Carrying a heavier weight is healthy: Obesity‐reinforced fitness hypothesis in metabolically healthy obesity

Over 50 years ago, the Framingham Heart Study linked obesity with coronary heart disease and cardiovascular death. Two decades later, the term “metabolic syndrome” was coined to explain the association of obesity, diabetes mellitus, and a few other risk factors with atherosclerosis. The link between obesity and cardiovascular disease is believed to be through a number of metabolic pathways and their complications such as atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. However, recent data suggest that in some people obesity may be devoid of metabolic complications and without increased risk for cardiovascular morbidity and mortality, the so-called “metabolically healthy obesity” (MHO). Indeed higher body mass index (BMI) values in the overweight to mild obesity range (25-35 kg/m2) may confer certain survival advantages in both the general population (1) and some chronic disease states such as chronic kidney disease (2) and heart failure (3) as well as among the elderly (4). Nevertheless, MHO may still be linked to a higher risk of type 2 diabetes mellitus (5). In addition, heavy weight is associated with other non-cardiovascular sequelae such as osteoarthritis, chronic back pain, gallbladder disease, asthma, and various cancers. Nonetheless, evidence is overwhelming that there may be biologic plausibility beyond statistical findings related to MHO. In this issue, Guo and Garvey (5) have shown that, while MHO was associated with a small increase in the risk of type 2 diabetes mellitus, it was not associated with an increased risk of cardiovascular events or mortality. Their data was from two large cohort studies: the Atherosclerosis Risk of Communities Study (ARIC) and the Coronary Artery Risk Development in Young Adults (CARDIA). However, the analysis of MHO-outcome relationship was limited to 4,990 ARIC participants. Use of ARIC for these analyses was a smart choice given its representativeness considering the fact that the study participants were randomly selected from four diverse geographical areas comprising both sexes and diverse race/ethnicities. In addition, the study's 18.7-year follow-up duration harbors to a large number of end point events, yielding a large statistical power and adding to the scientific merit of this study. A potential explanation for the Guo and Garvey (5) results is the potential cardiovascular protection conferred by cardiorespiratory fitness that can reduce the adverse effects of obesity on cardiovascular and all-cause mortality. Higher cardiorespiratory fitness is associated with a healthier metabolic profile including in populations with obesity, in whom the obesity sequelae are vastly attenuated by the fitness status. Hence, we argue that carrying a heavier body weight constantly may lead to a higher level of fitness in individuals with obesity who are ambulatory and physically active as compared to thinner persons with the same activity level. We believe that walking with a heavier weight leads to a larger muscle mass along with higher muscle strength and hence resulting in an overall healthier muscle profile. Muscle mass is the likely source of protective cytokines including myormone and irisin (6). Moreover, there are known benefits of subcutaneous fat—as opposed to visceral fat—such as higher levels of circulating adiponectin and other anti-inflammatory adipokines and cytokines (7) that may aggravate the muscle enhancement of heavier-body-ambulation. The potential effect of our hypothetical “Obesity-Reinforced Fitness” (Figure 1) on the obesity-mortality association is supported by several studies including a meta-analysis of 10 studies (total sample size: 92,986) in which the risk of death was dependent upon fitness rather than BMI (8). In this study, unfit individuals with obesity had a 2.5-fold higher risk of death, while fit individuals with obesity had a similar death risk as in fit normal-weight individuals (8). Similarly, a cohort study of 10,498 individuals has shown the strong relationship between fitness and metabolic health (9). In this study, the second and third tertiles of cardiopulmonary fitness were respectively associated with 26% and 53% decreased risk of metabolic syndrome in men and 20% and 63% decreased risk in women, compared to the first tertiles of cardiopulmonary fitness in each sex (9). Moreover, a collective analysis of eight studies examining cardiorespiratory fitness concluded that fitness was higher in individuals with MHO compared to those with metabolically abnormal obesity (10). The obesity-reinforced fitness hypothesis. In non-sedentary individuals with obesity who are mobile, carrying heavier weight leads to enhanced fitness and greater muscle mass and strength along with more favorable cytokines and adipokine profile. Fit individuals with obesity are at little or no risk for cardiovascular sequelae. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] In summary, the study by Guo and Garvey (5) sheds some light on the contentious relationship between MHO and cardiovascular morbidity and mortality and corroborates our obesity-reinforced fitness hypothesis. Heavier but mobile individuals carry larger weight and hence may have larger muscle mass and somewhat favorable metabolic profile, while inflammatory cytokines derived from visceral fat may also be elevated. Studies of this kind have a crucial role in exploring the consequences associated with such important subgroups as MHO and directing the appropriate preventive interventions to the affected individuals. In addition, this report paves the way for further investigations of the interplay between body weight, metabolic health, and cardiopulmonary fitness and their potential roles in cardiovascular outcomes and longevity in the populations with obesity.