Metabolically-healthy Obese (MHO): contentious unicorns?

by Wei Perng, PhD

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Obesity is one of the greatest current public health concerns, as it is a major risk factor for metabolic diseases like type 2 diabetes, cardiovascular disease, and metabolic syndrome, which is a cluster of risk factors that raises risk for heart disease and other health problems.

There are several distinct and overlapping pathways linking obesity to these disorders, including insulin resistance (when the body’s cells fail to respond to insulin), altered lipid levels (lower high-density lipoprotein [HDL], the “good cholesterol,” and higher low-density lipoprotein HDL, the “bad” cholesterol), and chronic inflammation. Higher body mass index (BMI, or weight divided by height squared, expressed as kg/m2) is an indicator of overall body size that generally corresponds with a worse metabolic profile. This makes sense considering that being heavier typically correlates with having more fat mass or adipose tissue, which actually functions as an endocrine organ capable of secreting biologically active molecules that could interfere with normal physiological processes. However, researchers have recently uncovered a subgroup of individuals with normal metabolic profiles, despite being overweight (BMI ≥25 kg/m2) or obese (BMI ≥30 kg/m2). Known as metabolically healthy obese (MHO), these metabolic unicorns have spurred interest in the scientific community for two reasons. First, because clinicians often use weight status as a “first pass” to identify at-risk persons for further metabolic assessment, existence of the MHO phenotype would have important implications for the use of BMI to identify high-risk persons. Second, understanding physiological differences between the metabolically healthy obese and metabolically unhealthy obese (MUO) will provide insight into etiological pathways of metabolic disease.

Hold the hype. While some studies show that MHO are at lower risk for cardiovascular events and mortality compared to MUO, and are not at risk compared to normal weight (BMI ≥18.5 and <25 kg/m2) individuals (e.g. Appleton et al. 2013, Hamer et al. 2012, Durward et al. 2012), there is now contradictory evidence from original research (e.g. Thomsen et al. 2014, Aung et al. 2014) as and a recent meta-analysis (Bell et al. 2014) that MHO are still at greater risk for diabetes and cardiovascular events than normal weight persons. What might explain the inconsistencies?

Lack of consensus on MHO definition. There are currently 5 working definitions of what it means to be metabolically healthy obese. Consequently, the prevalence of MHO varies from 20 to 30% of obese patients, depending on the definition used:

  -  Lack of metabolic syndrome: Metabolically healthy based on the absence of metabolic syndrome using the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) or the International Diabetes Federation criteria for Metabolic Syndrome (MetS). The NCEP-ATPIII define MetS as exhibiting 3 or more of the following: increased waist circumference (>102 cm for men and >88 cm for women), altered lipid levels (≥150 mg /dL, HDL <40 for men or <50 mg/dL for women), elevated blood pressure (≥135/85 mmHg), and impaired fasting glucose (≥100 mg/dL).

  - Insulin sensitivity: Normal insulin function as assessed by the homeostatic model assessment of insulin resistance (HOMA-IR), an index that takes into account fasting insulin and fasting glucose levels.

  - Karelis criteria: a combination of MetS cut-offs in conjunction with C-reactive protein (CRP), a measure of inflammation     

  - Scoring in the 4th quartile of the Matsuda index, which evaluates insulin sensitivity using results from a 75-gram oral glucose tolerance test (OGTT).

  - Wildman criteria: Having no more than 1 of the following metabolic abnormalities: triglycerides ≥1.7 mmol/L, SBP/DBP ≥130/85 mmHg, fasting glucose: ≥5.6 mmol/L, HOMA-IR >90th percentile, CRP >90th percentile, HDL <1.3 mmol/L

As you can see, these definitions use different components and cut-off values to define “metabolically healthy.”  Further, some of these cut-points are population-specific (e.g. being in the 4th quartile of an index score), making it difficult to translate across different populations.

MHO may be a transient state. Earlier this summer, I attended a lecture by Dr. Frank Hu, Professor of Nutrition and Epidemiology at the Harvard School of Public Health, on obesity and physical inactivity. In addition to emphasizing the fact that the standard definition of obesity using a BMI cut-off does not always equate to excess fat mass (“NFL linemen likely don’t need to lose weight”), Dr. Hu cautioned against trivializing obesity, since the MHO state may be transitory in nature. Most studies assessing MHO status have done so at a single point in time. However, with changes in lifestyle and normal aging processes, metabolically healthy obesity can morph into its evil twin, MUO.

So, what is the take home message? Obesity, whether it is the metabolically-healthy kind or not, is likely not a healthy state because it can harm more than just metabolism. For example, excess adiposity can damage weight-bearing joints, leading to debilitating conditions like osteoarthritis. Obesity is also linked to poor psychological well-being, sleep apnea,  allergies, and development of several cancers.  And even using the broadest definition of MHO, most obese individuals (70% or more) are not metabolically healthy. In the end, a healthy diet and a physically active lifestyle are still the most important points to emphasize.