REVIEW CURRENT OPINION Lean, but not healthy: the ‘metabolically obese, normal-weight’ phenotype Cherlyn Dinga, Zhiling Chana, and Faidon Magkosa,b Purpose of review Obesity is commonly associated with metabolic dysfunction but there are obese persons who are 05/27/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XI41p+sDLxbvlJvgPKJYKCChu4AQ7aSiyxN6Txunm8aAM3UyKGgK1Q== by https://journals.lww.com/co-clinicalnutrition from Downloaded Downloaded metabolically healthy. On the opposite side of the coin, there are lean persons who carry multiple cardiometabolic risk factors, typically referred to as metabolically obese, normal-weight (MONW). This from has called into question our understanding of obesity and metabolic dysfunction, as an appearance of https://journals.lww.com/co-clinicalnutrition normal weight may mask significant comorbidities and delay health interventions. Recent findings High heterogeneity in MONW prevalence rates has been observed, with estimates ranging from as low as 5% to as high as 45%. Reasons for this include sample size effects, differences in MONW definition, social and demographic factors, as well as assumptions made in establishing normal weight. MONW study participants are often characterized by excess visceral adipose tissue and ectopic fat deposition, by adipose tissue inflammation, altered inflammatory and adipokine profiles, reduced skeletal muscle mass BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XI41p+sDLxbvlJvgPKJYKCChu4AQ7aSiyxN6Txunm8aAM3UyKGgK1Q== and low cardiorespiratory fitness. However, more often than not, groups of MONW study participants have been somewhat ‘fatter’ than the control groups of metabolically healthy lean study participants, which in itself could be responsible for some of the observed differences. Very limited data are available regarding interventions to improve metabolic function in MONW study participants. Summary There is a need for more research to better understand the characteristics of the MONW phenotype, the cause of metabolic dysfunction in the absence of obesity, and evaluate potential therapies so as to facilitate the establishment of clinical guidelines. Keywords body fat, calorie restriction, exercise, normal weight, obesity INTRODUCTION led to sensible deductions that excess adipose tissue According to the definition provided by the WHO, is pathological, and provides a convenient etiological obesity and overweight are collectively defined as basis for common contemporary medical disorders. abnormal or excessive fat accumulation that may Indeed, several mechanistic studies have been central undermine health [1]. The WHO definition uses in the support of this dogma. the BMI as an indicator of body fat, and generally In the recent decades, however, the exponential considers a person with a BMI at least 25 kg/m2 to be increase in overweight and obesity [8] has revealed overweight, and a person with a BMI at least 30 kg/m2 interesting trends, which would otherwise be to be obese [1]. Obesity has become increasingly detrimental to society and quality of life. It burdens a on national healthcare systems, strains economic Clinical Nutrition Research Centre, Singapore Institute for Clinical 05/27/2020 Sciences, Agency for Science, Technology and Research (AÃSTAR) resources and has far reaching social consequences b [2–5]. With regards to its effects on health, strong and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore epidemiological evidence suggests that obesity is an Correspondence to Faidon Magkos, PhD, Clinical Nutrition Research independent risk factor for a myriad of diseases, Centre, Singapore Institute for Clinical Sciences, Agency for Science, including cardiovascular disease, type 2 diabetes mel- Technology and Research (AÃSTAR), Brenner Centre for Molecular litus (T2DM), nonalcoholic fatty liver disease, and Medicine, 30 Medical Drive, Singapore 117609. Tel: +65 6407 0323; has been linked to the development of several debil- e-mail: [email protected] itating health conditions, such as sleep apnea, Curr Opin Clin Nutr Metab Care 2016, 19:408–417 hypertension, stroke, and cancer [5–7]. This has DOI:10.1097/MCO.0000000000000317 www.co-clinicalnutrition.com Volume 19 Number 6 November 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Metabolically obese, normal-weight phenotype Ding et al. approximately 40% of individuals from a society KEY POINTS involved in the practice of self-imposed caloric Normal body weight is not a marker of metabolic restriction exhibited impaired glucose tolerance, health; approximately 5–45% of lean individuals have despite having low BMI values and total body fat metabolic abnormalities, which are typically associated [21]. There are good explanations to consider this an with obesity. exception rather than the norm, and most normal- weight individuals with significant obesity-related Metabolic dysfunction in lean people has been linked comorbidity consistently exhibit patterns of excess to increased intra-abdominal (visceral) adipose tissue, & increased liver and muscle fat content, increased fat body fat [22 ,23]. cell size, adipose tissue inflammation, altered From a clinical perspective, normal body weight inflammatory and adipokine profiles, reduced skeletal puts metabolically unhealthy individuals at height- muscle mass, lack of physical activity, and low ened risk of associated comorbidities by masking the cardiorespiratory fitness. need for screening and thus delaying diagnosis [23]. MONW study participants are typically somewhat The likely result is that individuals may seek medical fatter than comparison groups (even though within the attention only at more advanced stages of cardio- lean range), so it is not clear which of these metabolic disease, making treatment options more abnormalities are inherent to the phenotype and which complicated and harder to implement. It may also are the result of increased total body fat. lower drug efficacy and patient compliance rates, as There is very little information regarding therapeutic well as increase the exposure of affected individuals approaches (e.g., diet and exercise) to improve to unfavorable risk–benefit ratios for medication, metabolic abnormalities in lean people with surgery, or physical therapy. These possibilities may metabolic dysfunction. explain the stronger associations found between diabetes risk (and development) and common risk factors in normal-weight individuals compared with overweight or obese individuals [22&]. There is, obscured by low numbers in a situation of lower therefore, good reason to better understand the obesity rates. The existence of metabolically healthy metabolically obese, normal-weight (MONW) phe- obese (MHO) persons [9,10&&,11] and documented notype, and evaluate interventions for its reversal. associations of excess body fat with favorable health outcomes [12–14] have left the wider medical community baffled, and brought into question THE METABOLICALLY OBESE, NORMAL- our current understanding of how obesity-related WEIGHT PHENOTYPE comorbidities develop. There are perplexing indica- tions that overfeeding and mild weight gain do not Definition necessarily cause metabolic dysfunction in MHO Ruderman et al. [24] first described the MONW study participants [15&&]. Similarly, diet or exer- phenotype as individuals in the healthy range of cise-induced weight loss interventions may not standard body weight tables who have metabolic necessarily decrease cardiometabolic risk in MHO abnormalities commonly associated with adult- individuals [16], and may even lead to a paradoxical onset obesity. Much like patients with the classical response (e.g., a decrease in insulin sensitivity presentations of adult-onset obesity, Ruderman et al. instead of the expected increase) [17]. Studies also [24] explained that MONW individuals could seem to suggest that increased adipose tissue mass present with hyperinsulinemia, increased adipocyte may offer protection against the detrimental effects size, and hypertriglyceridemia, which could be cor- of metabolic syndrome, and has been associated rected with caloric restriction. Many years later, with improved survival rates of patients receiving De Lorenzo et al. [25] introduced the concept of inpatient care [12–14]. normal-weight obesity (NWO), defined as persons Conversely, several normal-weight individuals with normal BMI but increased body fat and reduced by virtue of BMI have been shown to exhibit the lean mass. Although both NWO and MONW phe- clustering of metabolic disorders normally associ- notypes are associated with increased cardiometa- ated with the obese, metabolically unhealthy phe- bolic risk, current NWO criteria may be far more notype [9,18&]. In studies examining cardiovascular inclusive – by definition they could comprise meta- events, cardiac and all-cause mortality in metabol- bolically healthy, normal-weight persons who meet ically unhealthy people, normal-weight individuals the criteria for excess body fat [25–27]. To facilitate were just as or more likely as overweight and obese scientific discussion, it would seem appropriate at persons to yield to cardiovascular and fatal events this juncture to conceptually discern the MONW [18&,19,20]. At the extreme end of this paradigm, from NWO for purposes of clarity. In assessing the 1363-1950 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-clinicalnutrition.com 409 Copyright