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M Blüher Metabolically healthy obesity 171:6 R209–R219


Are metabolically healthy obese individuals
really healthy?
Matthias Blüher should be addressed
Department of Medicine, University of Leipzig, Liebigstrasse 20, D-04103 Leipzig, Germany to M Blüher

Obesity has become one of the major public health concerns of the past decades, because it is a key risk factor for type 2
diabetes, cardiovascular diseases, dyslipidemia, hypertension, and certain types of cancer, which may lead to increased
mortality. Both treatment of obesity and prevention of obesity-related diseases are frequently not successful. Moreover,
European Journal of Endocrinology

a subgroup of individuals with obesity does not seem to be at an increased risk for metabolic complications of obesity.
In this literature, this obesity subphenotype is therefore referred to as metabolically healthy obesity (MHO). Importantly,
individuals with MHO do not significantly improve their cardio-metabolic risk upon weight loss interventions and may
therefore not benefit to the same extent as obese patients with metabolic comorbidities from early lifestyle, bariatric surgery,
or pharmacological interventions. However, it can be debated whether MHO individuals are really healthy, especially
since there is no general agreement on accepted criteria to define MHO. In addition, overall health of MHO individuals
may be significantly impaired by several psycho-social factors, psychosomatic comorbidities, low fitness level, osteoarthritis,
chronic pain, diseases of the respiratory system, the skin, and others. There are still open questions about predictors,
biological determinants, and the mechanisms underlying MHO and whether MHO represents a transient phenotype
changing with aging and behavioral and environmental factors. In this review, the prevalence, potential biological
mechanisms, and the clinical relevance of MHO are discussed.

European Journal of
(2014) 171, R209–R219

The current obesity epidemic affects more than 20% of the Although prevention of obesity-related diseases and
general population in modern societies and contributes treatment of obesity itself are important tasks, both at the
to higher mortality due to an increase in type 2 diabetes, individual and population level, many strategies to reduce
hypertension, cardiovascular disease, stroke, as well as body weight and the obesity-associated risk have not been
several types of cancer (1, 2, 3, 4, 5, 6, 7). successful (8, 9, 10). In addition, not all obese individuals

Invited Author’s profile

Matthias Blüher is Professor in Molecular Endocrinology at the University of Leipzig and has extensive practical
experience in the treatment of patients with type 2 diabetes, obesity and endocrine disorders. He is also the Speaker of
the Collaborative Research Center – Obesity mechanisms (, and a Coordinator of the federally funded
Competence Network Obesity (CNO). Dr Blüher has a specific research focus in the study of adipose tissue function,
including regulation of adipose tissue cellularity and adipokine secretion. In addition to different clinical studies on
exercise regimens, diet strategies and bariatric surgery, he has conducted several clinical trials on the effects of
pharmacological interventions to treat diabetes and obesity. Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/EJE-14-0540 Printed in Great Britain
Review M Blüher Metabolically healthy obesity 171:6 R210

can be included into treatment programs. Therefore it associated with an increased risk for the development of
could help to reduce the medical and socioeconomic heart failure (21). Taken together, this study convincingly
burden associated with obesity treatment if those patients demonstrates that it is necessary to stratify obese patients
who will benefit the most from diet and exercise, according to MHO vs metabolically high-risk obesity, in
pharmacological or bariatric surgery interventions could particular with respect to the prediction of cardiovascular
be identified early (11). Metabolically healthy obesity disease (24). Moreover, benefits of lifestyle interventions
(MHO) may represent a subgroup of obese individuals in healthy obese individuals are questionable (25, 26).
in which excessive body fat accumulation does not lead Based on such findings and under the pressure of
to adverse metabolic effects including insulin resistance, limited healthcare resources, future guidelines for obesity
impaired glucose tolerance, dyslipidemia, and hyperten- treatment should distinguish between MHO and meta-
sion (12, 13, 14, 15). MHO prevalence ranges from w10 to bolically high-risk obese individuals (10, 11). Until now,
30% of obese individuals (13). current guidelines still recommend lifestyle intervention
Noteworthy, it has been shown in different indepen- for all obese individuals independently of their individual
dent studies that metabolically healthy obese individuals obesity-associated cardiometabolic risk (27). In particular,
may not significantly improve their obesity-related cardi- for the bariatric surgery treatment decision, the indivi-
ovascular and metabolic risk by anti-obesity treatment dual risk:benefit ratio should take a stratification of the
strategies (16, 17, 18, 19, 20). It has been recently reported obesity-associated metabolic risk into account.
that 60 sedentary obese postmenopausal women, who
have been defined as metabolically healthy obese, respond
Definition of MHO
differently to a 6-month restricted caloric diet compared
European Journal of Endocrinology

with at-risk obese people despite similar weight loss (18). To answer the question whether metabolically healthy
In the MHO group, insulin sensitivity deteriorated by obese individuals are really healthy, it is important to
w13%, whereas the same intervention improved insulin acknowledge that the criteria to classify MHO and cut-off
sensitivity significantly in the high-risk obese subgroup values for each parameter describing MHO vary from
(18). In another study of 103 men and women with MHO, study to study (13, 16, 28, 29). Most studies define
a lifestyle intervention also did not improve insulin MHO as the absence of any metabolic disorder including
sensitivity despite significant reductions in visceral fat type 2 diabetes, dyslipidemia, and hypertension in an
mass (16). Although one previous study found improved obese individual (BMIO30 kg/m2; reviewed in references
insulin sensitivity and reduced cardiovascular risk par- (13, 14, 30)). Although the influence of lifestyle, physical
ameters upon a 3–6 months multimodal lifestyle inter- fitness, ethnicity, gender, or age on the MHO phenotype is
vention program, the degree of insulin sensitivity in the widely accepted, current definitions do not include these
metabolically high-risk obese group did not reach the level variables (13). Variable associations between MHO and
of MHO study participants (20). However, in these short- reduced risk for cardiovascular diseases and mortality
term intervention reductions and incidence of type 2 (13, 21, 22, 23) highlight the need for harmonized
diabetes, cardiovascular events or mortality could not be classification criteria (13). Until very recently, there have
assessed (14). been no standardized criteria to define MHO individuals,
In a recent population-based prospective cohort except for the presence of obesity (BMIR30 kg/m2) (13, 18).
study, including a total of 61 299 men and women The need to harmonize MHO definitions has been
without evidence of cardiovascular disease at baseline, it recently addressed by the BioShare-EU project (13), an
has been demonstrated that individuals with MHO are not international collaboration between European and
at increased risk of acute myocardial infarction compared Canadian institutes and cohort studies. In the Healthy
with normal-weight, metabolically healthy study partici- Obese Project, data from more than 163 000 individuals in
pants (21). On the other hand, the risk for cardiovascular ten population-based cohort studies (age range 18–80
events was increased among metabolically unhealthy years) from different countries in Europe have been
individuals across the whole range of BMI (21). Additional evaluated to compare key characteristics defining MHO
observational studies support the finding that individuals and to characterize clinical and metabolic factors associ-
with MHO are at lower risk for cardiovascular disease and ated with MHO (13). Across all cohorts, the prevalence of
all-cause mortality (22), although this is not confirmed obesity was w17% with a range from 11.6% in a cohort
in all observations (23). Interestingly the study also from Italy to 26.3% in the KORA-cohort from Germany
demonstrated that obesity even in the MHO subgroup is (13). The harmonization effort in the Healthy Obese
Review M Blüher Metabolically healthy obesity 171:6 R211

Table 1 Criteria used for the definition of metabolically circulating C-reactive protein (reviewed in references
healthy phenotypes in different studies. (This table was (11, 14)). Different MHO definitions are a major limitation
modified from references (13, 14).) Importantly, studies include for the comparison between different observational
participants with normal body weight and obesity. studies and for the interpretation of associations between
MHO, cardiovascular disease, and mortality (reviewed in
Absence of metabolic syndrome
reference (14)). For example, different HOMA-IR cut-offs
derived from arbitrary decisions have been used to
Less strict Strict
Criteria criteria (13) criteria (13)
categorize MHO (Table 1) (23, 33, 34, 35, 36, 37). Different
MHO criteria may indeed identify different obese sub-
Diagnosis of CVD No No populations with only little overlap (14). In the NHANES
Blood pressure (mmHg) III, w44% of the obese study participants have been
SBP %140 %130 categorized as MHO, applying the NCEP ATP III criteria for
DBP %90 %85
Use of antihyper- No No metabolic syndrome (32), whereas only 20% met the strict
tensive medication predefined HOMA-IR cut-off !2.5 (33). Such divergent
Fasting blood %7.0 %6.1 definitions also support the concept that MHO does not
glucose (mmol/l)
HDL (mmol/l) describe a fixed or permanent phenotype. In one cross-
Men O1.03 O1.03 sectional data, we find a continuous relationship between
Women O1.3 O1.3 insulin sensitivity as determined by euglycemic–hyper-
Fasting triglycerides %1.7 %1.7
(mmol/l) insulinemic clamps and BMI in lean and obese individuals
(Fig. 1), which have been defined as metabolically healthy
European Journal of Endocrinology

Pharmacotherapy to No No
lower TG or increase following the NCEP ATP III criteria (38). At any given BMI
Insulin sensitivity
(Fig. 1), there are obese individuals with either extreme
Euglycemic clamp GIR O70 mmol/kg insulin sensitive or extreme insulin-resistant healthy
per min (38) obesity, but there is no cut-off clearly separating distinct
HOMA-IR !2.5 (23, 33, 35, Lower quartile/
36, 46) tertile (34, 37, 46) insulin-sensitive and -resistant subgroups (38). This
Matsuda-index Upper 25% of observation is further supported by data from 2472
distribution (37) participants of the Tübingen Family Study and the
Tübingen Lifestyle Intervention Program (15, 39). Despite
the strong association between BMI and waist circum-
Project used criteria to define the metabolic syndrome to ference, large variations have been found in insulin
characterize MHO (Table 1). In addition to the current sensitivity (determined using HOMA-IR) for individuals
World Health Organization (WHO) classification of with the same BMI (14). Noteworthy, similar continuous
obesity (BMIR30 kg/m2) (31), four parameters were used relationships between increasing BMI and deterioration
to define the metabolic phenotype based on the NCEP ATP of components of the metabolic syndrome have been
III criteria (32). Specifically, the definition of metabolic reported in children and adolescents (40). Therefore, these
syndrome in obese included: elevated blood pressure, data suggest that MHO represent the extreme phenotype
defined as i) systolic blood pressure R130 mmHg or of continuous relationships between increased BMI and
diastolic blood pressure R85 mmHg, or antihypertensive different metabolic deteriorations and does not reflect a
treatment; ii) fasting blood glucose R6.1 mmol/l, history distinct biologically defined phenotype (11). However,
of type 2 diabetes, or use of glucose-lowering agents; defining the MHO phenotype still represents an important
and iii) HDL serum concentrations !1.03 (in men) or tool to study the mechanisms of how fat accumulation on
!1.3 mmol/l (in women), fasting triglyceride serum con- obesity causes or contributes to metabolic and cardio-
centrations R1.7 mmol/l or drug treatment to alter HDL vascular diseases (12, 24).
or triglycerides (Table 1). The collaborators also applied
a set of less strict criteria to define MHO (Table 1) (13).
In the past, different definitions have been used
to identify MHO individuals. Previous definitions of In children and adolescents, prevalence of MHO has been
MHO included parameters such as insulin sensitivity recently defined in 21.5–31.5% (depending on the
determined by euglycemic–hyperinsulinemic clamps or classification system) of obese 8- to 17-year-old individuals
with HOMA-IR, blood pressure, lipid parameters, and with a BMI above the 85th percentile (41). The prevalence
Review M Blüher Metabolically healthy obesity 171:6 R212

NCDS from the UK, with a MHO prevalence of 9% in men

compared with 28.4% in women, whereas MHO preva-
140 lence was similar in men (19%) and women (21.1%) in the
BMI: 50.0 kg/m2 CHRIS study from Italy. Similar prevalence differences
Glucose infusion rate, steady state

FPG: 5.1 mmol/l
have been found by earlier studies in Caucasian, Asian,
clamp (µmol/kg per min)

HbA1c: 5.4%
100 HDL: 1.27 mmol/l

TG: 1.51 mmol/l
BP: 129/78 mmHg
and African American populations, which varied between
w9 and 34% (summarized in reference (11)). The
frequency of MHO was estimated with 11% among 888
randomly selected individuals with an age range between
0 BMI: 50.0 kg/m2
40 and 79 years in the Bruneck study (42), whereas in the
FPG: 5.8 mmol/l
20 30 40 50 60 70 HbA1c: 5.9% Finnish type 2 diabetes survey, MHO was observed in 9.2%
BMI (kg/m2) HDL: 0.83 mmol/l
TG: 1.96 mmol/l men and 16.4% women (28). Although it is difficult to
BP: 136/84 mmHg
directly compare these numbers with data from studies in
Asian and African American populations due to different
Figure 1 definitions of MHO, it is important to note that MHO can
Identification of insulin sensitivity in metabolically healthy be identified independent of ethnicity and geographic
obese individuals. Individuals for whom euglycemic–hyperin- regions of the world. For instance, MHO was found in
sulinemic clamp data were available to determine insulin a study from Taiwan (43) and in a study among African
sensitivity have been selected by the following criteria: fasting Americans (44), with a prevalence of 28.5%. In the
plasma glucose !7.0 mmol/l, HbA1c !6.0%, no medical history Chennai Urban Rural Epidemiology Study, MHO preva-
European Journal of Endocrinology

of hypertension, systolic blood pressure (SBP) !140 mmHg, lence was 13.3% among Asian Indians (45). Noteworthy,
diastolic blood pressure (DBP) !90 mmHg, leukocyte count in contrast to Caucasian and African American popu-
!8000 Gpt/l, C-reactive protein (CRP) !5.0 mg/dl, no lations, prevalence estimations in the Asian studies were
concomitant medication except contraceptives. Insulin based on an obesity WHO Asia Pacific guidelines
sensitivity was determined by glucose infusion rate (GIR) during definition using a BMI R25 kg/m2 (43, 44, 45). Moreover,
the steady state of an euglycemic–hyperinsulinemic clamp. it has been recently suggested that MHO prevalence may
The dotted hyperbolic line is a regression curve of GIR over be underestimated, when BMI as compared with body fat
BMI based on all available subjects. Two individuals mass is used (46).
(BMIZ50.0 kg/m2; pictures of the abdominal region) are The age-standardized prevalence of metabolic syn-
selected to represent either insulin sensitive, metabolically drome in obese individuals also shows great variance
healthy, or insulin resistant obesity, which do not fulfil all ranging from 24% in the Italian CHRIS study to 65% in the
criteria (13) to define metabolically healthy obesity. FPG, fasting Health2000 cohort from Finland in women and from 43%
plasma glucose; TG, triglycerides; BP, blood pressure. (CHRIS) to 78% (Finnish DILGOM study) in men (13).
Interestingly, the prevalence of metabolic syndrome
of healthy obesity and the metabolic syndrome have been among obese was mainly driven by elevated blood
recently investigated in the BioShare-EU project (13). pressure, whereas increased blood glucose contributed
Among 11 465 men and 16 612 women with obesity, age- least to the diagnosis of metabolic syndrome (13).
standardized prevalence of MHO was 12% across all ten The BioShare-EU project also demonstrated that the
cohorts, with great variation between cohorts from prevalence of MHO significantly decreases with age in
different regions in Europe (13). For men, the highest both genders, independent of geographical region and
prevalence of MHO (19%) was found in the CHRIS study the MHO criteria applied (13). The only exception was
from Italy followed by the KORA study (13.5%) from the Italian CHRIS study, in which frequency of MHO
Germany (13). MHO prevalence was in general higher in individuals was relatively constant up to an age of 60 years
women compared with men and could be identified in (13). These data are at least suggestive for the hypothesis
28.4% in the UK NCDS, 23.1% in the Dutch LifeLines, that MHO represents a transient phenotype.
21.8% in the German KORA, and 21.1% in the Italian
CHRIS studies (13). Lowest prevalence of MHO was
Is MHO a fixed or transient phenotype?
identified both for men and women detected in Finnish
cohorts with 2.3–3.6% for men and 7.3–12.3% for women In all cohorts systematically studied for the occurrence of
(13). The greatest gender difference has been found in the MHO, even in the oldest age groups, metabolically healthy
Review M Blüher Metabolically healthy obesity 171:6 R213

obese individuals could be found (13). In obese metabolic diseases (48). The latter hypothesis is supported
individuals, the MHO prevalence was particularly high by the notion that MHO is more frequently observed in
(w8% of the 60 years and older) in a Dutch study (13). pre-menopausal women and changes into metabolically
However, until 2013, there were only a few small and high-risk obesity with increasing age (13, 49).
contradictory prospective studies on the natural course of The transitory nature of MHO over time can be
MHO, and one could speculate whether MHO represents demonstrated using patients’ case examples: from our
a stable phenotype or whether transitions from MHO to own experience, we found metabolic improvements
metabolically high risk obese individuals occur. Recently, toward MHO in a 53-year-old initially extremely obese
the prospective Pizarra study has investigated individual man (BMI: 53.4 kg/m2), who underwent a Roux-en-Y
changes in the diagnosis of MHO over time (47). In 1051 gastric bypass surgery (Fig. 2). This patient initially
study participants, the baseline prevalence of MHO was presented with type 2 diabetes, hypertension, and
3.0–16.9% depending on the applied criteria, but signi- dyslipidemia, but upon weight loss, he ‘gradually’
ficantly changed in the 6 and 11 years follow-up developed MHO defined by different criteria (13). As
reevaluation. Moreover, although MHO individuals had early as 6 months after surgery, the patient could be
a significantly lower risk to develop type 2 diabetes, the categorized as MHO using previously reported less strict
obesity-associated diabetes risk was still significant over criteria, and 12 months after surgery the patient fulfilled
time (47). The authors therefore concluded that the the even more strict criteria for MHO (13) (Table 1). This
concept of MHO as a clinically important entity is case demonstrates the transitory nature of MHO over time,
questionable (47). For individual predictions of obesity- and there are many more examples that over time the
European Journal of Endocrinology

related outcomes, it is still not clear whether MHO MHO phenotype may change into a metabolically high-
maintains their phenotype during the entire life span or risk individual. Supporting the concept that MHO
whether MHO represents a delayed onset of obesity-related represents an intermediate rather than a permanent

BMI: 53.4 kg/m2

FPG: 7.5 mmol/l
HDL: 0.78 mmol/l
TG: 2.41 mmol/l BMI: 44.3 kg/m2
FPG: 6.7 mmol/l
BP: 151/101 mmHg
170 HDL: 1.09 mmol/l
TG: 1.66 mmol/l
160 BP: 138/87 mmHg
BMI: 36.6 kg/m2
MHO FPG: 5.7 mmol/l
HDL: 1.2 mmol/l
Body weight (kg)

less strict
TG: 1.4 mmol/l
140 criteria
BP: 124/82 mmHg BMI: 34.7 kg/m2
130 FPG: 5.5 mmol/l
MHO HDL: 1.31 mmol/l
strict TG: 1.35 mmol/l
120 criteria BP: 129/79 mmHg


Baseline 6 12 24
Months after bariatric surgery

Figure 2
The obesity phenotype changes upon weight loss after could have been diagnosed as metabolically healthy obese
Roux-en-Y gastric bypass surgery. Example of a patient initially (MHO) using previously reported less strict criteria; 12 months
presented with type 2 diabetes, hypertension, and dyslipidemia after surgery, the patient fulfilled even the strict criteria for
who underwent bariatric surgery and gradually developed MHO (13). The case demonstrates the transitory nature of
metabolically healthy obesity defined by different criteria as metabolically healthy obesity over time. FPG, fasting plasma
previously described (13). Six months after surgery, the patient glucose; TG, triglycerides; BP, blood pressure.
Review M Blüher Metabolically healthy obesity 171:6 R214

obesity subphenotype, individuals who have been Preserved insulin sensitivity

classified as MHO at baseline of the West Adelaide Health
Insulin sensitivity defined by euglycemic–hyperinsuline-
Study (50), w30% changed during the study course to an
mic clamps, HOMA-IR, the Matsuda-index, or other
obesity phenotype with high metabolic risk. Interestingly,
parameters has been frequently used in human studies
in this study only those individuals who maintained MHO
to distinguish MHO from metabolically unhealthy
had a significantly lower risk to develop type 2 diabetes
obesity (11, 14). However, the association between
and cardiovascular disease (50). Taken together, the
MHO and reduced cardiovascular risk (21) could not be
diagnosis of MHO at one time point does not (always)
related to differences in insulin sensitivity. We recently
translate into a life-long reduced cardio-metabolic risk,
compared individuals MHO with either insulin sensi-
although maintained MHO is clearly beneficial for
tivity or insulin resistance defined by the glucose
reduced cardiovascular risk (21, 24).
infusion rate during the steady state of an euglycemic–
hyperinsulinemic clamp (cut-off !60 or O70 mmol/kg
Mechanisms underlying the metabolically per min) (38). Confirming other studies (15, 18, 54), we
healthy phenotype found that independent of BMI and total body fat mass,
The MHO phenotype may be caused by several individuals with insulin sensitive MHO had significantly
mechanisms, which have been identified both in human lower visceral and liver but unchanged subcutaneous fat
and animal studies (reviewed in reference (14)), and accumulation (38). In addition, parameters of adipose
include preserved insulin sensitivity, specific fat distri- tissue function were significantly different between the
bution with low visceral and ectopic fat accumulation two MHO subphenotypes. The human insulin sensitive
European Journal of Endocrinology

(including low liver and skeletal muscle fat storage) MHO phenotype closely reflects the healthy obese
compared with subcutaneous fat depots, normal adipose phenotype of ob/ob mice with an experimental over-
tissue function defined by lower adipose tissue infiltration expression of adiponectin (55). A preserved expand-
of immune cells, and normal adipokine secretion pattern ability of subcutaneous adipose tissue may cause lower
as well as high physical activity and fitness (11, 14). visceral and ectopic fat stores and may underlie the
MHO phenotype (55). In another mouse model with an
overexpression of the mitochondrial membrane protein
Physical activity and preserved cardio-respiratory mitoNEET, with an ob/ob background, the subcutaneous
fitness adipose tissue expandability theory has been supported
The individuals’ obesity-associated risk to develop type 2 by the observation that these mice are normal insulin
diabetes and cardiovascular diseases can be reduced by a sensitive despite large subcutaneous adipose tissue
higher fitness level (51). A high fitness level despite being accumulation (56). These animal data are further
obese – a phenotype frequently referred to as ‘fit and fat’ – supported by studies employing pharmacological acti-
is associated with less visceral and intrahepatic fat vation of PPARg by thiazolidinediones. In patients with
accumulation, which could mediate the beneficial effects type 2 diabetes, thiazolidinedione treatment causes
of physical activity (11, 52). Among children, moderate- redistribution of the drug from visceral to subcutaneous
to-vigorous physical activity has been identified as the adipose tissue depots, increased adiponectin serum
strongest predictor of MHO (41). Indeed, in a recent concentrations, decreased liver fat content, and
study, MHO participants have been shown to have a better improved whole-body insulin sensitivity (57).
fitness than metabolically abnormal obese participants
(53). However, physical activity as a single factor may not
Normal adipose tissue function
explain the MHO phenotype entirely, especially because
MHO individuals had a lower risk of all-cause mortality, In addition to adipose tissue distribution, preserved
non-fatal and fatal cardiovascular disease, and cancer adipose tissue function determined by parameters such
mortality compared with metabolically high risk obese as lower adipocyte size, less macrophage infiltration into
patients even after adjusting for better fitness and other adipose tissue, and normal adipokine secretion patterns
confounders (53). High fitness level in MHO may therefore have been identified as contributing factors underlying
only be an indicator for a specific (healthier) lifestyle of insulin sensitivity in MHO (Fig. 3) (38, 55). Changes in the
this obesity subphenotype and does not necessarily adipose tissue biology of insulin-resistant MHO individ-
represent the major mechanism defining MHO (14). uals were accompanied by alterations in adiponectin,
Review M Blüher Metabolically healthy obesity 171:6 R215

Obesity Low visceral and ectopic fat accumulation

Metabolically high risk Metabolically healthy Individuals with MHO are characterized by a distinct fat
distribution with lower visceral fat mass, lower liver fat
and skeletal muscle fat content compared with obese
individuals with higher metabolic risk (12, 14, 15, 38). In
particular, increased liver fat content has been shown to be
independent of obesity and predict the risk of coronary
artery disease (62) and type 2 diabetes (63). The adverse
Visceral fat Visceral fat: normal
Visceral/subcutaneous Visceral/subcutaneous effects of hepatic steatosis may be mediated by
fat ratio fat ratio
Liver fat Liver fat
increased production of molecules including fetuin-A
Skeletal muscle fat Skeletal muscle fat (64) or retinol-binding protein (RBP)-4 (65, 66).

Clinical relevance of MHO

In the future, the diagnosis of MHO may be facilitated
Adipocyte size by recently standardized definitions of this phenotype
AT macrophages
(13). It has been shown that MHO individuals do
not significantly improve the risk for cardiovascular
Figure 3 and metabolic diseases upon weight loss interventions
European Journal of Endocrinology

Potential adipose tissue-related mechanisms underlying meta- (17, 18, 19). With limited healthcare resources, and not
bolically healthy obesity. Individuals with metabolically healthy always successful anti-obesity interventions, it remains
obesity are characterized by lower visceral fat mass, more an important challenge in clinical practice to determine
abdominal subcutaneous fat, lower liver and skeletal muscle which obese patient will benefit the most from different
fat, smaller adipocytes, and less macrophage infiltration of interventions. The concept of MHO became more
visceral adipose tissue compared with patients with high clinically relevant with recent data showing that
metabolic risk obesity. MRI scans of the abdominal region at individuals with MHO are not at increased risk for
L4 (pictures are taken with permission from Matthias cardiovascular diseases compared with healthy normal-
Raschpichler). Histological slides of omental adipose tissue from weight controls (21). It is therefore surprising that
either metabolically healthy or high risk obese individuals current guidelines for obesity treatment are mainly
(defined by the criteria in reference (13)). AT, adipose tissue. based on BMI and measures of body fat distribution
including waist circumference, and still do not dis-
tinguish between MHO and metabolically unhealthy
progranulin, chemerin, RBP4, fetuin-A, and DPP4 serum obese individuals and recommend lifestyle intervention
concentrations (38). Interestingly, the adipose tissue- for all obese individuals (10, 11). In clinical practice,
related mechanisms which may underlie the MHO additional stratification of obese individuals according to
phenotype are consistent across animal and human their metabolic and cardiovascular comorbidities (10, 13)
studies (38, 58). would provide a better guidance for individual decision
Importantly, we and others (59) have identified making (10). In post hoc analyses of the Swedish Obese
inflammation of visceral adipose tissue as the strongest Subjects study, BMI at baseline was not sufficient to
predictor of insulin-sensitive MHO (38). Increased predict the effectiveness of bariatric surgery on morta-
immune cell infiltration of visceral adipose tissue may lity, cardiovascular disease, type 2 diabetes, or cancer
reflect additional mechanisms contributing to MHO, (65, 66, 67). However, inclusion of baseline fasting
which have not been recognized previously. Such insulin concentrations – a surrogate parameter for
mechanisms may include accumulation of lipophilic insulin resistance – suggested that those individuals
food contaminants and endocrine disruptors (60) in with higher baseline values benefit more from the
visceral depots and could reflect a specific nutritional intervention with respect to reduced mortality and
behavior, but could also be the result of a specific incidence of type 2 diabetes (67).
microbiome environment in individuals with MHO (61). Patients with metabolically unhealthy obesity clearly
Further studies are necessary to test these hypotheses. benefit from lifestyle interventions (17, 18, 19), but
Review M Blüher Metabolically healthy obesity 171:6 R216

whether similar effectiveness of non-surgical anti-obesity MHO have an increased risk for the development of heart
treatment strategies can be expected for MHO individuals failure despite significantly lower risk of cardiovascular
is controversial (10, 11). In a previous study, MHO disease (21). This suggests that obesity itself may be
individuals did not significantly benefit from a structured more important than metabolic alterations for the
9-month lifestyle intervention program with regard to development of heart failure (21). However, to more
improvements in cardiometabolic risk parameters (16). precisely answer the question whether MHO individuals
In contrast, other interventions including lifestyle modifi- are really healthy, systematic studies on co-morbidities
cations (20) and bariatric surgery (68) led to improved of obesity other than metabolic and cardiovascular
cardio-metabolic risk factors in MHO. In another lifestyle disorders are necessary.
intervention, only metabolically high risk but not MHO
participants significantly improved insulin sensitivity
upon weight loss (16). These data highlight the import-
ance of stratification systems taking MHO into account.
A simple clinical and functional staging system, the The concept of MHO has recently gained much clinical
so-called Edmonton obesity staging system (EOSS), that relevance with novel prospective study data that individ-
allows clinicians to describe the morbidity and functional uals with MHO are not at increased risk of acute
limitations associated with excess weight has been myocardial infarction compared with metabolically
previously proposed (10, 69, 70). The EOSS staging system healthy normal-weight individuals (21). Importantly,
independently predicted increased mortality even after individuals with MHO may not improve their obesity-
adjustment for contemporary methods of classifying
European Journal of Endocrinology

related metabolic and cardiovascular risks by lifestyle

obesity (70). The clinical use of more sophisticated obesity changes, pharmacological, or bariatric surgery-induced
stratification systems seems to be particularly important weight loss (14). Previous criteria to define MHO were not
in the decision making for bariatric surgery (71). The standardized, but with a recent large-scale harmonization
risk:benefit ratio of bariatric surgery in MHO individuals effort, definition and diagnosis of MHO may be easier in
has so far not been systematically determined. future clinical practice (13). There is a need for person-
alized anti-obesity intervention strategies, which should
Are metabolically healthy obese consider metabolically high-risk obese patients who may
really ‘healthy’? benefit more from earlier interventions than MHO
individuals. As MHO seems to be a transient subpheno-
BMI alone or any anthropometric marker of adiposity do type, anti-obesity treatment strategies even leading to
not provide measurements of functionality, quality of life,
an only moderate weight loss may reverse metabolically
or other prognostic contextual factors that may further
unhealthy into healthy obesity. Until now, guidelines for
characterize clinical risk and guide clinical management
obesity treatment should consider distinct obesity sub-
(10, 71). ‘Health’ is defined by the WHO as ‘. a state
phenotypes such as the distinction between MHO and
of complete physical, mental, and social well-being and
metabolically high-risk obesity for a stratification of
not merely the absence of disease or infirmity’ (WHO,
therapeutic strategies.
Constitution of WHO:
definition/en/print.html). The presented transient MHO
case (Fig. 2) may therefore serve as an example that
Declaration of interest
‘metabolically healthy’ does not necessarily mean The author declares that there is no conflict of interest that could be
‘healthy’ obese. Although during the course of weight perceived as prejudicing the impartiality of the review.
loss this patient fulfilled the criteria of MHO, chronic pain
due to osteoarthritis in both knees remained a significant
impairment of his well-being. Quality of life of obese Funding
This research did not receive any specific grant from any funding agency in
individuals, including those fulfilling the criteria of
the public, commercial or not-for-profit sector.
MHO, is impaired by a number of psychological and social
factors, osteoarthritis, chronic pain, pulmonary disease,
cancer, and other conditions (7). Moreover, it is question-
Author contribution statement
able whether MHO individuals stay healthy (48, 50). M Blüher researched data and literature, wrote the manuscript and
In this context, it has been shown that individuals with evaluated patient cases included in this manuscript.
Review M Blüher Metabolically healthy obesity 171:6 R217

17 Shin MJ, Hyun YJ, Kim OY, Kim JY, Jang Y & Lee JH. Weight loss effect
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Received 30 June 2014

Accepted 10 July 2014
European Journal of Endocrinology