Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications

doi:10.1016/S2213-8587(13)70062-7

The Lancet Diabetes & Endocrinology

Volume 1, Issue 2, October 2013, Pages 152-162

https://doi.org/10.1016/S2213-8587(13)70062-7 Get rights and content

Summary

Obesity has become a worldwide epidemic that poses substantial health problems for both individuals and society. However, a proportion of obese individuals might not be at an increased risk for metabolic complications of obesity and, therefore, their phenotype can be referred to as metabolically healthy obesity. This novel concept of metabolically healthy obesity might become increasingly important to stratify individuals in the clinical treatment of obesity. However, no universally accepted criteria exist to define metabolically healthy obesity. Furthermore, many questions have been raised regarding the biological basis of this phenotype, the transitory nature of metabolically healthy obesity over time, and predictors of this phenotype. We describe the observational studies that gave rise to the idea of metabolically healthy obesity and the key parameters that can help to distinguish it from the general form of obesity. We also discuss potential biological mechanisms underlying metabolically healthy obesity and its public health and clinical implications.

Introduction

The health consequences of obesity are well documented. In particular, the worldwide increase in the incidence of type 2 diabetes, cardiovascular disease, and several types of cancer is thought to be largely attributed to the obesity epidemic.1, 2, 3, 4 Therefore, prevention and treatment of obesity to reduce risk of chronic diseases at the population and individual level is crucial. Although the deleterious metabolic effects of obesity are widely recognised at population level, individual differences exist in metabolic responses to obesity. Findings from many studies show that a subgroup of obese individuals might be protected from metabolic complications of obesity or might be at substantially lower risk than expected for their degree of obesity. This subgroup has been described as having metabolically healthy obesity.5, 6, 7, 8, 9 Many questions have been raised regarding the biological basis, transitory nature, and predictors of metabolically healthy obesity.

Findings from epidemiologic studies have shown that increased waist circumference is associated with mortality and cardiovascular disease independent of overall adiposity.4, 10 Additionally, data from several small studies suggested that some obese people are not insulin resistant.5, 11, 12, 13 This finding was unexpected, because generally, a strong positive association exists between body-mass index (BMI) and insulin resistance. Insulin resistance is thought to represent one of the most important pathomechanisms of metabolic diseases and also of certain types of cancer.14, 15 In addition to body fat distribution and insulin resistance, other metabolic risk factors might also be useful in the characterisation of metabolically healthy obesity in view of their well-established association with risk, including lipid profiles, blood pressure, inflammation, or physical fitness.

In this Personal View we describe observational data that gave rise to the idea of metabolically healthy obesity. We then discuss the key parameters that might help to distinguish metabolically healthy obesity from the general form of obesity, such as smaller waist circumference, increased physical fitness, decreased insulin resistance, and low prevalence of metabolic risk factors despite a high BMI. We also discuss potential biological mechanisms underlying this phenotype and its clinical implications.

Section snippets

Observational data supporting the idea of metabolically healthy obesity

Individuals with metabolically healthy obesity are a subset of individuals who meet the standard BMI cutoff point for obesity (≥30 kg/m²), but are regarded as metabolically healthy because they do not have other major cardiovascular risk factors (figure 1). This subgroup is believed to be at much lower risk of cardiovascular morbidity and mortality compared with obese individuals with major cardiovascular risk factors, who can consequently be judged as being metabolically at risk or

Findings from animal studies

To identify mechanisms underlying adiposity-mediated metabolic diseases in human beings, data from animal studies need to be considered. In such studies, predominantly genetic modification of animals allows precise investigation of the interplay of metabolically relevant tissues and molecular signalling pathways. Three rodent models have provided important information about the protective effects of the expansion of adipose tissue on metabolism. The most compelling evidence that metabolically

Findings from human studies

Consistent with data from animal studies, obese individuals also have different fat distribution patterns that are related to distinct metabolic phenotypes.8, 40 Large differences can be seen in skeletal muscle and, predominantly, in liver fat content (figure 3).⁸ Liver fat content is substantially associated with insulin sensitivity, and much more so than visceral fat mass.8, 41, 42, 43, 44 Furthermore, liver fat content, but not visceral fat mass, was independent of atherosclerotic risk

Effectiveness of interventions in metabolically healthy obesity

In view of the magnitude of the obesity epidemic, stratification of obese individuals, in terms of their risk for obesity-related metabolic diseases, becomes more important for prevention and treatment purposes. Scarce resources can be more effectively used among those at risk; various prevention and treatment strategies can be very expensive and time consuming. Therefore, an important question is whether metabolically healthy obesity is indeed a concept allowing the discrimination of obese

Clinical and public health implications

The lack of a standard definition of metabolically healthy obesity makes it unclear how the concept of metabolically healthy obesity can be incorporated into clinical practice. Nevertheless, clinicians need to carefully assess the metabolic status of obese people to devise strategies to reduce their risk of cardiovascular disease, mortality, and possibly cancer incidence. This reduction can be achieved with a measurement of the waist circumference, to provide an assessment of the body fat

Conclusions

The idea of metabolically healthy obesity is not new, but the concept has only recently been widely recognised in the discipline. Insufficient standard criteria to define metabolically healthy obesity and the largely unknown biological mechanisms are barriers to the application of the metabolically healthy obesity phenotype to clinical practice. Nonetheless, this idea underscores the need to consider other metabolic and anthropometric parameters in addition to BMI. This concept might be used in

Search strategy and selection criteria

We searched PubMed for full-text original studies and review articles written in English between Jan 1, 1990, and May 31, 2013, to identify reports on metabolic parameters and mortality in obese people. The search terms used were “metabolically healthy obesity”, “metabolically benign obesity”, “metabolic syndrome”, “insulin sensitivity”, “insulin resistance”, “fitness”, “bariatric surgery”, and “lifestyle intervention” together with “mortality”. The reference lists of the identified papers were

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Personal ViewMetabolically healthy obesity: epidemiology, mechanisms, and clinical implications

Summary

Introduction

Section snippets

Observational data supporting the idea of metabolically healthy obesity

Findings from animal studies

Findings from human studies

Effectiveness of interventions in metabolically healthy obesity

Clinical and public health implications

Conclusions

Search strategy and selection criteria

Lancet

Lancet

Metabolism

Am J Clin Nutr

Mayo Clin Proc

Mol Aspects Med

Atherosclerosis

Trends Endocrinol Metab

Lancet Oncol

Adiposity as compared with physical activity in predicting mortality among women

N Engl J Med

Global obesity: trends, risk factors and policy implications

Nat Rev Endocrinol

General and abdominal adiposity and risk of death in Europe

N Engl J Med

Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals: effect of differences in insulin sensitivity

Arch Intern Med

Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease

J Clin Endocrinol Metab

Identification and characterization of metabolically benign obesity in humans

Arch Intern Med

The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004)

Arch Intern Med

Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies

Lancet

Metabolic and body composition factors in subgroups of obesity: what do we know?

J Clin Endocrinol Metab

All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals

Diab Vasc Dis Res

Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis

Science

Insulin signalling and the regulation of glucose and lipid metabolism

Nature

Waist circumference as compared with body-mass index in predicting mortality from specific causes

PLoS One

High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease

Gut

Are metabolically normal but obese individuals at lower risk for all-cause mortality?

Diabetes Care

Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men

Circulation

Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: the Cremona Study

Diabetes Care

All-cause mortality risk of metabolically healthy obese individuals in NHANES III

J Obes

Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter?

Diabetes Care

Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men

JAMA

Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study

Am J Epidemiol

Cardiorespiratory fitness and adiposity as mortality predictors in older adults

JAMA

Cardiorespiratory fitness, adiposity, and all-cause mortality in women

Med Sci Sports Exerc

The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness

Eur Heart J

Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study

Circulation

Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality

J Clin Endocrinol Metab

Higher mortality in metabolically obese normal weight people than in metabolically healthy obese subjects in elderly Koreans

Clin Endocrinol (Oxf)

Letter by Stefan et al regarding article, “Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men”

Circulation

Personal View
Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications