Jan Willem Elte, The Netherlands
Obesity is one of the most devastating disorders of the present time and its preavalence is rapidly rising. Obesity is a heterogenous condition with multiple different phenotypes. Metabolically unhealthy obesity (MUO) carries a large number of adverse metabolic changes , but metabolically healthy obesity (MHO) is considered to display a relatively favorable metabolic profile.
A recent comprehensive review article in the European Journal of Internal Medicine (Tanriover et al Eur J Int Med 111 (2023), 5-20) provides a good overview of the problem and will be summarized in this newsletter. The format of the article will be followed.
Although MHO is considered to display a relatively favorable metabolic profile, it is still associated with a number of chronic diseases and has the potential risk of progression into the unhealthy phenotype. Therefore, it should not be considered as an entirely benign or “healthy” condition.
Definition
A first problem is the definition, as there are more than 30 different definitions of MHO available. The most commonly used definitions of MHO define it as the absence of any metabolic as well as cardiovascular (cv) disorder in an obese individual (BMI ≥ 30 kg/m²), including hypertension, type 2 diabetes, dyslipidemia and atherosclerotic cardiovascular disease (ascvd). A consensus definition should be reached.
The prevalence
The prevalence of MHO in 55 studies showed a great variation with an estimated prevalence ranging between 6 and 75%. There is also variation by gender. In general, MHO is more frequent in females than in males, in younger ages than in increased age, in BMIs lower than 35 kg/m² and in individuals with European ancestry than in South Asian, African and South American ancestry.
The progression of MHO
MHO is now considered to be a transient state of metabolic health. Around a third to a half of the individuals with MHO eventually progresses to the metabolically unhealthy state (MUO). Determinants of progression to MUO are: a higher BMI, waist-to-hip ratio and waist circumference. Also increased visceral adiposity, elevated fasting insulin values and a decreased HDL cholesterol at baseline, are related to risk of progression. Protective factors against the transition are: having a healthy lifestyle and diet with an increased level of physical activity and avoiding smoking.
Pathophysiology
Adipose tissue consists of a biologically active group of cells. Visceral adipose tissue (VAT), found throughout the internal organs, is responsible for insulin resistance and adverse cardiometabolic effects (dyslipidemia, glucose intolerance and hypertension). In the MUO group there is an extensive accumulation of VAT, whereas VAT is decreased and the less dangerous subcutaneous adipose tissue (SAT) is increased in the MHO group, resulting in a similar BMI in both groups, but a different cardiometabolic profile.
Many hormones – some are called adipokines – are involved in the pathogenesis of obesity and its consequences.. Therefore they are now in use as therapeutics (see below). Some of the adipokines are similar in those individuals with MHO and MUO, some differ.
Low-grade inflammation, especially in adipose tissue, plays a critical role in the development of obesity-associated disorders. In MUO individuals inflammatory markers are higher than in MHO persons.
The pathophysiology of obesity also has a genetic element, although it is not regarded as a genetic disease. Further studies are needed.
The clinical significance of metabolically healthy obesity
MHO has been associated with non-communicable diseases including atherosclerotic disease such as CVD, cerebrovascular disease and peripheral artery disease, hypertension, type 2 diabetes, various types of cancer and chronic kidney disease. A meta-amalysis found that individuals with MHO had a sinificantly increased risk of developing cardiovascular diseases compared to metabolically healthy normal (MHNW) subjects. There is no association with heart failure, but the risk of major vascular events, including stroke is increased. CVD incidence in the MHO group was apparent only after 10 years in their cohort and only in those who transitioned into the metabolically unhealthy state. MHO thus seems to be a transitional state.
The challenges in the management of metabolically healthy obesity
The major therapeutic alternatives include dietary modifications, exercise, bariatric surgery and medications such as glucagon-like-peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. Beneficial effects of GLP-1 analogs such as liraglutide, exenatide and semaglutide on body weight have been demonstrated. They also decrease liver fat content. Empaglifozine, a SGLT-2 inhibitor, has been linked with weight loss with a decline in visceral adipose tissue and liver fat content. Dapaglifozine also has a beneficial effect on body weight. Tirzepatide, acting as an agonist to GLP-1 and GIP, has beneficial effects in terms of weight reduction, lowering serum HbA1,c, fall in in liver fat content, decline in body fat percentage and improvement in metabolic parameters such as serum triglyceride, cholesterol, lipoprotein levels.
Conclusion
MHO is associated with chronic diseases such as cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease , certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore MHO should not be considered as a benign condition. Management strategies exist of lifestyle modifications, exercise, bariatric surgery and certain medications. MHO requires a consensus definition. Further studies are needed.
In a later short comment in the Eur J Int Med by Sbraccia it is argued that MHO might be a misleading term. Obesity /MHO independently of any cardiometabolic abnormalities, leads to an increased risk of heart failure with all the associated CV complications. These data warrant to ban the use of MHO definition in the clinical setting. Obesity, encompassing all its severity range, is always a very unhealthy condition. Metabolically healthy obesity (MHO) exists, but it is a temporary condition that does not allow to presage any good.
(https://doi.org/10.1016/j.ejim.2023.05.003 Received 28 April 2023; Accepted 2 May 2023)
