The prevalence of obesity has increased worldwide over the past 30 years, making it a major public health concern [1]. Obesity is associated with a reduced life expectancy, largely because obese individuals are at an increased risk of type 2 diabetes, cardiovascular disease (CVD), and several types of cancer [2]. However, not all obese subjects are at a higher risk of mortality, which suggests that there is a subset of healthy obese individuals, i.e., those exhibiting so-called “metabolically healthy obesity” (MHO) [3-6]. MHO is characterized by the absence of metabolic abnormalities such as dyslipidemia, insulin resistance, hypertension, and an unfavorable inflammatory profile [3-6]. In addition, a subgroup of normal-weight individuals with abnormal metabolic parameters (those exhibiting metabolically unhealthy non-obesity [MUNO] or metabolically obese normal weight [MONW]) has also been suggested [7]. Thus, a range of metabolically healthy and unhealthy obese and non-obese phenotypes exists, which has been recognized since the 1980s (Fig. 1) [5].

The prevention and treatment of obesity is an enormous medical and socioeconomic task that is not always successful [8]. Notably, different independent studies have shown that individuals with MHO may not be able to significantly reduce their obesity-related cardiovascular and metabolic risk using anti-obesity treatment strategies [6,9,10]. Moreover, the benefits of lifestyle interventions in these individuals are questionable [6,11]. Thus, the “one size fits all” approach to tackle obesity may be ineffective, and there is a clear need to better understand obesity-associated metabolic health subtypes to improve the diagnosis of the type of obesity and reduce the dependence on medical care. This review aimed to present several current issues regarding MHO including its definition, epidemiology, natural course, suggested mechanisms, and clinical implications in the context of patient prognosis.

The main obstacle to the advancing of our understanding of the MHO phenotype and its long-term metabolic fate is that of the inconsistent definition of metabolic health and obesity among studies [3-6]. To answer the question of whether individuals with MHO are really healthy, it is important to acknowledge that the criteria used to classify MHO vary from study to study [3-6]. As shown in Table 1 [12-17], several sets of criteria have been used to define MHO. In general, healthy obesity indicates the absence of metabolic disorders, including type 2 diabetes, dyslipidemia, and hypertension, in an obese individual [8]. A previous study found that the prevalence of the MHO phenotype varies according to the definition used [18], which contributes to the inconsistencies found in the association between this phenotype and health outcomes. Furthermore, not all metabolic health definitions include insulin resistance (according to a homeostasis model assessment [HOMA]) [12], blood pressure, or fasting plasma glucose concentrations [13], whereas others consider inflammatory markers [14]. As a further complication, the cutoff values for each parameter, including insulin resistance and inflammatory markers, are not based on an established value and are dependent on the risk distribution in the population being studied [14,15]. Although Hinnouho et al. [18] suggested that MHO individuals were at an increased risk of mortality, regardless of the definition used, the different definitions make comparing findings, such as prevalence and long-term health effects, among studies difficult [14,19]. Defining the MHO phenotype is an important aspect of studying the mechanisms by which fat accumulation in obese subjects causes or contributes to metabolic disorders and CVD [6,20]. Therefore, the MHO definition needs to be standardized.

In addition to components of metabolic syndrome and insulin resistance, physical fitness is a potential alternative means for defining MHO [4]. However, the degree of fitness is often based on varying study percentiles and fitness might only be a common lifestyle determinant of MHO; therefore, physical fitness alone might not be a surrogate for identifying MHO subjects who are otherwise defined using metabolic parameters [4].

As mentioned above, the main difficulty in estimating the actual prevalence of MHO is the lack of consensus pertaining to its definition. For example, the prevalence of the MHO phenotype greatly varies among studies (2.2% to 11.9% in the general population and 6% to 40% in the obese population) depending on the study design and, particularly, the criteria used for its definition [3]. We recently demonstrated that 30.3% of the population in a health screening cohort were obese using body mass index (BMI) as the criteria (i.e., BMI ≥ 25 kg/m²) and nearly half (55.2%) of obese subjects were “metabolically healthy” using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria to define metabolic health [21]. In another smaller Korean study on 186 obese male subjects, Yoo et al. [22] reported that the prevalence of MHO was 24.2% by Meigs et al. [15], 28.5% by Karelis et al. [13], 59.7% by Wildman et al. [14], and as high as 70.4% by the NCEP ATP III [21].

Rey-Lopez et al. [23] recently performed a systemic review on the prevalence of MHO based on the prevalence of different variables among studies; they reported that the MHO prevalence ranged from 6% to 75%. They also suggested that the prevalence may vary according to several sociodemographic factors such as gender, age, and race/ethnicity [23]. The authors stratified the analysis according to gender and age, and revealed that the MHO prevalence was higher in women and younger-aged individuals [23]. Regarding race/ethnicity, the prevalence of MHO seemed to be higher in populations from Asia compared with Caucasian or multiethnic origin populations [23]. Considering the marked heterogeneity of MHO definitions and the varied prevalence described in the literature, it is clear that a common definition of MHO definition needs to be established urgently. Furthermore, the findings that approximately half of obese subjects are metabolically healthy when classified using dual-energy X-ray absorptiometry body fat percentage compared with approximately one-thirds using BMI [24] suggest that caution should be used when obesity is defined since so many body measures are available.

A subject’s health status can switch from metabolically healthy to metabolically unhealthy and vice versa. For example, Soriguer et al. [25] showed that 30% to 40% of individuals with MHO converted to a metabolically unhealthy status after 6 years of follow-up. Similarly, metabolically healthy obese subjects progressed from being healthy to becoming unhealthy over the follow-up period in a prospective community-based cohort study in Korea [26]. In addition, the Northwest Adelaide Health Study in Australia showed that approximately one-thirds of individuals with MHO at baseline converted to a metabolically unhealthy obesity (MUO) phenotype after 5.5 to 10.3 years of follow-up, and a lower risk for type 2 diabetes was only evident in subjects with sustained MHO [27].

Because there is an accumulation of evidence suggesting that MHO is not a static condition, attention has focused on the variables that predict metabolic deterioration to MUO in individuals with MHO. According to a study conducted in Spain, the factors that predicted the transition from MHO to MUO were an increase in BMI, waist circumference, and waist-to-hip ratio [28]. Conversely, the incorporation of a healthy lifestyle, including a healthy diet, high level of physical activity, no smoking, or smoking cessation, helped prevent the transition [28]. Hwang et al. [29] recently demonstrated that nearly two-thirds of Japanese Americans with MHO developed MUO over 10 years, and a higher conversion to MUO was associated with greater visceral abdominal fat, female gender, higher fasting insulin levels, and lower baseline high density lipoprotein cholesterol levels. The proposed features that preserve metabolic health in individuals with MHO include a healthier lifestyle, greater incretin response to meals, less abdominal fat distribution, less visceral and ectopic fat accumulation, lower levels of inflammation, and greater insulin sensitivity (Fig. 2) [3-6]. Therefore, sustaining these factors in MHO individuals may prevent the progression to an MUO phenotype. Collectively, these results suggest that MHO is a dynamic concept that should be considered over time.

Although the exact mechanism underlying the MHO phenotype remains unclear, several plausible mechanisms have been suggested in both human and animal studies [4,6]. These include preserved insulin sensitivity, a specific fat distribution with low visceral and ectopic fat accumulation (including low liver and skeletal muscle fat storage) compared with subcutaneous fat depots, normal adipose tissue function defined by lower immune cell infiltration into adipose tissue, normal adipokine secretion patterns, a high level of physical activity, and fitness [4,6]. A complex interconnection between genetic, environmental, and behavioral factors is also thought to play a crucial role in the pathogenesis of the abovementioned mechanisms (Fig. 3) [8].

Obesity is a multifactorial disorder that is influenced by the interplay between genetic, behavioral, lifestyle, and environmental factors, including fetal programming, the control of appetite and energy expenditure, and the availability and nutritional content of food [8]. These factors and their interactions lead to an expansion in fat mass because of an increase in the mean fat cell volume and the number of adipocytes [8,30]. In most obese individuals, the adipocyte storage capacity may be exceeded and lipids may accumulate ectopically in visceral fat depots, liver, muscle, and β-cells, whereas in healthy obese individuals subcutaneous adipose tissue has the intrinsic ability to expand, leading to preserved insulin sensitivity (Fig. 3) [8]. However, the genetic and/or environmental factors that cause these different phenotypes of subcutaneous fat expandability are largely unknown [8]. A multidisciplinary clinical project called the “FAT expandability (FATe) Project” was recently launched to elucidate the mechanisms behind the expansion of subcutaneous adipose tissue and find biomarkers for determining the expansion limit and predicting obesity-associated complications [31]. In the FATe project, imaging techniques, metabolomics, and transcriptomics will be used to identify the factors that set the limit expansion of subcutaneous adipose tissue in a cohort of Caucasian individuals with varying degrees of obesity [31]. This approach seems to be very promising according to the results of another recent proteomics study, in which dysregulated inflammatory and lipid processes were identified as the primary molecular hallmarks of MHO [32].

Inflammation in adipose tissue was proposed as another key factor that explains the metabolic alterations associated with obesity [33]. However, studies that compared the inflammatory status among individuals with MHO have yielded conflicting results [34-37]. For example, Phillips and Perry [34] demonstrated that individuals with MHO presented with a more favorable inflammatory status than their metabolically unhealthy counterparts, including lower concentrations of complement component-3, C-reactive protein (CRP), tumor necrosis factor α, interleukin 6, and plasminogen activator inhibitor 1, higher adiponectin levels, and a reduced white blood cell count. In contrast, a recent study on a Western population that used the same MHO definition showed that circulating concentrations of proinflammatory factors, including CRP, were increased in both the MHO and MUO groups [36], similar to our recent findings [21,38,39]. Although these conflicting findings may be explained by differences in the ethnicities and age groups, low numbers of subjects, limited inflammatory profiling, and/or the use of different metabolic health criteria to define MHO, a better understanding of the association between MHO and inflammation is warranted.

Numerous studies have shown that individuals with MHO are at a lower risk of CVD and mortality compared with individuals with MUO and are not at elevated risk compared with normal-weight individuals [3-6]. However, the prognostic value of MHO is a subject of much debate and faces a considerable challenge [18,40]. In addition, the value may depend on the health outcomes being examined [40].

Some obese subjects are insulin sensitive, or metabolically healthy. The prevalence of MHO varies according to the population and definition used. There is currently no consensus criterion for the definition of MHO. Numerous possible mechanisms underlying MHO have been suggested, including adipose tissue distribution and inflammation. However, the prognostic value of MHO is the subject of much debate and faces a considerable challenge. The lack of a standard definition for metabolic health and obesity, as well as the dynamic properties of MHO, may have contributed to these inconsistent results. Successfully achieving a universally accepted definition of MHO would improve and simplify future studies and strengthen inter-study comparisons. Furthermore, categorizing MHO using the current criteria may not mean that all individuals exhibiting the condition are the same. There seems to be a subgroup of MHO patients with a benign course, lower levels of systemic inflammation and ectopic fat, including FLD, and a higher level of cardiorespiratory fitness. Because the currently suggested criteria are insufficient to define the precise nature of MHO (e.g., systemic inflammation and ectopic fat), we recommend that more sensitive diagnostic criteria are warranted to define individuals with MHO.

According to the World Health Organization, “overweight and obesity” are defined as abnormal or excessive fat accumulation that may impair health [71], whereas “health” is defined as a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity [72]. Therefore, the MHO concept may serve as an example of “metabolically healthy” but does not necessarily mean “healthy” obese. BMI alone or any anthropometric markers of adiposity do not provide measurements of functionality, quality of life, or other prognostic contextual factors that may further characterize the clinical risk and guide clinical management [6,73]. Therefore, systematic studies on comorbidities of obesity other than metabolic cardiovascular disorders are necessary to assess more accurately whether MHO individuals are really “healthy.”