The "Metabolically-obese Normal-weight" Phenotype and Its Reversal by Calorie Restriction
Condition: Glucose Metabolism Disorders; Obesity, Visceral; Obesity; Endocrine; Insulin Sensitivity/Resistance
MeSH terms: Obesity; Insulin Resistance; Metabolic Diseases; Glucose Metabolism Disorders; Obesity, Abdominal
Study type: Interventional

Summary: 
      The prevalence of overweight and obesity in Singapore is approximately half of that in the
      United States, yet the incidence of type 2 diabetes is similar, and is expected to double in
      the near future. This indicates that metabolic dysfunction, particularly insulin resistance,
      is widely prevalent even among individuals who are considered normal-weight or lean by
      conventional measures, i.e. body mass index (BMI) and percent body fat. These individuals are
      often referred to as "metabolically-obese normal-weight" (MONW), and have increased risk for
      cardiometabolic disease despite their normal BMI and total body fat values. The prevalence of
      the MONW phenotype varies across populations and differs markedly among different
      ethnicities. However, our understanding of the complex interactions between ethnicity, body
      composition, and metabolic dysfunction and its reversal remains rudimentary. Previous
      attempts to characterize the MONW phenotype are confounded by the small but significant
      differences in BMI or percent body fat between groups (even if all subjects were lean, within
      the "normal" range), with MONW subjects being always "fatter" than the corresponding control
      subjects. There are no published studies that prospectively recruited groups of metabolically
      healthy and unhealthy lean individuals matched on BMI and percent body fat. Furthermore,
      although weight loss improves body composition and many of the cardiometabolic abnormalities
      in most obese patients, little is known about the possible therapeutic effects of calorie
      restriction in MONW subjects.

      Accordingly, a better understanding of the MONW phenotype and the evaluation of therapeutic
      approaches for its reversal will have important implications for public health. By
      facilitating earlier identification of these subjects, who are more likely to go undiagnosed
      and thus less likely to be treated before clinically overt cardiometabolic disease develops,
      results from this study will allow for earlier and effective intervention.
    

Detailed description: 
      By the year 2050, it is estimated that more than half of the Singapore population will be
      overweight or obese, defined as having a body mass index (BMI, calculated as the weight in
      kilograms divided by the square of height in meters) equal to or greater than 25 kg/m2 (Phan
      et al. 2014). This is likely responsible, at least in part, for the concomitant increase in
      obesity-related co-morbid conditions, particularly type 2 diabetes (Phan et al. 2014; Ni
      Mhurchu et al. 2006). The relationship between BMI and the risk for type 2 diabetes in
      populations from the Asia-Pacific region is linear within a wide range of BMI values (from
      ~21 kg/m2 to ~34 kg/m2), so that for every 2 kg/m2 increase in BMI (which corresponds to ~6
      kg for a normal-weight person of average stature), the risk for developing type 2 diabetes
      rises by ~27 % (Ni Mhurchu et al. 2006). In Singapore, the prevalence of type 2 diabetes is
      expected to double from 7.3 % in 1990 to ~15 % in 2050, predominantly as a result of the
      fattening of the population, with the burden being greater for those of Indian descent than
      those of Chinese descent (Phan et al. 2014). This is expected to reduce productivity, inflate
      healthcare costs, and increase mortality among Singaporeans (Phan et al. 2014; Ma et al.
      2003).

      The prevalence of type 2 diabetes in Singapore is similar to that in the United States, even
      though the prevalence of overweight and obesity (BMI ≥25 kg/m2) in Singapore is approximately
      half that in the US (Yoon et al. 2006). This observation corroborates findings from many
      studies showing that markers of metabolic dysfunction (e.g. hyperglycemia, hyperinsulinemia,
      insulin resistance, dyslipidemia, and hypertension) are highly prevalent among Singaporean
      adults even at normal BMI values, i.e. even among people who are considered "normal-weight"
      or "lean" by conventional measures (Deurenberg-Yap et al. 1999; Deurenberg-Yap, Chew, et al.
      2001). The existence of people who have normal body weight but also have metabolic
      dysfunction, and therefore greater risk for developing cardiometabolic disease, was
      recognized several decades ago (Ruderman et al. 1998; Ruderman, Schneider, and Berchtold
      1981). At the extreme of this paradigm, even among members of the Calorie Restriction Society
      who undergo self-imposed calorie restriction for years based on the belief that this will
      help them ensure a long and healthy life, there are many individuals (~40 %) with impaired
      glucose tolerance, despite very low BMI and total body fat (Fontana, Klein, and Holloszy
      2010). These individuals are often referred to as "metabolically-obese normal-weight" (MONW)
      or "metabolically-abnormal lean" or "metabolically-unhealthy lean" subjects. The prevalence
      of this phenotype ranges from 5 % to 45 % depending on the BMI and the metabolic criteria
      used for its definition, as well as the characteristics of the population (i.e. age, sex, and
      ethnicity) (Conus, Rabasa-Lhoret, and Peronnet 2007; Teixeira et al. 2015). Similar
      variability has been observed across Asia (Lee et al. 2011; Luo et al. 2015; Yoo et al. 2014;
      Jung et al. 2015; Indulekha et al. 2015). For example, among the Chinese, ~8 % of the
      population as a whole, or ~13 % of those who are considered lean by virtue of body fat
      percent (i.e. ≤25 % for men and ≤35 % for women), are metabolically unhealthy, defined as
      having three or more metabolic abnormalities characteristic of the metabolic syndrome (Luo et
      al. 2015). Among Indians, on the other hand, 15-25 % of the population (or 20-40 % of those
      who are considered lean by virtue of BMI, i.e. <25 kg/m2) satisfies the criteria for
      metabolic syndrome (Indulekha et al. 2015; Geetha et al. 2011). The MONW phenotype in Asians
      is associated with 3-fold greater risk for carotid atherosclerosis (i.e. cardiovascular
      disease) (Yoo et al. 2014) and 4.5-8.5-fold greater risk for developing type 2 diabetes (Luo
      et al. 2015). In fact, MONW subjects have increased risk for cardiometabolic disease (Luo et
      al. 2015; Yoo et al. 2014) and greater all-cause mortality (Choi et al. 2013) not only
      compared to metabolically-healthy lean subjects, but also compared to metabolically-healthy
      obese subjects. This underscores the importance of metabolic dysfunction independent of
      excess body weight and total adiposity.

      The mechanisms responsible for the development of metabolic abnormalities in lean people are
      not entirely clear. The MONW phenotype can manifest early in life, e.g. during childhood
      (Guerrero-Romero et al. 2013), which corroborates the existence of genetic predisposition for
      metabolic dysfunction in the face of low BMI values (Yaghootkar et al. 2014). Previous
      studies have identified a number of factors associated with the MONW phenotype, including
      increased intra-abdominal (visceral) adipose tissue, increased liver and muscle fat content,
      increased fat cell size, adipose tissue inflammation, altered inflammatory and adipokine
      profiles, reduced skeletal muscle mass, lack of physical activity, and low cardio-respiratory
      fitness (Badoud et al. 2015; Dvorak et al. 1999; Ruderman et al. 1998; Conus, Rabasa-Lhoret,
      and Peronnet 2007; De Lorenzo et al. 2007; Karelis et al. 2004; Kim et al. 2013; Lee 2009;
      Oliveros et al. 2014; Teixeira et al. 2015; Di Renzo et al. 2006; Conus et al. 2004;
      Indulekha et al. 2015; Luo et al. 2015; Fontana, Klein, and Holloszy 2010). All of these
      factors have been directly or indirectly associated with insulin resistance (defined by a
      variety of methods), which is by far the commonest metabolic correlate of the MONW phenotype
      across all ethnicities, age groups, and sexes (Conus, Rabasa-Lhoret, and Peronnet 2007;
      Oliveros et al. 2014; Karelis et al. 2004; Ruderman et al. 1998). In fact, the greater
      prevalence of the MONW phenotype in Indians (Indulekha et al. 2015; Geetha et al. 2011) than
      in the Chinese (Luo et al. 2015) mirrors results obtained recently by our team, showing that
      among lean Singaporean men (BMI <25 kg/m2 or body fat ≤20 %), those of Indian descent have
      significantly lower insulin sensitivity, evaluated as the insulin-mediated glucose disposal
      rate during a hyperinsulinemic-euglycemic clamp procedure, compared to those of Chinese
      descent (Khoo et al. 2014). Similar results have been reported by other investigators in
      smaller groups of subjects (Liew et al. 2003) or when using simpler indices of insulin
      sensitivity (Khoo et al. 2011; Tai et al. 2000). Therefore, an insulin resistant glucose
      metabolism, broadly defined by subnormal responses to physiological insulin concentrations
      (Kahn 1978), is the hallmark of the MONW phenotype.

      Owing to the lack of a consistent definition, there is some variability among studies in the
      phenotypic characterization of MONW subjects (Teixeira et al. 2015). This is further
      complicated by the small but significant differences in BMI and, more commonly, percent body
      fat between groups of metabolically healthy and unhealthy lean subjects, with MONW subjects
      being always somewhat "fatter" (even though within the "lean" range) (Ruderman et al. 1998;
      Di Renzo et al. 2006; Badoud et al. 2015; Luo et al. 2015; Indulekha et al. 2015; Dvorak et
      al. 1999; Conus et al. 2004; De Lorenzo et al. 2007). Likewise, BMI and body fat are
      typically greater in relatively insulin-resistant (e.g. Indian) than in relatively
      insulin-sensitive (e.g. Chinese) individuals in studies reporting on ethnic differences in
      insulin action among lean people (Khoo et al. 2014; Khoo et al. 2011). This in itself could
      be responsible for the differences observed in metabolic function. There is considerable
      (~2-fold range) variability between individuals in the percent body fat (Gallagher et al.
      2000; Gallagher et al. 1996) and the insulin-mediated glucose disposal rate (a direct measure
      of whole-body insulin sensitivity) (Bradley, Magkos, and Klein 2012) for the same BMI value
      within the normal-weight range (i.e. BMI <25 kg/m2), so that people with the same BMI can
      have very different body fat and insulin sensitivity without this necessarily being
      associated with the presence or absence of generalized metabolic dysfunction. Even among lean
      and metabolically-healthy Asians, total body fat is a major correlate of insulin-mediated
      glucose disposal (Rattarasarn et al. 2003). It is thus possible that some of the reported
      differences between metabolically healthy and unhealthy lean subjects arise from normal
      variability and the differences in body fat between groups, rather than being an inherent
      characteristic of the MONW phenotype. In support of this possibility, when metabolically
      healthy and unhealthy lean subjects (defined as those having normal and impaired glucose
      tolerance, respectively) were retrospectively matched on total body fat, there were no
      differences between phenotypes in circulating concentrations of metabolic and inflammatory
      markers (i.e. high-density lipoprotein (HDL)-cholesterol, triglycerides, free fatty acids,
      C-reactive protein, adiponectin, and leptin) (Fontana, Klein, and Holloszy 2010). There are
      no studies that prospectively recruited groups of metabolically healthy and unhealthy lean
      individuals matched on BMI and percent body fat. A deeper understanding of the MONW
      phenotype, as proposed here, is important to dissect the metabolic abnormalities that are
      inherent to the phenotype from those merely associated with differences in total body fat.
      This will allow for proper identification and more efficient therapeutic targeting of MONW
      individuals, who are at greater risk for cardiometabolic disease.

      Little is known about possible interventions for improving metabolic function in MONW
      subjects. It is well established that diet-induced weight loss can improve body composition
      and many of the cardiometabolic abnormalities in most obese patients (e.g. decreases total
      body fat, intra-abdominal adipose tissue, and ectopic fat deposition in liver and muscle;
      increases insulin sensitivity; improves blood lipid profile; and reduces blood pressure)
      (Dattilo and Kris-Etherton 1992; de Leiva 1998; Goldstein 1992; Kirk et al. 2009; Muscelli et
      al. 1997; Pi-Sunyer 1993; Pasanisi et al. 2001; Escalante-Pulido et al. 2003; Mazzali et al.
      2006; Klein, Wadden, and Sugerman 2002), so that a moderate 10 % weight loss has become the
      cornerstone of obesity treatment (Jensen et al. 2014). However, MONW individuals are by
      definition lean, so recommending even moderate amounts of weight loss may not be a feasible
      therapeutic target (Miller and Parsonage 1975). It is therefore important to better
      understand the metabolic effects of smaller amounts of weight loss. Recently, the principal
      investigator conducted a randomized controlled trial to evaluate the effects of mild weight
      loss (5 % of initial body weight) on cardiometabolic function in non-Asian subjects with
      obesity and insulin resistance and found that even this small amount of weight loss decreases
      fat deposition in the liver and the intra-abdominal area, and increases insulin action in
      skeletal muscle, liver, and adipose tissue (Magkos et al. 2016). These results demonstrate
      that mild weight loss can improve many cardiometabolic abnormalities in
      metabolically-unhealthy obese subjects, but whether the same holds true for
      metabolically-unhealthy lean subjects is not known. A small, non-randomized, single-arm study
      in 7 lean, insulin-resistant offspring of parents with type 2 diabetes reported that modest
      ~6 % diet-induced weight loss reduced intra-myocellular lipid (i.e. fat within skeletal
      muscle fibers) content and increased insulin-mediated glucose disposal rate (both by ~30 %
      compared with baseline values), but did not significantly affect intra-abdominal adipose
      tissue volume or liver fat content (Petersen et al. 2012). It is thus not known whether mild
      diet-induced weight loss produces similar changes in body composition, fat distribution, and
      metabolic function in lean versus obese metabolically unhealthy subjects.
    

Intervention name(s): Calorie restriction
Intervention type(s): Behavioral
Intervention description(s): Calorie restriction with behavioral modification and provision of one catered, reduced calorie meal a day
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science