|Year : 2023 | Volume
| Issue : 1 | Page : 1-6
Metabolically Healthy Obesity: An Eye-opener
Purushothaman Padmanabhan, Nagendram Dinakaran, Somnath Verma, S Keerthana
Department of Medical Gastroenterology, Meenakshi Medical College Hospital and Research Institute, Kancheepuram, Tamil Nadu, India
|Date of Submission||29-Nov-2022|
|Date of Acceptance||29-Nov-2022|
|Date of Web Publication||28-Dec-2022|
Department of Medical Gastroenterology, Meenakshi Medical College Hospital and Research Institute, Kancheepuram - 631 552, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Obesity is a global public health problem. Obese persons are likely to develop complications like degenerative joint diseases, diabetes mellitus, dyslipidemia, cardiovascular diseases, fatty liver,cancer of esophagus and pancreas resulting in reduced life expectancy, poor quality of life and burden to economy. A subset of obese subjects does not develop metabolic abnormalities and they are described as metabolically healthy obese (MHO). This entity is a debatable one, and not well accepted. Here we review the merits and demerits of MHO. This is a narrative review and we have not applied advanced statistical procedures. The review articles by Stefan, Bluher and the cross-references are widely quoted in this article. Apart from this, we collected full-text articles from “PubMed,” and “ClinicalKey” platforms using the search term “Metabolically healthy obesity.” As evident in the literature, MHO is a significantly prevalent condition (10%–20%) with wide variation depending on the criteria used. This condition is subject to conversion to unhealthy with risk for development of cardio-metabolic abnormalities like diabetes and DL. The impact of intervention is remarkable but equivocal. MHO should not be considered a safe condition. The transit nature of MHO offers an opportunity for intervention. MHO is an eye-opener for future research.
Keywords: Metabolically healthy obesity, obesity-metabolic abnormalities, stable obesity-pathobiology and obesity
|How to cite this article:|
Padmanabhan P, Dinakaran N, Verma S, Keerthana S. Metabolically Healthy Obesity: An Eye-opener. Gastroenterol Hepatol Endosc Pract 2023;3:1-6
|How to cite this URL:|
Padmanabhan P, Dinakaran N, Verma S, Keerthana S. Metabolically Healthy Obesity: An Eye-opener. Gastroenterol Hepatol Endosc Pract [serial online] 2023 [cited 2023 Jan 27];3:1-6. Available from: http://www.ghepjournal.com/text.asp?2023/3/1/1/365725
| Introduction|| |
Obesity is a global public health problem
Worldwide obesity has nearly tripled since 1975. We give the summary extracted from World Health Organization (WHO) fact sheet as such so that readers can appreciate the problem. “In 2016, more than 1.9 billion adults, 18 years and older were overweight. Of these over 650 million were obese. 39% of adults aged 18 years and over were overweight in 2016 and 13% were obese. Most of the world's population live in countries where overweight and obesity kills more people than underweight. 39 million children under the age of 5 were overweight or obese in 2020. Over 340 million children and adolescents aged 5–19 were overweight or obese in 2016. Obesity is preventable.” Though it appears to be a problem of this century, obesity and its ill effects were appreciated in ancient time. The primitive art available from the Paleolithic age shows evidence of human obesity. Hippocrates also mentioned this condition and warned society against obesity and its ill effects. The low- and middle-income group countries share the major burden of obesity. These countries are already burdened by underweight, malnutrition, and infectious diseases. India is in no way an exception. ICMR-INDIAB collaborative study conducted between 2008 and 2010 with 14,277 participants revealed the prevalence of general obesity (GO) as 24.6%, 16.6%, 11.8%, and 31.3% in Tamil Nadu, Maharashtra, Jharkhand, and Chandigarh centers, respectively. Abdominal obesity (AO) was found in 26.6%, 18.7%, 16.9%, and 36.1%, combined obesity (CO) in 19.3%, 13.0%, 9.8%, and 26.6%, and overweight in 15.2%, 11.3%, 7.8%, and 15.9% in the respective centers. The study found a higher prevalence among urban population and risk factors were female gender, hypertension, diabetes mellitus (DM), high socioeconomic status, and physical inactivity. Age was related to AO and CO and not with GO. This study was confined only to four centers which limited its generalization. But the prevalence is high. National Family Health Survey-5 reported that the proportion of women and men between the age of 15 and 49 years, who were overweight or obese (body mass index [BMI] ≥25 kg/m2 in women and men) had increased across nearly all states except Gujarat and Maharashtra. The prevalence of obesity was 33.2% in urban women, 19.7% in rural women, 24% in all women, 29.8% in urban men, 19.3% in rural men, and 22.9% in all men. The data from India on metabolic syndrome/metabolic abnormalities is also alarming. Kamble P study showed a prevalence of metabolic syndrome as 5% in rural population in the region of Wardha applying NCEP-ATP III (National Cholesterol Education Programme-Third Adult Treatment Panel) Criteria with Asia Pacific Guidelines. This is in contrast to Dasgupta study from Kolkata (urban center) stating the overall prevalence of 44.6% (35.4% in males and 55.6% in females). Selvaraj I study reported a prevalence of 30.7% as per NCEP-ATP III criteria and 36% as per modified NCEP-ATP III criteria among rural women in South India, Tamil Nadu. Obesity is linked to many disorders. Obesity is a risk factor for DM, dyslipidemia (DL), cardiovascular diseases (CVD), degenerative joint diseases, gastroesophageal reflux disease, fatty liver, various cancers like colorectal cancer, esophageal carcinoma, and pancreatic cancer., The effect of obesity can be classified as mechanistic related, e.g., osteoarthritis, and metabolic related, e.g., DM. Obesity contributes to reduced life expectancy, impaired quality of life, and disabilities. The health burden and subsequent economic fall-out is enormous. From the social aspect obese persons are stigmatized because of its cosmetic effect and this prevents them to seek medical help early. The World Federation of Obesity defined obesity itself as a disease. It is a chronic remitting and relapsing disease. Obesity is considered an inflammatory condition. The reduction of cardiometabolic complications and improved quality of life with management of obesity was enlightened by many studies.
| Obesity is Not Increased Body Mass Index Alone|| |
Obesity is defined as “abnormal or excessive fat accumulation that presents a risk to health.”
BMI is a simple index of weight for height that is commonly used to classify overweight and obesity in adults. It is defined on a person weight in kilograms divided by the square of his height in meters (kg/m2). For adults WHO defines overweight as BMI ≥25 kg/m2 and obesity BMI ≥30 kg/m2. BMI between 18.5 and 24.9 kg/m2 is considered healthy body mass and <18.5 kg/m2 is considered underweight or lean. WHO child growth percentile charts are available for children and adolescents. BMI is a commonly used, simple bedside measure of obesity. It is a good instrument for epidemiological studies. It is useful for population-level measure of overweight and obesity as it is the same for both sexes and for all ages of adults. In case of muscular people especially athletes, its role becomes questionable. BMI does not give a measure of body fat mass and BMI does not distinguish weight associated with muscle and fat. Many types of investigations are available now to find out lean body mass. Dual-energy X-ray absorptiometry, plethysmography, and bioelectric impedance are few examples. BMI also does not distinguish body fat distribution. Fat distribution i.e., visceral (truncal/central) obesity can predict the development of metabolic syndrome and its attended diseases than peripheral distribution (android and gynecoid type). This can be inferred by waist circumference measurement or waist: hip ratio and waist: height ratio. Insulin sensitivity and its measurement is also advocated and it is a risk factor for cardiovascular events. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is widely used in predicting cardiometabolic risks. Magnetic resonance imaging and computerized tomogram (scan) have also come into practice for determination of obesity. Assessment of physical fitness also occupies an important role in the evaluation of cardio-metabolic risk. Measurement of inflammatory markers, e.g., C-reactive protein (CRP) is also used in clinical research to predict cardiometabolic risk.
| Concept of Metabolic Healthy Obesity (MHO)|| |
The concept of metabolically healthy obesity (MHO) is derived from the observation that there are people with obesity who do not develop cardiometabolic complications at a given point of time. As early as the 1950s, Jean Vague observed that individuals with obesity have a different predisposition to cardiac and metabolic complications which will be related to body adipose tissue distribution. WHO definition of health is “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.” This topic happens to be debatable with conflicts and contradiction. The term MHO, also described as “obesity paradox” throw the question whether it represents a healthy state or a disease. This novel concept had gained momentum from 2010 and resulted in large volume of literature with varying results. There is no universally accepted definition resulting in inconsistency results from studies. The general consensus is BMI ≥30 kg/m2 is considered obesity and MHO can be defined by the absence of any cardiometabolic disorders like DM, DL, hypertension or CVD. An individual who with standard BMI cutoff point for obesity (≥30 kg/m2) can be considered having MHO with the following criteria. (1) Absence of AO on the basis of waist circumference. (2) Absence of components of metabolic syndrome, e.g., normal blood pressure, normal lipid values, normal fasting blood glucose concentration. (3) Insulin sensitivity on the basis of (HOMA-IR). (4) High level of cardiorespiratory fitness. The cutoff for waist circumference varies from population to population. It is ≤102 cm in men and ≤88 cm in women for the USA (ATP III value). The waist circumference of ≤90 cm for men and ≤80 cm for women is followed for South Asians based on a Chinese, Malay and Asian– Indian population. For Europids, the value is ≥94 cm for men and ≥80 cm for women. The criteria for metabolic syndrome are variable. International Diabetic Federation consensus statement and National Cholesterol Education Programme – Third Adult Treatment Panel III (NCEP-ATP III) criteria are widely used.
The heterogeneity of definition and criteria are the limiting factors in interpretation of studies. The studies report wide difference regarding the association between MHO and cardiometabolic abnormalities and this results in difficulty in drawing conclusion and recommendation. There are definitions of MHO which use parameters like insulin sensitivity, HOMA-IR, and systemic inflammation (CRP). This subgroup is documented to be at much lower risk for cardiovascular morbidity and mortality compared with obese persons with major cardiometabolic abnormalities or metabolically unhealthy obese (MUO). At the same time subjects with underweight or lean, developing metabolic abnormalities and increased risk for CVD is also an issue supported by many studies.
| Prevalence|| |
Since there is a lack of standardized definition of MHO, there is wide variation in reporting the prevalence of MHO among studies. There is a reasonable conclusion that the prevalence of MHO various between 5% and 45%. [Table 1] gives prevalence as reported by few studies. The variation in the prevalence and significant prevalence in children is a notable feature.
|Table 1: Studies of prevalence and epidemiology of metabolically healthy obese|
Click here to view
| MHO and Risk of Metabolic Abnormality|| |
By MHO, it is meant to be a benign condition and few studies substantiate this concept. But large body of evidence is against this benign nature. MHO is also linked to metabolic abnormalities like DM, DL, and cardiovascular risk but not to the extend as MUO. It is a dynamic state and at least 2/3 of subjects can become MUO over a period of time. This conversion from MHO to MUO is not unidirectional and MUO can revert to MHO, especially with intervention. MHO transforming into MUO is labeled as transient or unstable MHO and MHO which do not transform as stable MHO. [Table 2] shows some of the studies reporting the transit nature of MHO.
| Risk of Diabetes Mellitus in MHO|| |
MHO is related to a significantly lower incidence of DM and CVD compared to MUO. Large epidemiological data shows contradictory results showing MHO at higher risk of CVD, type 2 (T2 DM)., The review by Bell J. A. concluded that MHO subjects showed a substantially increased risk (relative risk [RR] of 4.03) of developing T2DM compared to MHNW. The RR for MHO exceeded one in every study, indicating a consistently increased risk across study population.
| Impact of Intervention in MHO|| |
It is well established that MHO is transitory in nature and more than half of MHO transform into MUO. Transit or unstable MHO who convert to MUO has a greater risk of development of cardiometabolic abnormalities than stable MHO who remains metabolically healthy but obese. There is no definite way to predict the conversion. The management of obesity consists of lifestyle changes, pharmacotherapy, and bariatric surgery including bariatric endotherapy. There is a tremendous advance in every field with documents of evidence. Lifestyle changes that are diet, physical activities, and behavioral therapy result in 3%–10% of weight loss with reduction of morbidity around 8%–10%. But, the weight loss is ill sustained, difficult to maintain with resultant weight regain. Hence, bariatric surgery is advocated which can result in sustained weight loss up to 20% with considerable reduction in morbidity and mortality. The improved quality of life and physical fitness can sustain over 2–5 years on follow-up. Bariatric surgery also results in improvement of metabolic status. The reversion of glucose intolerance and DM is remarkable after bariatric surgery and this can be explained by the metabolic normalization with bariatric surgery. Kantartzis studied 9 months of lifestyle intervention in MHO group with and without insulin resistance. He concluded that insulin sensitivity improved in both groups but the improvement in MHO Insulin Resistance group did not reach a level that will protect MHO from development of DM or CVD complications. Janiszewshi study involved lifestyle intervention in the form of energy-restricted diet or exercise in selected men and women and showed weight loss, reduction in total and AO with improvement in selected cardio-metabolic risk factors. In MHO men and women, insulin sensitivity improved by 22% and 18.5%. This was in contrast to a study by Karelis which showed modest weight reduction achieved by caloric restriction resulted in a 13% deterioration in insulin sensitivity among a group of postmenopausal women (cross-reference; full text not available). Sjostrom reported weight loss in Swedish obese subjects after bariatric surgery followed up period varying from 10 to 20 years. Apart from weight loss and overall reduction of mortality rate, decreased incidence of DM (HR: 0.17), myocardial infarction (HR: 0.71), stroke (HR: 0.66), and cancer in women (HR: 0.58) were noted. The diabetes remission risk was increased several folds – OR: 8.12 at 2 years and OR: 3.45 at 10 years. This study was criticized since the number needed to treat is high i.e., 55. Most of the studies used insulin resistance and reported the fasting insulin concentration at baseline was significantly related to the effectiveness of intervention. This makes one to think that management of obesity is beyond weight reduction and the metabolic abnormalities need special mention in obesity management.
| Metabolic Healthy Obesity – Pathobiological Consideration|| |
MHO is a controversial topic which may be due to the absence of a standardized definition, transit, and heterogeneous nature of the entity. The interest in this topic is generating more than 200 research articles per year. The article by Norbert Stefen is thought provocative and we take the opportunity here to bring few observations from his articles., Obesity is defined and classified according to BMI. This simple measure of BMI is also useful to predict cardiometabolic risk associated with obesity. A better index for prediction of risk is visceral (truncal/central) obesity. The differential fat distribution pattern is used for assessment of CVD risk. The differential fat distribution in obese individuals is related to distinct subtypes of obesity. Liver fat content is substantially associated with insulin sensitivity than visceral fat mass. Fatty liver or liver fat content is an independent risk factor for CVD morbidity and mortality. Similarly, high liver fat is also related to T2DM. The low liver fat denotes a low-risk phenotype like MHO. Besides the fat storage the inflammatory signaling is also relevant to MHO. The release of pro-inflammatory hepatokine (fetuin A) mediates lipid-induced insulin resistance and sub-clinical inflammation is low in liver with less fat. A reduced infiltration of immune cells into adipose tissues and subsequent secretion of cytokines and adipokine which are metabolically beneficial was found in metabolically obese but insulin-sensitive subjects. The single-nucleotide polymorphism in adiponectin receptor 1 gene with hyperadiponectinemia determines MHO. The therapeutic advantage of thiazolidinedione resulting in increased adiponectin concentration leading to expansion of subcutaneous adipose fat and decrease in liver fat content and insulin sensitivity is noteworthy. The activation of peroxisome proliferator-activated receptor-gamma led on to interest in exploring signaling pathways in the pathogenesis. MHO is also associated with higher cardiorespiratory fitness. Few studies show the benefit of physical fitness and fitness is better than fatness as a risk factor for CVD mortality. The gut microbiome has a possible role. The interaction of diet and drugs with gut microbiome, dysbiosis, and metabolome influencing obesity can be an area of future research.
This is a narrative review and no advanced statistical methods were applied.
| Conclusion|| |
We have presented the merits and demerits of MHO.The limitation with studies are lack of standardized definition. MHO is transitory in nature with tendency to transform to MUO. The benefit from intervention is equivocal. The merit is this is an eye-opener for research. It is not possible to predict which MHO will turn into MUO but MHO can remain stable in a subset of persons. The physical fitness/exercise is considered to be a favorable factor for MHO and cardiometabolic risk. [Figure 1] summarizes these issues in a schematic form. We hope that this review will encourage further research in this area.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]