Elsevier

Nutrition

Volume 32, Issue 1, January 2016, Pages 14-20
Nutrition

Review
Metabolically healthy obese individuals: Key protective factors

https://doi.org/10.1016/j.nut.2015.07.010Get rights and content

Abstract

Objectives

Obesity is a significant quality of life-impairing health problem affecting industrialized nations. However, despite carrying a large fat mass, some very obese individuals exhibit normal metabolic profiles (metabolically healthy obesity). The physiological factors underlying their protective and favorable metabolic profiles remain poorly defined.

Methods

A search of the National Library of Medicine PubMed database was performed using the following keywords: Metabolically healthy obese, metabolically normal obese, insulin resistance, metabolically unhealthy normal weight, and uncomplicated obesity.

Results

This article reviewed factors associated with severe obesity that lacks complications, and suggests putative activities by which these obese individuals avoid developing the clinical features of metabolic syndrome, or the metabolic complications associated with severe obesity.

Conclusions

Despite the knowledge that visceral fat deposition is the seminal factor that ultimately causes insulin resistance (IR) and the detrimental inflammatory and hormonal profile that contributes to increase risk for cardiovascular disease, it remains unknown whether metabolically healthy obesity (MHO) has genetic predisposing factors, and whether MHO ultimately succumbs to IR and the metabolic syndrome, indicating a need for prophylatic bariatric surgery.

Introduction

Obesity (BMI > 30) remains highly prevalent in the US, with approximately 35% of the adult population estimated to be obese [1]. Obesity has become a national health care priority imposing significant cumulative medical complications and costs due to the comorbidities that frequently accompany excessive adiposity. However, a number of obese men and women have been identified who exhibit less visceral adiposity and fewer adverse metabolic disturbances and cardiovascular risk factors than would be expected on the basis of their body mass index (BMI), a condition that has been termed metabolically healthy obesity (MHO) or uncomplicated obesity [2].

Limited data exist concerning the key protective factors accountable for the healthy metabolic profile that is characteristic of MHO. Identifying the characteristics that distinguish individuals with MHO from those obese men and women with metabolic syndrome will contribute to greater understanding of those protective metabolic, genetic, and etiologic factors and may serve to redirect the focus of global approaches to the management of the obese ‘at risk’ individual. In the preparation of this discussion, a search of the National Library of Medicine PubMed database was performed using the following keywords: Metabolically healthy obese, metabolically normal obese, insulin resistance, metabolically unhealthy normal weight, and uncomplicated obesity.

Extensive central or visceral adiposity is accompanied by a set of comorbidities (the metabolic syndrome) that includes insulin resistance (IR), type 2 diabetes mellitus (T2 DM), hypertension, dyslipidemia, a systemic proinflammatory condition, and cardiovascular disease [3], [4], [5], [6], [7]. A cornerstone of the metabolic syndrome, IR is typically accompanied by an increased presence of more atherogenic low-density lipoprotein (LDL) particles, including: lower circulating concentrations of high-density lipoprotein-associated cholesterol (HDL cholesterol), elevated circulating concentrations of triacylglycerol (TG), endothelial dysfunction, microalbuminuria, and impaired fasting plasma glucose clearance with elevated fasting plasma glucose concentrations [8], [9]. Men are more prone to develop visceral adiposity as a by-product of excessive caloric intake combined with sedentary lifestyles [10], increased activity of the hypothalamic-pituitary-adrenal axis [11], and decreased sympathetic nervous system activity [12], [13].

Both the deposition of visceral adipose tissue and the development of IR are associated with an overabundance of portal vein free fatty acids (FFA) [14], [15]. Increased influx of FFA to the liver stimulates hepatic production of apolipoprotein B-containing, TG-rich very low-density lipoprotein (VLDL) particles, while hepatic insulin resistance releases VLDL secretion from inhibition by insulin; together, increased FFA supply and VLDL secretion produce hypertriglyceridemia, a predominance of small, dense, cholesterol-depleted LDL particles, and low circulating concentrations of large cholesterol-enriched HDL particles [16], [17]. In addition to dyslipidemia, IR results in fasting hyperglycemia (T2 DM) accelerated pancreatic insulin secretion with fasting hyperinsulinemia, and increased sympathetic nervous system activity that contributes to the development of hypertension. Furthermore, visceral adipose tissue is a source of the proinflammatory cytokine, C-reactive protein (CRP), and circulating CRP concentrations are directly correlated with the amount of visceral adipose tissue present as well as with the risks for hypertension, obesity, insulin resistance, and coronary vascular disease [18], [19]. Consequently, the metabolic syndrome is the result of several factors acting in concert to produce an unfavorable metabolic profile that promotes the development of chronic degenerative diseases, particularly among the obese.

Metabolically healthy obese individuals represent between 10%–45% of the adult obese population, with higher prevalence among younger obese individuals and obese women (differences in diagnostic criteria account, in part, for the discrepancies in prevalence estimates) [20], [21], [22], [23], [24], [25], [26]. The absence of insulin resistance or of criteria indicative of the metabolic syndrome, among others, has been proposed as criteria diagnostic for the MHO phenotype [25]. Several studies have identified MHO based on insulin sensitivity using the hyperinsulinemic-euglycemic clamp technique [27], [28], [29]; however, this technique is invasive, expensive, and time consuming. The identification of individuals with MHO is hampered by the absence of a standardized definition of the condition.

Despite this ambiguity, MHO is characterized by the absence of at least some of the increased risks for degenerative diseases that accompany typical adult obesity. For example, the relative risks for developing cardiovascular disease in individuals with MHO are not significantly greater than those observed in metabolically healthy non-obese individuals [30], [31]. Consistent with these reports, a recent Finnish study that included 61,299 participants that were monitored up to twelve years found that MHO did not increase the risk for myocardial infarction, although the risk for heart failure was greater in men and women with MHO than in metabolically healthy non-obese participants [32]. More importantly, Ortega et al. [33] reported 62% and 57% lower risks for cardiovascular and all-cause mortalities, respectively, in subjects with MHO compared to the risks for subjects exhibiting ‘metabolically unhealthy obesity (MUO).’ These findings suggest that metabolic health confers a measure of protection against cardiovascular disease in the obese.

Metabolically healthy obesity can be produced by genetic predisposition, lifestyle factors, or a combination of both. Visceral adiposity is a fundamental obstacle to the metabolic health of the obese and causes chronic systemic inflammation, linking obesity with metabolic disease [3], [4], [5], [6], [7]. It also appears that variations in inate endocrine functions and responses to nutriture, physical activity (PA), and cardiorespiratory fitness (CRF) interact to facilitate the healthy metabolic profile of MHO. Consistent with the inconsistent descriptions of MHO, the elucidation of the factors or mechanisms underlying this protective profile is far from complete.

Central obesity, clinically defined by the ratio of waist circumference to hip circumference (≥0.95 in men or ≥0.80 in women) or by waist circumference alone and (≥102 cm in men and ≥88 cm in women [34]), is associated with metabolic and cardiovascular changes related to the metabolic syndrome [35]. A genetic correlation exists between IR and visceral fat, suggesting that central fat distribution is not only a predictor of IR, but it also shares considerable genetic influence with IR [36]. Janssen [37] recently suggested that waist circumference is a more important determinant of obesity-related health risk than BMI. According to this interpretation, overweight, obese and normal weight persons (according to BMI) with the same waist circumference share comparable risks for developing the components of the metabolic syndrome. In contrast, individuals with normal BMI (and therefore considered to be of normal weight) with excessive waist circumference exhibit metabolic characteristics associated with the metabolic syndrome [38], [39]. Could it be that body fat distribution is a cardinal feature determining metabolic fate?

Individuals with MHO have lower visceral adipose tissue content compared with metabolically unhealthy obese individuals [27]. A clue to the etiology of MHO is provided by the results of a morphologic study of women with the metabolic syndrome in spite of enjoying normal weight (metabolically obese normal weight). These women exhibit greater relative fat mass and lower fat-free mass and a tendency for greater accumulation of central visceral fat [38], [39], [40], [41]. This combination of characteristics is associated with reduced insulin sensitivity, suggesting that it may presage MHO (Table 1). Consistent with this suggestion, Brochu et al. [27], using a hyperinsulinemic-euglycemic clamp technique, compared insulin sensitivity between metabolically healthy postmenopausal obese women and postmenopausal at risk subjects with impaired insulin sensitivity. Women with MHO exhibited greater insulin sensitivity despite having 50% total body fat but 50% less visceral adipose tissue than the metabolically unhealthy postmenopausal women. These data suggest that a smaller amount of visceral adipose tissue, despite the presence of large amounts of body fat, is a significant factor in the maintenance of the favorable metabolic profile of MHO. Karelis et al. [42] also observed an inverse association between visceral fat and insulin sensitivity distinguished in obese sedentary postmenopausal women with MHO from similar women who were ‘at risk’ for developing coronary artery disease.

T2 DM is associated with a greater tendency to accumulate visceral fat at a given body weight [43], and this propensity may be a consequence of an impaired subcutaneous fat storage capacity. Genetic studies have supported this hypothesis. Yaghootkar et al. [44] demonstrated the genetic basis for the influence of adipose tissue storage and expandability capacity on metabolic health. Using genetic association data obtained from publicly available genome-wide association studies, these researchers documented a genetic link between the three diseases of the metabolic syndrome and demonstrated that reduced subcutaneous adiposity is the central linking mechanism.

Monogenic examples of insulin resistance illustrate the causal role of inadequate subcutaneous adipose tissue in the etiology of cardiometabolic disease [45]. Recently, Scott et al. [46] observed that a genetic tendency for insulin resistance is associated with smaller subcutaneous adipose tissue depots in a manner similar to that observed in monogenic forms of lipodystrophy, implicating inadequate lipid storage capacity in the etiology of T2 DM. A putative mechanism for the pathogenesis of insulin resistance is the incapacity of adipose tissue to expand in the face of sustained positive energy balance, and exceeding this limit results in lipid storage in tissues less well adapted to perform this function [47].

MHO is associated with lower visceral and hepatic fat content than is observed in insulin resistant obese individuals [48]. Stefan et al. [49] demonstrated that individuals with MHO exhibited 54% less fat accumulation in the liver than was measured in metabolically unhealthy obese subjects. Furthermore, a recent study showed that MHO have a lower fatty liver index, and lower serum activities of hepatic enzymes, compared with metabolically unhealthy obesity [50]. These data also implicate ectopic fat deposition as a factor contributing to the metabolic consequences of obesity; in contrast, reduced ectopic fat deposition is a protective feature of MHO. Increased ectopic fat deposition resulting in organ-specific insulin resistance (lipoxicity) is an emerging factor in the pathophysiological etiology for T2 DM. Studies of the genetics of insulin resistance have demonstrated that of the 19 loci recently found to be associated with fasting plasma insulin concentrations, only one (the FTO gene) was mediated entirely by higher BMI, highlighting the role of other pathways in the etiology of insulin resistance [45], [51].

Cumulatively, the impact of these robust data strongly indicate that relative amounts of body fat, and the relative distribution of body fat between visceral and peripheral sites, and not BMI per se, is important in determining whether an individual's metabolic profile will be favorable or unfavorable.

Inflammation promotes insulin resistance. Greater adipose tissue inflammation is closely associated with increased metabolic risk for T2 DM, cardiovascular disease, and fatty liver disease, whereas obese adults without adipose tissue inflammation exhibit reduced metabolic risk [52], [53]. For example, in one study, approximately 40% of obese young adults had subcutaneous abdominal adipose tissue with crown-like structures, indicating the presence of adipose tissue inflammation; these individuals had approximately 30% more visceral adipose tissue, 41% more liver fat, 54% higher fasting plasma insulin concentrations, 23% less β-cell function, and 22% higher plasma tumor necrosis factor alpha (TNF-α) concentrations [53]. In addition, individuals with the metabolic syndrome have significantly greater numbers of infiltrating macrophages/crown-like structures in their adipose tissues compared to those without the metabolic syndrome [52].

Obesity is a low-grade inflammatory disease [54], [55]. A broad range of inflammatory molecules, including TNF-α and IL-6, are produced and secreted by adipose tissue and exert both local and systemic effects. The subsequent infiltration of immune cells such as macrophages into adipose tissue produces proinflammatory changes within the tissue [56]. On the other hand, antiinflammatory adipokines, such as adiponectin, IL-4, IL-10, IL-13, IL-1 receptor antagonist (IL-1 Ra), and transforming growth factor beta (TGF-β) are abundant within the adipose tissues of lean individuals, whereas obese adipose tissue is dominated by the release of proinflammatory adipokines, including leptin, resistin, TNF-α, IL-6, IL-18, retinol-binding protein 4 (RBP4), lipocalin 2, angiopoietin-like protein 2 (ANGPTL2), CC-chemokine ligand 2 (CCl2), CXC-chemokine ligand 5 (CXCL5), and nicotinamide phosphoribosyltransferase (NAMPT) [56].

The concentrations of acute phase proteins are increased in the plasma of obese individuals, including CRP, complement factors, and interleukins. This inflammatory state contributes to the development of T2 DM and the other components of the metabolic syndrome. Changes in body weight in obese patients are accompanied by parallel changes in the production and secretion of inflammatory markers, such as CRP, TNF-α, IL-6, and IL-8 [18], [55], [57], [58]. In obese subjects, adipose tissue is infiltrated by macrophages in response to cytokines, FFA, and complement factor C3 [59]. Increased adipocyte size and number are linked to greater macrophage infiltration and activation through adipocyte release of MCP-1 [60], [61], [62], [63], [64], while weight reduction is associated with reduction in macrophage infiltration and improvement in inflammatory profile. Although the link between the inflammatory response and IR is not completely understood, a putative mechanism involves increased lipolysis resulting from the link between elevated circulating FFA concentrations and IR in skeletal muscle and liver [63]. However, adiposity itself does not necessarily lead to inflammation. Hypoglycemic agents, such as pioglitzone and rosiglitazone, and in particular, the thiazolidinediones, promote significant weight gain as body fat, but with a decrease in visceral fat accumulation [64], [65]. These findings demonstrate, once again, that a redistribution of body fat within adipose tissue compartments could protect against the development of the metabolic syndrome.

In addition to differences in body composition and fat distribution, MHO is characterized by smaller amounts of visceral fat, lower fasting plasma concentrations of insulin, triacylglycerol, CRP, α1-antitrypsin, and higher plasma concentrations of antiinflammatory cytokines [42]. Thus, individuals with MHO exhibit a more favorable inflammatory profile than that exhibited by individuals ‘at risk’ for insulin resistance. Other investigators have reported that high plasma CRP concentrations were more frequent among women who were dysmetabolic [66], [67]. This lower ‘inflammation state’ appears to result in protection in MHO. Recent data from a cross-sectional study support the notion that MHO is accompanied by a more favorable inflammatory status than is metabolically unhealthy obesity [68].

The favorable inflammatory profile could be the major factor in the decreased cardiovascular risk in MHO. Chronic subclinical inflammation is associated with cardiovascular disease and may be a feature of the metabolic syndrome [69]. However, the role of obesity as an independent etiologic factor for cardiovascular disease is still controversial [70]. For example, in a series of studies, excess body fat was associated with impaired diastolic function, but not with ventricle hypertrophy, suggesting that IR is a stronger determinant of left ventricle mass than is BMI [71].

Another group has suggested that the metabolic syndrome, and not obesity per se, predicts future cardiovascular risk in women [67]. They reported that in unadjusted and adjusted analyses, increases in BMI were not associated with changes in the 3-year risk for premature death. Conversely, each unit increase in dysfunctional metabolic status (from normal to the metabolic syndrome to T2 DM) was associated with an approximately 2-fold increase in the adjusted risk for premature death. Therefore, the adverse effect of being dysmetabolic on long-term risk of cardiovascular events was independent of BMI, and being overweight or obese did not independently impose increased cardiovascular risk. Together, these studies suggest that the presence of an abnormal inflammatory profile, the metabolic syndrome, and T2 DM is more important than the simple presence of obesity in determining cardiovascular risk in women and, in particular, their risk for developing ischemic heart disease.

Ghrelin, leptin, adiponectin, resistin, and visfatin regulate energy homeostasis and degree of body fatness [72]. The exact role of adipokines and other inflammatory markers in the pathophysiology of IR and obesity is still uncertain [73]. For example, of the numerous messengers produced by adipocytes, only plasma adiponectin concentrations are inversely correlated with an increase in fat mass. Ghrelin secretion is decreased in obesity and is suppressed by the hyperinsulinemia of IR [74], [75].

Leptin is secreted in proportion to fat accumulation and modulates endothelial function by stimulating the release of nitric oxide, and changes in endothelial function after weight loss are correlated with changes in plasma leptin concentration [76], [77], [78]. In addition, increased leptin secretion promotes cholesterol ester synthesis in macrophages during hyperglycemia and may stimulate the activation of TNF-α, a vasoconstrictive downregulator of endothelial nitric oxide synthase. Pharmacologic inhibition of leptin secretion improves insulin sensitivity and endothelial function [79].

Obesity, T2 DM, visceral obesity and IR are associated with reduced secretion of adiponectin [80]. The ratio of high-to low-molecular weight adiponectin in the serum is a crucial contributor to insulin sensitivity [81], and high-molecular-weight adiponectin protects against IR. Weight loss leads to a relative increase in the ratio of high-to low-molecular weight adiponectin in the serum [82]. Furthermore, TNF-α suppresses the transcription of adiponectin by adipocytes and serum adiponectin concentrations are lower in individuals who are obese [83]. Variations in the adiponectin gene, APM1, are associated with T2 DM, the regulation of body fat accumulation and distribution, and features of the metabolic syndrome [84]. Furthermore, adiponectin inhibits the adhesion of macrophages to endothelial cells, an essential process in the pathogenesis of atherosclerosis [85]. Increased circulating concentrations of adiponectin, therefore, can contribute to increased inflammatory macrophage activity within adipose tissue. On the other hand, serum adiponectin concentrations have been reported to be higher in individuals with MHO than in individuals with metabolically unhealthy obesity [86], [87]. Interestingly, there was no difference in mean serum leptin concentrations, although a high serum leptin/adiponectin ratio was associated with increased risk for the metabolic syndrome in young severely obese patients [88].

Resistin is considered an adipokine although it appears that human adipose tissue resistin production occurs primarily within macrophages and monocytes [56] while macrophages that infiltrate atherosclerotic aneurysms secrete resistin [3], [89]. Current evidence suggests that resistin is a proinflammatory cytokine that acts on substrate metabolism causing impairment of insulin action, particularly in the liver [90]. Although a comprehensive functional description for resistance in humans is still to be determined, its proinflammatory properties indicate an important role in inflammatory processes.

Visfatin is an adipokine that is secreted by visceral fat adipocytes and decreases insulin sensitivity [56], [91]. There are significant positive relationships between visceral visfatin expression and BMI, percent body fat, and waist circumference [87]. In addition, elevated circulating concentrations of visfatin and resistin are even higher in metabolically unhealthy obese individuals than they are in individuals with MHO [92].

Adipose tissue is a key regulator of inflammation, and inflammation is involved in the onset and development of atherosclerosis, the metabolic syndrome, and T2 DM. Although the results of these initial studies suggest that MHO is characterized by a lower inflammatory cytokine environment than is metabolically unhealthy obesity, further studies are necessary to better identify those adipose tissue hormones that promote a healthy metabolic profile in obese adults.

The decisive feature of MHO is the absence of visceral fat accumulation. Until definitive data emerges linking genetic predisposition to MHO, currently recommended lifestyle modifications appear beneficial. Thus, the promotion of lifestyle modifications that are directed at minimizing visceral fat accumulation is a fundamental public health measure. Based on data demonstrating that sedentary lifestyles contribute to visceral fat accumulation [93], a rational measure is the incorporation of a regular exercise program into routine behaviors. Furthermore, recent studies have demonstrated that physical activity and cardiorespiratory fitness are associated with decreasing the effects of the metabolic syndrome and fewer metabolic complications [94], [95]. Indeed, metabolically healthy obese individuals tend to be more physically fit than are metabolically unhealthy obese individuals [50]. Exercise is a recognized stress reducer, decreasing activity of the hypothalamic-pituitary-adrenal axis and attenuating the contribution of that axis to visceral fat accumulation [96]. The link between the consumption of carbohydrates, and particularly sucrose/refined sugar, and sympathetic nervous system activity suggests that the adoption of a more nutritionally balanced diet may minimize visceral fat accumulation.

However, even these measures can produce variable outcomes in MHO, as demonstrated by a study in which individuals with MHO responded to 6-mo of an energy-restricted diet with deterioration of insulin sensitivity, while the insulin sensitivity of subjects with metabolically unhealthy obesity improved significantly [97]. At this time, bariatric surgery remains among the best options for those patients suffering from severe obesity, with excellent results regarding long term weight loss and decreases in peripheral and visceral fat depot sizes [98].

Debate continues concerning whether individuals with MHO are truly healthy. Published literature diverges regarding the relative risk of disease among this population. Individuals with MHO are at decreased risk for developing cardiovascular disease compared with metabolically unhealthy obese individuals [99]. Long-term studies have suggested that MHO is a transient state. For example, among a group of Japanese Americans with MHO, two-thirds developed the metabolic syndrome during 10 y of observation, and the metabolic abnormality was independently associated with visceral fat accumulation, female sex, higher fasting plasma insulin concentration, and lower serum HDL-associated cholesterol concentration [100]. Consistent with this report, among the 1051 participants in the Pizarra Study, the prevalence of MHO decreased during 11 y of observation [101].

Although several epidemiologic studies have observed that individuals with MHO are not at increased risk for developing cardiovascular disease (CVD) compared to metabolically healthy normal weight (MHNW) individuals [102], [103], [104], [105], studies with longer follow up periods (>15 y) have reported that individuals with MHO were at an increased risk for major CVD events as compared to MHNW individuals [106], [107]. Recently, analysts conducting a systematic review of the associations of BMI and metabolic status with total mortality and cardiovascular events reported that individuals with MHO appear to be at increased risk for cardiovascular events, as compared to metabolically healthy normal weight individuals [30]. These researchers concluded that obese individuals are at increased risk for adverse long-term outcomes, even in the absence of metabolic abnormalities, compared with metabolically healthy normal-weight individuals.

A recent study evaluated the prevalence of elevated plasma high sensitive-CRP (hs-CRP) concentrations and hepatic steatosis in individuals with MHO, MHNW, and metabolically unhealthy normal-weight (MUNW) individuals [108]. They observed that both elevated plasma high sensitive-CRP (hs-CRP) concentrations and hepatic steatosis are more prevalent among individuals with MHO and MUNW individuals than they are among MHNW individuals. However, they are most prevalent among individuals with MHO, suggesting that obesity in the absence of metabolic risk factors is not entirely benign but is associated with subclinical vascular inflammation. Another recent study reported that 42% of their subjects with MHO developed metabolic syndrome within 10 y [109], again suggesting that MHO is not without increased health risks. However, the identification of predictors, biological determinants, and mechanisms underlying MHO, determining whether MHO represents a transient phenotype that is affected by aging, behavioral, and environmental factors, and accurately calculating the true health risks associated with MOHO remain fertile soil for diligent study through properly designed and conducted longitudinal studies.

Lee et al. [110] studied the characteristics of obese individuals who underwent bariatric surgery. More than 25% of their patients did not exhibit T2 DM or hypertension, suggesting that they represented cases of MHO. However, 89% were afflicted with liver steatosis, 7% exhibited nonalcoholic steatohepatitis, and 19% had hepatic fibrosis, supporting the conclusion that MHO is not a metabolically inconsequential condition. Goday et al. [111] also studied severely obese patients undergoing bariatric surgery. They reported that those with MHO presurgery experienced (in addition to expected weight loss) significant reductions in resting blood pressure, fasting plasma glucose concentration, IR, serum total cholesterol concentration, serum LDL-associated cholesterol concentration, and plasma triacylglycerol concentration, along with a significant increase in serum HDL-associated cholesterol concentration, 1 year after bariatric surgery, demonstrating that patients with MHO can receive metabolic benefit from bariatric surgery. Better characterization and understanding of the prognostic significance of MHO in bariatric surgery may help refine the prevention and treatment of obesity.

Section snippets

Conclusion

MHO is common among the obese population and constitutes a unique subset of characteristics that reduce metabolic and cardiovascular risk factors despite the presence of excessive fat mass. The protective factors that grant a healthier profile to individuals with MHO are becoming elucidated (Table 1). Visceral fat deposition is the seminal factor that ultimately causes IR and the detrimental inflammatory and hormonal profile that contributes to increased risk for cardiovascular disease. Whether

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