumference observed if these anthropometric measures are modelled individually [1, 2].

Waist circumference is a measure of central obesity and, if adjusted for BMI (thus keeping overall body fatness comparable), it more strongly reflects the accumulation of fat in the abdominal region relative to other body parts. However, metabolic abnormalities in both obese and normal-weight individuals seem to be linked to visceral or ectopic fat (specifically in the liver) [3, 5], which are only partly reflected by overall abdominal fat accumulation. Genetic analyses suggest that lipodystrophy-like mechanisms are related to insulin resistance [26], supporting the notion that metabolically unhealthy phenotypes may be associated with body-fat distribution patterns that favour visceral and ectopic fat accumulation over fat deposition in the periphery [27]. This phenomenon might particularly be present in the MUHNW phenotype [6]. Still, the relative contribution of different fat compartments, including those in the periphery, to metabolic risk in the context of the MHO and MUHNW phenotype is, so far, understudied. Data suggest that among normal-weight individuals, subcutaneous thigh fat mass is more strongly related to abnormal metabolic risk factors than liver fat, while among obese individuals, thigh fat mass seems largely unrelated to these risk factors [6]. The long-term relevance of such phenotypes in the context of metabolic health for hard endpoints such as CVD has not been studied yet.

A major point of critique of the MHO concept relates to the potential conversion of individuals with MHO to an unhealthy phenotype over time [3]. Such conversion would be expected to result in an increased CVD risk. Cohort studies found higher CVD risk for MHO subgroups with longer duration of follow-up, indicating a transient nature for the phenotype [8, 10]. This has been confirmed by studies with follow-up of up to 10 years, the majority of which suggest that between one-third and one-half of individuals with MHO convert to an unhealthy phenotype [13, 28‐37] (Table 2). Very few studies have been conducted over longer time periods. In the Whitehall II study [30], about half of initially healthy obese individuals converted to an unhealthy phenotype over 20 years. This proportion was larger in the Nurses’ Health Study [13], where only 16% and 6% of women with MHO remained metabolically healthy after 20 and 30 years, respectively. Interestingly, metabolic health is also a transient phenotype among normal-weight individuals. While ~60% of individuals with normal weight were observed to remain metabolically healthy after 10 years of follow-up in a variety of cohort studies [13, 29, 32], only ~30% remained metabolically healthy after 20 years in the Nurses’ Health Study and ~15% remained metabolically healthy after 30 years of follow-up [13]. Again, the use of different definitions and measures of risk factors to define metabolic health complicates comparisons across studies. Still, it is clear that metabolic health appears to be a transient phenotype. This finding implies that, by only considering baseline metabolic health status in prospective studies, there is a real risk of harbouring considerable misclassification over time. If possible, repeated measures should be used in studies of metabolic health to update exposure status over time.

So, how is long-term risk affected by maintenance of metabolic health vs transition to unhealthy phenotypes? Studies do not clearly show that persistent MHO is unrelated to CVD risk, even if maintained over a long time. In the Nurses’ Health Study, those who maintained an MHO phenotype over 20 years still had a higher risk of CVD over the 10 years’ follow-up when compared with individuals who were metabolically healthy and within the normal weight category over the same time period [13]. On the other hand, conversion to a metabolically unhealthy phenotype increased CVD risk similarly among obese individuals and individuals with normal weight. The effect of conversion from metabolically healthy to unhealthy phenotypes on subsequent CVD risk may also depend on the effectiveness of pharmacological interventions. For example, hypercholesterolaemia may be less detrimental with regards to CVD risk as compared with the development of type 2 diabetes or hypertension [13], possibly due to more effective treatment regimens to lower blood cholesterol levels (and, hence, CVD risk).

With the observation that maintenance of metabolic health seems to be difficult for many, if not most, irrespective of their BMI, but that conversion to unhealthy phenotypes markedly increases CVD risk [13], the question arises as to which risk factors trigger such a conversion. Conversion from metabolically healthy to unhealthy phenotypes has been related to higher baseline BMI or waist circumference [28, 29, 36] and also to longer duration of obesity [38]. Furthermore, in a study of 85 Japanese-American men and women, transition from MHO to metabolically unhealthy obesity (MUHO) was associated with greater visceral fat, but significant associations were not observed with greater abdominal subcutaneous fat [39]. Weight loss can improve metabolic risk profiles [7], even among individuals with the MUHNW phenotype, and it is also likely that weight loss is an important strategy to lower risk of conversion of metabolically healthy individuals to metabolically unhealthy phenotypes. Notably, metabolic risk factors are not merely markers of body fatness or fat distribution; instead, lifestyle choices (specifically diet) has been shown to be related to many of the metabolic risk markers used to define unhealthy phenotypes. For example, landmark trials, such as The Dietary Approaches to Stop Hypertension (DASH) trial [40], have shown that a diet rich in fruits and vegetables can reduce blood pressure. In addition, the reanalysis of the retracted PREDIMED (Prevención con Dieta Mediterránea) diet trial has not only observed lower CVD risk among those assigned to a Mediterranean diet supplemented with olive oil or with nuts [41], but also found that marked improvements in risk factor profiles were observed with little effect on body weight. Moreover, isoenergic studies suggest that modification of macronutrient composition can affect lipid levels [42]. The vast majority of premature deaths due to CVD events appear to be attributable to high-risk lifestyle patterns in combination with body fatness [43]. Still, the relative contribution of different lifestyle factors and weight gain to different cardiometabolic risk factors may be heterogeneous. For example, the relationship between fruits and vegetables with blood pressure and CVD risk have been well documented, but the level of consumption of these dietary items seem less important with regard to type 2 diabetes risk [44].

Although an increasing number of prospective cohort studies have evaluated subgroups of obese and normal-weight individuals, the concept of metabolic health remains controversial. Epidemiological research could inform this debate, as shown in the Text box. In summary, it is hoped that ongoing research in this area will eventually allow clinicians and researchers to come to an agreement with regards to the definition of metabolic health so that it may be monitored in obese and normal-weight individuals. This may enable optimal targeting for the prevention of complications associated with poor metabolic health, including CVD, to reduce the associated health and cost burdens.