Metabolically Healthy Obesity – A Myth or a Reality?
Introduction
In my post titled What is obesity – is it merely about BMI? I had discussed, how obesity is defined, the composition of the human body, and fat patterning as well as factors affecting total body fat and fat patterning. Obesity is now recognized as a serious chronic disease; in my post titled Is obesity a disease or a risk factor for other conditions? I had discussed the magnitude of obesity and why obesity is associated with so much ill-health. In my post, Complications of obesity: the mother of all diseases, I had discussed the various health complications associated with obesity. However, there are no easy solutions to obesity, and managing your body weight is challenging at the best of times. In my post titled Weight Loss Maintenance After Weight Loss, I had discussed how over the long term, the vast majority of individuals regain the weight they have lost and that this relapse has a strong physiological basis and is not simply the result of the voluntary resumption of old habits. In my last post, Does obesity hit a point of no return? I had discussed the prospects of long-term success in weight loss maintenance. In the backdrop of the difficulties in maintaining weight loss, I had suggested that emphasis should be on measuring metabolic health and NOT weight. Therefore, in this post, I will discuss the concept of metabolically healthy obesity and debate as to whether it is a myth or a reality.
Metabolic profile in obese individuals
Although the deleterious metabolic effects of obesity are widely recognized at the population level, not all obese subjects have an adverse metabolic profile predisposing them to develop type 2 diabetes or cardiovascular disease. Findings from many studies show that a subgroup of individuals with obesity may be protected from obesity-related cardiometabolic diseases or maybe at a significantly lower risk than expected for their degree of obesity. Metabolically healthy obesity (MHO) is a concept derived from this clinical observation that a subgroup of people with obesity does not exhibit overt cardiometabolic abnormalities. Individuals with metabolically healthy obesity display a relatively favourable metabolic profile compared with the group that has already developed the health consequences of obesity referred to as metabolically unhealthy obesity (MUO), despite having comparable levels of total excess body fat.
The idea of metabolically healthy obesity is not new, even though the concept has only recently been widely recognized in the discipline of obesity. The concept of metabolically healthy obesity developed following the observations in an article titled ‘The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculus disease’, published in The American Journal of Clinical Nutrition in 1956. The study found that individuals with obesity have a different predisposition to diabetes and atherosclerosis, which could be related to body fat distribution.
How do you define Metabolically Healthy Obesity?
Despite the growing recognition of the concept of metabolically healthy obesity, there is no unified definition of metabolically healthy obesity. Despite the general consensus that a BMI > 30 kg/m2 is a prerequisite for defining metabolically healthy obesity, more than 30 different definitions of metabolic health have been used in various clinical studies. Most studies define metabolically healthy obesity as the absence of any metabolic disorder and cardiovascular disease, including type 2 diabetes, dyslipidemia, hypertension, and atherosclerotic cardiovascular disease (ASCVD) in a person with obesity. However, diverse metabolically healthy obesity definitions are important limitations for the interpretation of studies reporting a wide range of associations between metabolically healthy obesity, cardiovascular disease, mortality, and risk for metabolic diseases.
What is the prevalence of Metabolically Healthy Obesity?
Assumptions about the prevalence of metabolically healthy obesity are not very reliable and show a large variation due to a lack of a standardized definition of this phenotype. Based on various studies, the prevalence of metabolically healthy obesity in adults varies between 12 – 35%, with significant regional, gender and age differences. Various studies have reported a higher prevalence of metabolically healthy obesity phenotype in women compared to men (apparently due to greater gluteofemoral fat distribution in women); also, the prevalence of metabolically healthy obesity has been seen to decrease with increasing age, thereby indicating that with time a significant number of previously metabolically healthy obese individuals cease to be metabolically healthy (i.e. develop metabolic disorders). Studies in Asian populations, based on the WHO Asia Pacific Guidelines definition of obesity, found metabolically healthy obesity in 13.3% of Asian Indians, thereby suggesting that these populations are more prone to develop metabolic disorders. In children, depending on the classification system used, the prevalence of metabolically healthy obesity ranges between 21.5 – 31.5%. In sum, irrespective of the definitions used and remarkable regional and gender variation, MHO does not appear to be a rare condition.
What are the characteristics of obese but metabolically healthy individuals?
Despite general clinical awareness of metabolically healthy obesity, there is only limited understanding of the factors underlying this protective phenotype of obesity. Many physiological and phenotypic differences that might distinguish metabolically healthy but obese individuals from at-risk (metabolically unhealthy) individuals will be discussed here briefly.
Low visceral and ectopic fat but higher subcutaneous leg fat content
Individuals with metabolically healthy obesity are characterised by a distinct fat distribution with lower visceral fat mass but higher subcutaneous leg fat content (in other words, a high amount of leg [gluteofemoral] fat provides a protective effect in MHO individuals), lower liver fat and skeletal muscle fat content compared with obese individuals with higher metabolic risk. In particular, the increased liver fat content has been shown to be independent of obesity and predict the risk of coronary artery disease and type 2 diabetes. Other important characteristics include preserved insulin sensitivity and normal adipose tissue function.
It is evident from the above discussion that body fat distribution is more important than the overall fat mass. As per the ‘adipose tissue expandability and spillover hypothesis’, the altered fat distribution with increased visceral and liver fat deposition and low leg fat mass might be the result of an impaired expendability of healthy subcutaneous adipose tissue stores mainly, in the gluteofemoral region.
Greater cardiorespiratory fitness and physical activity
Metabolically healthy obese individuals are more active, spend less time in sedentary behaviour, and have a higher level of cardiorespiratory fitness (yet no difference in muscular strength) than metabolically unhealthy obese (MUO) individuals, suggesting that their healthier metabolic profile could be at least partially due to these healthier lifestyle factors and attributes. Studies have found that both in children and adults, higher physical activity and cardiorespiratory fitness (CRF) have been recognised as an important correlate of the MHO phenotype.
Studies have demonstrated that once fitness is duly accounted for and an accurate measure of adiposity is used, metabolically healthy but obese individuals had a lower risk of all-cause mortality, non-fatal and fatal cardiovascular diseases and cancer mortality than their metabolically unhealthy obese peers, suggesting a key role of fitness in these associations.
Are obese but metabolically healthy individuals really healthy?
Importantly, the concept of metabolically healthy obesity can only be applied to individuals fulfilling the described cardiometabolic criteria and should not be misinterpreted as a subgroup of people with obesity without any health impairments, and therefore not in need of any treatment. As has been discussed in my post Complications of obesity: the mother of all diseases, referred to above, obesity affects almost every aspect of health from reproductive and respiratory function to memory and mood. Besides the metabolic diseases (e.g. type 2 diabetes, dyslipidemia, fatty liver disease) and cardiovascular diseases (e.g. hypertension, myocardial infarction, stroke) obesity is associated with a number of non-metabolic complications such as osteoarthritis and other musculoskeletal disorders, reproductive disorders (including infertility), depression, cognitive impairment, asthma, obstructive sleep apnea, back pain, renal disease, skin infections, some types of cancer (e.g. breast, ovarian, prostate, liver, kidney, colon), and various psycho-social effects – all of which can have an impact on the quality of life, unemployment, lower productivity, and social disadvantages. Therefore, the absence of metabolic risk factors in people with obesity does not justify labelling individuals with obesity as “healthy” and should remain an indication to initiate treatment even if there are no cardiometabolic abnormalities at the time of prognosis.
Moreover, most of the epidemiological evidence supporting a link between obesity and CVD incidence and CVD mortality is based on a one-time point assessment; however, obesity is a disease with long evolution, at least if it appears in childhood, adolescence or even early and middle adulthood. Therefore, the prognosis of a patient who just became obese might be different from another who has been obese for the past 20 years, as an example. A study titled ‘Association of changes in body mass index during earlier adulthood and later adulthood with circulating obesity biomarker concentrations in middle-aged men and women’ published in the journal Diabetologia in Apr 2011, in a prospective study of 1612 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Pots-dam study, showed that the parameter ‘time’ is extremely important for the pathogenic judgment of a disease such as obesity. The study concluded that an increasing BMI in earlier adulthood (25-40 years) is more strongly associated with unfavourable circulating levels of obesity biomarkers later in life than is an increase in BMI in later adulthood (42-55 years).
A major contribution to this topic was made by a study titled ‘The number of years lived with obesity and the risk of all-cause and cause-specific mortality’ published in the International Journal of Epidemiology in Aug 2011. In this study, 5036 participants (aged 28-62 years) of the Framingham Cohort Study were followed up every 2 years from 1948 for up to 48 years. The study found that the number of years lived with obesity is directly associated with the risk of mortality. Furthermore, a dose-response relationship was clear for all endpoints: all-cause, CVD, cancer and other-cause mortality, but was less pronounced for cancer mortality compared with the other three outcomes. For every additional 2 years lived with obesity, the risk of mortality increased by ~ 6- 7%. For mortality from cancer, the risk increased by ~3%.
Another study titled ‘Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle age’, published in The Journal of American Medical Association in Jul 2013 concluded that longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. In this background, it will be dangerous if we will put the stamp of “metabolically healthy obese” on a child, adolescent or young adult even in the presence of apparently normal metabolic profile.
Various studies have assessed the stability of the MHO phenotype over time. A meta-analysis titled ‘The prevalence, metabolic risk and effects of lifestyle intervention for metabolically healthy obesity: a systematic review and meta-analysis was published in the journal Medicine in Nov 2017. The authors conducted a systematic review and meta-analysis to firstly obtain a reliable estimation of the prevalence of metabolically healthy obese individuals in obesity, then assessed the risk of developing metabolic abnormalities among MHO individuals. The study found that almost one-third (35%) of obese individuals were metabolically healthy. However, approximately half (49%) of the MHO individuals developed one or more metabolic abnormalities within 10 years and therefore ceased being “metabolically healthy”. The authors went on to suggest that MHO individual should maintain or adopt a healthy lifestyle to counterbalance the effects of obesity and keep them in a metabolically healthy condition. (I will cover the fat but fit paradox in my next post).
Another study titled ‘Metabolically Healthy Obesity, Transition to Metabolic Syndrome, and Cardiovascular Risk’, published in the Journal of the American College of Cardiology in May 2018, investigated the joint Association of obesity (> 30 kg/m2) and metabolic syndrome (International Diabetes Federation consensus definition) with CVD and mortality across a median of 12.2 years among 6809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis). The study concluded that metabolically healthy obesity is not a stable or reliable indicator of the future risk of CVD; almost one-half (48%) of those with metabolically healthy obesity at baseline developed metabolic syndrome during follow-up. Conversion from a metabolically healthy obesity phenotype to a metabolically unhealthy obesity phenotype led to a significantly higher odds of CVD compared with those who stayed MHO and to the metabolically healthy normal weight (MHN) reference group; although lower than for those with metabolically unhealthy obesity (MUO) from baseline.
In this context, another important finding of this study was that the duration of metabolic syndrome was significantly associated with higher odds of CVD in a graded and linear fashion. In other words, the risk of CVD increased with the duration of the metabolic syndrome. This lends support to the theory that risk resulting from obesity is cumulative and provides an explanation at the individual level for why the meta-analysis found an increased risk for metabolically healthy obesity only with a longer duration of follow-up. As both the transition to metabolic syndrome and the longer duration of metabolic syndrome was associated with CVD, individuals with metabolically healthy obesity may experience a lag in risk while they progress to metabolic syndrome and develop the resultant cardiometabolic risk.
Importantly, individuals with obesity who maintained their metabolically healthy phenotype over time were not found to be at increased risk of CVD compared with MHN; however, this group differs from the rest of the MESA participant in highly specific ways and makes up only a very small portion of the cohort. A study titled ‘Obesity Severity and Duration Are Associated With Incident Metabolic Syndrome: Evidence Against Metabolically Healthy Obesity From The Multi-Ethnic Study of Atherosclerosis published in The Journal of Clinical Endocrinology and Metabolism in Aug 2016, examined the cumulative risk associated with chronic obesity. The study concluded that both duration and severity of obesity are positively associated with incident metabolic syndrome, suggesting that metabolically healthy obesity is a transient state in the pathway to cardiometabolic disease. The study found that the obese participant who remained free of metabolic syndrome throughout the follow-up, differed from the rest of the MESA participants in highly specific ways; they were younger (mean age 58 years), more likely to be female (63%) and Hispanic (46% compared to 34% Caucasians, 0% Asian and 20% African American), and had a higher BMI (mean of 35.0 kg/m2) at baseline compared to other participants. However, this group constituted only 3% (251 of 6809 MESA participants) of the cohort. These results quite convincingly suggest that very few individuals can truly maintain long-term metabolic health when exposed to continued obesity.
The above observations also suggest that there is a likelihood of underestimating risk based on metabolically healthy obesity at a single time point; this has clear implications for clinical practice and resource management. The above study, besides multiple other mediation analysis, found that the association between obesity and CVD was strongly mediated by metabolic syndrome, reinforcing the premise that obesity is an originating cause of cardiometabolic risk. The above results fully support the concept that cardiometabolic risk is due to cumulative exposure from obesity, and that prevention of obesity will be central to the prevention of CVD.
Conclusion
It is evident from the above discussion that although stable metabolically healthy obesity may be a low-risk state, the lack of reliable predictors for MHO stability and the increased risk of transitioning to MUO from continuing obesity itself severely limit the use of metabolically healthy obesity to predict future risk in the clinical setting. There is enough data to suggest that metabolically healthy obesity phenotype is not a cardiometabolically benign condition; therefore metabolically healthy obesity seems to have very limited relevance as a public health target and should not be treated differently from obesity with established type 2 diabetes and/or cardiovascular diseases. In an editorial titled ‘A disease can be neither healthy nor benign’ published in the Romanian Journal of Diabetes Nutrition and Metabolic Diseases in Aug 2011, Trigoviste cautioned – the designation “healthy” gives the illusion that everything is OK, thus encouraging that nothing should be done.