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Metabolic and Body Composition Factors in Subgroups of Obesity: What Do We Know?

Département de Nutrition, Unité Métabolique, Université de Montréal, Montréal, Québec, Canada H3T 1A8

Address all correspondence and requests for reprints to: Dr. Antony D. Karelis, Unité Métabolique, Département de Nutrition, Université de Montréal, 2405 Chemin Cote Ste-Catherine, Pavillon Liliane de Stewart, Montréal, Québec, Canada H3T 1A8. E-mail: antony.karelis{at}umontreal.ca.

	Abstract

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
Obesity is thought to be a heterogeneous disorder with several possible etiologies; therefore, by examining subtypes of obesity we attempt to understand obesity’s heterogeneous nature. The purpose of this review was to investigate the roles of metabolic, body composition, and cardiovascular disease risk in subtypes of obesity. We briefly consider two subtypes of obesity that have been identified in the literature. One subset of individuals, termed the metabolically healthy, but obese (MHO), despite having large amounts of fat mass compared with at risk obese individuals shows a normal metabolic profile, but remarkably normal to high levels of insulin sensitivity. Preliminary evidence suggests that this could be due at least in part to lower visceral fat levels and earlier onset of obesity. A second subset, termed the metabolically obese, but normal weight (MONW), present with normal body mass index, but have significant risk factors for diabetes, metabolic syndrome, and cardiovascular disease, which could be due to higher fat mass and plasma triglycerides as well as higher visceral fat and liver content. We also briefly consider the potential role of adipose and gastrointestinal hormonal profiles in MHO and MONW individuals, which could lead to a better understanding of potential factors that may regulate their body composition. This information will eventually be invaluable in helping us understand factors that predispose to or protect obese individuals from metabolic and cardiovascular disease. Collectively, a greater understanding of the MHO and MONW individual has important implications for therapeutic decision making, the characterization of subjects in research protocols, and medical education.

	Introduction

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
THE DEVELOPMENT OF obesity is affected by a host of contributing factors, thus making it a complex medical problem. Over the past 20 yr, the prevalence of obesity has increased significantly in North America and Europe, a trend that now appears to be increasing at an alarming rate across most age groups. The major public health consequences of obesity are recognized by every international health organization (1). Public health officials are conscious about the need to mobilize resources to combat this epidemic by developing more effective strategies for treating people who are obese and to prevent the development of obesity and/or obesity-related complications.

One prominent issue in the obesity field is gaining a greater understanding of the subtypes of obesity. A greater understanding of obesity subtypes may eventually be useful in guiding primary and secondary prevention treatment efforts. One of the major challenges in this field, however, has been the inability of investigators to adequately determine or characterize factors that distinguish one subtype of obese individual from another. These issues have broad implications for the clinical treatment of obesity, medical and nutritional education efforts for health care professionals, and even the selection of patients for research protocols.

Interestingly, all obese individuals do not display a clustering of metabolic and cardiovascular risk factors. Moreover, all lean individuals do not present with a healthy metabolic and disease-free profile. In the 1980s, several investigators (2, 3, 4, 5) began to identify the existence of different subtypes of obesity. Although the existence of these different subtypes of obesity has been described, the metabolic and body composition factors and prevalence of obesity-related diseases such as cardiovascular disease are presently poorly understood. Therefore, the purpose of this review was to examine the roles of metabolic, body composition, and cardiovascular disease risk in two subtypes of obesity.

	The metabolically healthy, but obese (MHO), individual

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
A unique subset of obese individuals has been described in the medical literature that appear to be protected or more resistant to the development of metabolic disturbances associated with obesity. These subjects, termed MHO individuals, interestingly, have large quantities of fat mass, but demonstrate remarkably normal to high levels of insulin sensitivity and rather favorable cardiovascular risk profiles (Fig. 1). Despite a general clinical awareness of the MHO individual, there appears to be little understanding of the constellation of factors that constitute this protective profile. Thus, an important question is why are some individuals protected against metabolic syndrome phenotypes?

View larger version (26K): [in this window] [in a new window]   FIG. 1. Differences in metabolic characteristics in MHO individuals and at risk obese individuals.

These valuable studies stimulated additional smaller scale research in the area in which a larger battery of phenotypes was examined in the MHO individual. Questions remained about whether there were other metabolic phenotypes that may be unique to the MHO individual and potentially provide clues to their protective profile. For example, work by Brochu et al. (9) extended our knowledge of the roles of other phenotypes, including, body composition, body fat distribution, and energy expenditure, in the profile of the MHO individual. In this study MHO subjects were classified based on a cut-off point for insulin sensitivity using the hyperinsulinemic/euglycemic clamp (>8.0 mg/min·kg lean body mass) and obese at risk subjects with impaired insulin sensitivity (<8.0 mg/min·kg lean body mass). It is well recognized that insulin resistance develops on a continuum; thus one can argue with the imperfect use of cut-off points to differentiate high vs. low insulin sensitivity phenotypes. Nonetheless, the use of the clamp to initially identify the MHO individual is logical given the importance of insulin action in the metabolic syndrome. Metabolic phenotypes in 43 sedentary, obese, postmenopausal women (50–70 yr old) were analyzed, and 17 of the 43 subjects were identified as being MHO. After categorization of these individuals, the question was whether other phenotypes tracked with the insulin sensitivity values.

Despite similar levels of total body fatness in MHO and at risk obese postmenopausal women, MHO individuals showed 49% less visceral adipose tissue (as measured from computed tomography) than at risk subjects with the metabolic syndrome. It should be noted that the levels of visceral fat in the MHO group were still significant (141 ± 53 cm²), albeit less than those in the at risk group. Consistent with these findings, MHO women showed a more favorable lipid profile, as evidenced by lower fasting triglycerides, higher high density lipoprotein (HDL) cholesterol, lower fasting glucose and insulin concentrations, and reduced glucose and insulin area under the curve after an oral glucose tolerance test (Table 1). Interestingly, in stepwise regression analysis, in which glucose disposal was the dependent variable, visceral adipose tissue explained the most unique variance (22%). This finding is in line with other studies that suggested that the amount of visceral fat is an important factor associated with variations in insulin sensitivity (11, 12) and thus is not totally surprising. The second independent variable that was associated with a more favorable metabolic profile in the MHO individual in the study by Brochu et al. (9) was an earlier onset of obesity (<20 yr of age). This variable explained 13% of the variation observed in insulin sensitivity. This finding is supported by results reported by Muscelli et al. (13), who showed a positive association between duration of obesity and variation in insulin sensitivity. Thus, an explanation for this finding may be that with increased duration of obesity (i.e. childhood onset) some compensatory metabolic adaptations may be operative that would serve to preserve normal levels of insulin sensitivity. In support of this idea, Muscelli et al. (13) suggested that the interplay between primary insulin hypersecretion (driven by central nervous stimuli) and secondary insulin hypersecretion (the part that is compensatory to insulin resistance) could adapt as a function of time.

Several other studies have investigated obese individuals with a favorable metabolic profile (14, 15, 16). For example, in a recent study (14), nonobese or obese Japanese subjects with normal visceral fat area had a significant decrease in multiple risk factors related to obesity compared with subjects with high visceral fat area. This finding underscores the idea that even in the face of high levels of total body fat, lower levels of visceral fat may confer some metabolic advantages. This study suggested that 100 cm² of visceral fat area is a reasonable cut-off point as an indicator to risk disorders related to obesity in Japanese individuals. In contrast, Despres and Lamarche (17) suggested that a visceral fat accumulation greater than 130 cm² could be associated with a decrease in insulin sensitivity. In addition, Matsuzawa (15) reported evidence that Japanese Sumo wrestlers could be described as metabolically healthy due to normal amounts of visceral adipose tissue and lipid levels despite consuming 5000–7000 kcal/d. However, upon retirement from their wrestling profession, metabolic abnormalities developed in these Japanese Sumo wrestlers, such as increased insulin resistance, due potentially to a significant decrease in physical activity. Unfortunately, the amount of visceral adipose tissue after retirement was not reported in this study.

Interestingly, a recent study expanded the cardiovascular profile characterization in MHO individuals (16). Oflaz et al. (16) examined vascular endothelial function (as measured by flow-mediated dilation), intima media thickness of the common carotid, and anthropometric/metabolic parameters in MHO and lean individuals. In this study, intima media thickness of the common carotid was significantly higher, and flow-mediated dilation was significantly lower in MHO individuals despite a normal metabolic profile. Also in that study, lipid profile, blood pressure, insulin sensitivity (homeostasis model assessment), and anthropometric measurements could not explain the flow-mediated dilation or intima media thickness in the MHO and lean individuals. In addition, early atherosclerotic changes in MHO individuals are evident compared with healthy lean individuals, suggesting that factors other than obesity-related risks could be responsible for this observation. Thus, it is not our intention to convey the idea that MHO individuals are at an optimal state of health, as evidenced by the work of Oflaz et al. (16). A more prudent statement would be that MHO individuals are at a lower risk than at risk obese individuals, but at a higher risk than the general population.

Visceral fat has been associated with a decrease in insulin sensitivity, which could lead to an increase risk of cardiovascular disease (18). The higher levels of insulin sensitivity in MHO individuals may be due in part to lower amounts of visceral fat despite the presence of large amounts of total body fatness. Further investigations may want to consider the examination of adipocytes as a source of potential differences in insulin sensitivity. Larger adipocytes have been associated with an increase in insulin resistance (19), and normal size adipocytes have been associated with early onset of obesity (5). Therefore, the measurement of cell size and number in adipose tissue could indicate whether there is an increased number of normal sized adipocytes in MHO individuals and, in turn, could explain at least in part the higher insulin sensitivity observed in MHO individuals. Future research is needed to clarify this hypothesis.

	The metabolically obese, but normal weight (MONW), individual

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
MONW persons are a subgroup of individuals who have normal weight and body mass index (BMI), but display a cluster of obesity-related abnormalities. Although there has long been clinical recognition of this group of individuals, to our knowledge they were first described in detail in the 1980s (3, 4) and recently reviewed (20). As described, these individuals can be young and display premature signs of insulin resistance, hyperinsulinemia, and dyslipidemia that may eventually increase their risk for the development of diabetes and cardiovascular disease. From a clinical perspective, the presence of these metabolic and cardiovascular diseases could go undetected for years due to the individual’s young age and normal body weight, which may mask the need for early detection and treatment. As these "abnormal" characteristics are usually associated with those present in obese individuals, the literature identifies them as MONW (Fig. 2). Despite the clinical awareness of MONW individuals, there exists uncertainty as to the constellation of factors that are involved in this "risky" profile. It has been suggested, however, that body composition and body fat distribution abnormalities may play an important role in the development of metabolic complications in these individuals (20). Although it has been suggested that there is a high prevalence of MONW individuals in the general population (20), the exact percentage is unclear. However, in the study by Dvorak et al. (21) and in a recent study from our laboratory (unpublished), group sampling data show that this prevalence could be 18% and 13%, respectively.

View larger version (21K): [in this window] [in a new window]   FIG. 2. Differences in metabolic characteristics in MONW individuals and normal healthy individuals.

Dvorak et al. (21) examined phenotypic characteristics associated with the MONW individual in young women (Table 2). MONW subjects were classified based on a cut-off point for insulin sensitivity using the hyperinsulinemic/euglycemic clamp (<8.0 mg/min·kg lean body mass) and normal subjects with high insulin sensitivity (>8.0 mg/min·kg lean body mass). In this study BMI, body mass, and fat-free mass were not significantly different between groups. Despite no differences in BMI, differences in body composition and body fat distribution were noted. That is, total fat mass (+20%), body fat percentage (+16%), and sc fat (+33%) as well as visceral fat (+26%) were all significantly higher in the MONW individual.

Similar results were observed in a recent study from our laboratory (unpublished) indicating that young MONW women, despite having normal BMI, showed distinct differences in body composition compared with healthy normal young women. In this study MONW women showed a higher relative fat mass, a lower fat-free mass, and a tendency for greater central fat mass. In addition, MONW women showed significantly higher total cholesterol and low density lipoprotein cholesterol levels, but plasma triglycerides were similar in both groups. This could suggest that the percent body fat mass (even within a normal BMI range) may be predictive of reduced insulin sensitivity in MONW, young, normal weight women. Collectively, the relative level of body fatness may be an important first step to screen and identify MONW subjects. In addition, the researchers concluded that the higher fat mass in MONW women could be mediated indirectly by low cardiorespiratory fitness, as demonstrated by lower levels of the maximum rate of oxygen uptake (VO_2max) and reduced physical activity energy expenditure as shown by low leisure time physical activity and greater time spent watching TV (Conus, F., D. B. Allison, R. Rabasa-Lhoret, M. St-Onge, D. H. St-Pierre, A. Tremblay-Lebeau, and E. T. Poehlman, unpublished observations). These findings suggest that physical inactivity may be an important marker of the MONW young woman in relation to body composition.

Several recent studies have investigated in more detail other metabolic disturbances in the MONW individual. For instance, excessive fat on the upper part of the body or abdomen, as measured by the waist to hip ratio, is associated with an increase risk of diabetes and cardiovascular disease (26). Indeed, there is evidence to suggest that young healthy men (27) and in young adults (28) who fit the description of the MONW individual show an increase in intraabdominal fat, and this is associated with a decrease in insulin sensitivity as well as an increased risk for cardiovascular disease. Finally, it may be hypothesized that MONW individuals have a decrease in fat storage in adipose tissue. This, in turn, could explain the increase in plasma triglycerides levels observed in the previous studies (22, 23). In addition, this could increase fat storage in nonphysiological depots such as liver and muscle. In support of this conclusion, Seppala-Lindroos et al. (29) indicated a higher content of fat accumulation in the liver in nonobese men who display high levels of plasma insulin and triglycerides as well as lower levels of HDL cholesterol. The researchers suggested that the increase in liver fat could be associated with a decrease in insulin sensitivity.

	Is there a role for adipose and gastrointestinal (GI) hormones in MHO and MONW individuals?

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
Although not systematically examined, future areas of investigation may want to target measures of adipose and GI hormones to help us understand health profiles in MHO and MONW individuals. The rationale for this concept is that adipose tissue secretes potent paracrine/endocrine factors that influence local metabolism and have broader effects on other metabolic parameters, including satiety, insulin sensitivity, and energy expenditure, which could influence body composition in MHO and MONW individuals. Proteins such as acylation-stimulating protein, leptin, adiponectin, resistin, and other novel GI hormones (ghrelin) could influence adipose and overall metabolism as well as insulin sensitivity (30). Thus, a key issue is whether MHO and MONW individuals display a hormonal profile that distinguishes them from either at risk obese individuals or normal healthy individuals, respectively. Recent studies show that levels of stomach-derived ghrelin (31, 32) and adipose tissue-derived adiponectin (33, 34) are inversely related to insulin resistance. Interestingly, increased visceral fat accumulation is believed to down-regulate both ghrelin (31) and adiponectins (33, 35) level. The levels of other adipose tissue-derived hormones, such as resistin (35), leptin (31), and acylation-stimulating protein (36, 37), are reported to be positively correlated with insulin resistance and visceral fat accumulation. Although these results remain preliminary and correlative, they provide tantalizing evidence that several adipose tissue- and GI-derived hormones may be involved in the favorable insulin sensitivity/visceral body fat axis and may explain in part the positive and negative deviation noted, respectively, in MHO and in MONW individuals. To our knowledge only one study has examined plasma levels of adiponectin in Japanese MONW individuals (38). In that study, plasma levels of adiponectin showed no significant differences between MONW and normal subjects; however, a significant correlation between plasma levels of adiponectin and the rate of glucose infusion was observed in MONW subjects. This suggests that adiponectin could be involved in the development of insulin resistance in MONW individuals. Thus, determining the role of adipose tissue/GI hormone profiles could potentially underline the pathophysiology of the protective profile of the MHO individual or the abnormal metabolic characteristics of the MONW individual.

	Significance of the MHO and MONW subgroups in research and clinical medicine

Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 
An understanding of the MHO individual has important implications for both clinical and academic work. Sims (39) underscored the need to appreciate the effects of subtypes of obesity in clinical and research aspects. He suggested, for example, that attempts to weight-reduce MHO individuals by means of diet and/or exercise may actually be counterproductive and potentially harmful. The overall success rate for losing weight and maintaining a reduced body weight is quite poor. MHO individuals may contribute to this poor record by their strong tendency to regain lost body weight. One may even question the need to aggressively treat MHO individuals, given their favorable metabolic profile. In contrast, early identification and treatment of the metabolic abnormalities of MONW individuals could be effective in the primary prevention (i.e. diet and/or exercise) of obesity and its associated disease, such as diabetes and cardiovascular disease. Moreover, in clinical research, volunteers are frequently excluded from participation if they have one or more of the phenotypes of the metabolic syndrome. This recruitment or exclusion strategy could increase the percentage of MHO individuals within a given protocol. If MHO individuals are statistically analyzed within the same cohort with at risk obese individuals, the mixing of "apples and oranges" may render data interpretation quite problematic. In addition, MONW individuals are frequently undetected and undiagnosed. Therefore, recruiting MONW individuals with lean individuals could also render data difficult to interpret. Finally, in medical education, it is important to educate health care professionals and physicians about the different needs of subsets of obese individuals. The tendency to treat obese or lean individuals with a "one size fits all" approach will be counterproductive with the MHO or MONW individual, respectively. Identifying the physiological and behavioral factors that could classify an individual as MHO or MONW would be valuable. This area of investigation could have important implications for therapeutic medical decision-making (i.e. whether to treat individuals), subject characterization in research protocols, and medical education.

Interesting future areas of investigation may want to target free fatty acid trapping (40). A greater understanding of the regulation of free fatty acid transport, storage, and utilization in MHO and MONW individuals would be valuable in identifying mechanisms that could regulate these subsets. In addition, genetic studies (using the microarray technique) will offer the possibility to engage in discovery-driven research. Simply put, is there a distinct profile of genes found in MHO and MONW individuals? Ultimately, after the gene expression is measured, one may attempt to identify those genes for which there is differential expression in MHO and at risk obese individuals as well as MONW and metabolically healthy individuals. This area of research could potentially broaden our knowledge of factors that predispose subtypes of obese individuals to develop metabolic complications.

	Footnotes

 
This work was supported by grants from the Canadian Institutes of Health Research and the Canadian Foundation of Innovation.

Abbreviations: BMI, Body mass index; GI, gastrointestinal; HDL, high density lipoprotein; MHO, metabolically healthy, but obese; MONW, metabolically obese, but normal weight.

Received February 2, 2004.

Accepted March 18, 2004.

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Top Abstract Introduction The metabolically healthy, but... The metabolically obese, but... Is there a role... Significance of the MHO... References

 

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