Factors of Metabolically Healthy Obesity in Asia: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Bryan Mathis.

Obesity is a chronic, progressive disease of caloric energy storage that manifests as excess visceral or subcutaneous lipid deposition. A systemic condition, surplus adipose tissue generates inflammation through secretion of cytokines while the neuroendocrine and metabolic energy balance systems resist loss of stored fat as a conserved survival mechanism. Thus, obesity is not disease of storage, but a metabolic condition that resets energy homeostasis and inflicts gradual damage to the cardiopulmonary and glucose management systems. Obesity without this concomitantly increased cardiopulmonary risk is termed metabolically healthy obesity (MHO) while metabolically unhealthy obesity (MUHO) represents the endpoint of obesogenesis, but increases in cardiovascular, cancer, and all-cause mortality.

  • body mass index
  • diabetes
  • metabolically healthy obesity
  • obesity

1. Introduction

Obesity is a global health crisis that has reached East Asia (China, Japan, and South Korea) and its population of over 1.5 billion people. After industrialization, the availability of processed foods and Westernization of dietary trends have resulted in an estimated 40.9% overweight/obese prevalence among adults in the Asia–Pacific region, with an estimated economic impact of up to 12% of total health care spending on obesity or related diseases [1]. This will only worsen as the population ages.

From the economic standpoint of the rapidly aging Asian population alone, an obesity pandemic would be unsustainable, as care for type 2 diabetes and cardiovascular diseases are expensive and long-term commitments. Additionally, obesogenesis in East Asian children is also increasing, which will affect population-level quality of life and further increase demand on limited resources for obesity-related care [3][2]. Therefore, if East Asians currently suffering from obesity can maintain MHO status for as long as possible before intervention, it would buffer the burden on the socialized medical systems found in East Asia as well as improving quality of life with regard to metabolic syndrome. However, since excessive fat has been found to increase peak loading of the musculoskeletal movement chain, the effect of weight stress could increase the failure rate of hip implants in the aging and cause balance issues even in younger populations [4,5][3][4] Thus, even if it not a state of total health, MHO is preferable to MUHO since a healthy metabolism may facilitate weight loss through exercise by reducing weight stress on the legs and hips.

In general, the first-line treatment strategy of “eat less, move more” is ineffective for MUHO in the long-term (partly due to obesity effects on the movement chain’s peak loading stress) but, as MHO is characterized by cardiopulmonary fitness and normal glucose regulation, maintenance of MHO and weight loss through diet and exercise may be possible in these individuals if targeted interventions remove known causes of MUHO pathogenesis [4][3]. While bariatric surgery (expensive and permanent) has shown some promise, obesity is a nearly incurable disease and, thus, prevention of obesogenesis and maintenance of MHO are of utmost importance to relieve the socialized medical systems of East Asia. However, in-depth analyses of the causes of obesity and potential factors for shifting from MHO to MUHO in East Asia are scarce.

2. Factors in Metabolically Healthy and Unhealthy Obesity

2.1. Age

Aging bodies tend to suffer increased risk of metabolic syndrome, with a Norwegian study of 10,206 adults finding 47.2% (male) and 64.4% (female) prevalences in the 80–89 age range [6][5]. This indicates that a large percentage of obese adults, even those with MHO, will eventually transition into MUHO status as they age and their resting metabolic rate and glucose control decrease, especially in post-menopausal women [7,8][6][7].
In East Asia: Asia is facing a demographic problem of aging, as exemplified in “elderly” societies such as China, which is currently experiencing growth rates in the elderly up to five times higher than total population growth [9][8]. Japan, where over 25% of the population is elderly and birth rates are below replacement, will also encounter infeasibly high societal costs for obesity-related disease similarly to South Korea with 14% of the total population aged 65 or over [10,11][9][10]. If even metabolically healthy obesity continues at the present rate, these new elderly individuals will eventually face the pathogenesis of diverse obesity-related diseases that will heavily strain the socialized healthcare systems common to East Asia.

2.2. CICO vs. CIM

The Calories In Calories Out (CICO) model, or energy balance model (EBM), treats every calorie as equal without accounting for the variability of resting energy expenditure based on time of day or other factors. While over 60–70% of daily caloric expenditure stems from basal metabolism, around 10% comes from the thermogenic effect of food intake (the energy used for digestion and nutrient assimilation) while the remaining 20% or so is the energy expended to move or exercise [12][11]. In this model, all calories are equal from an obesogenic perspective and substitutions (e.g., replacing fat calories with carbohydrate calories) are expected to have an effect dictated by simple mathematics (if calories in < calories out, then weight loss will occur). However, this model does assert that the brain tightly controls energy balance within the body through a network of nervous/endocrine messaging and that modern, processed food is confusing the neurological system with regard to food reward and dopamine release [13][12]. In this regard, the EBM is considered as a holistic system that measures caloric demand by internal body sensors but does not control for the degradation of assimilative and communicative machinery within the body (e.g., the inability of brains affected by leptin resistance to respond properly to leptin signaling [13][12]. The Carbohydrate–Insulin Model (CIM), on the other hand, focuses on the differential effects of metabolic glucose dysregulation and hormonal action on shifting calories from even healthy foods directly into fat via sustained increases in insulin response after meals [14][13]. In this model, processed carbohydrates (especially fructose and other insulinogenic starches) and excess protein spike insulin as a defensive response against uncontrolled blood sugar, driving the liver to convert sugars directly into heart- and artery-damaging lipids (blood triglycerides, cholesterol, and visceral fat) [14][13]. This effect is mirrored in type 2 diabetics, who receive insulin shots and experience a concomitant and tightly associated weight gain [15][14]. This theory is also bolstered by studies in non-diabetic obese patients who take metformin (gluconeogenesis inhibitor) or rosiglitazone (insulin response enhancer) and lose significantly more body weight than controls [16,17,18][15][16][17]. This model, however, does not take into account non-carbohydrate obesogenesis and insulin control, which could be substantial in individuals who consume excessive fat on low-carbohydrate diets and continue to gain non-muscle body weight [13][12]. In East Asia: The metabolic model may be relevant to prevent the sequelae of MUHO in East Asia as a health insurance study in Japan that summarevieweized 2548 total patients of normal or obese statuses taking either metformin or dipeptidyl peptidase-4 (glucose metabolism) inhibitors found that metformin resulted in a significant HbA1c reduction, increasing insulin sensitivity independent of BMI [19][18]. However, a study of 53,469 Singaporean adults of Han Chinese heritage found that, while the carbohydrate load of the typical Asian diet was not related to heart disease pathogenesis, transitioning from simple carbohydrates to produce and slow-digesting whole grains did reduce risk significantly [20][19]. Taken together, study results indicate that the CICO model could be outdated and MUHO is most likely driven, at least in part, by insulin resistance. This could explain why a majority of MUHO cases proceed to type 2 diabetes while pathogenesis in MHO is delayed significantly because these individuals still retain a normal glucose response and insulin sensitivity. Thus, with regard to MHO, shifting Asians from white rice to whole grains and produce could be protective against MHO to MUHO progression.

2.3. Damage from Reactive Oxygen Species

Metabolic damage results from excessive reactive oxygen species (ROS) generated by chronic inflammation, NADPH oxidases during hyperglycemia, polyol and hexosamine sugar shunting, excess blood lipids that generate superoxide anion radicals, and increased hydroxyl radicals generated by sustained, high leptin levels that also generate nitrogen radicals [21,22][20][21]. Over time, this cumulative damage could induce a shift from MHO to MUHO due to excess NADH that imbalances the membrane proton gradient and reduces insulin sensitivity through a vicious cycle mediated by JNK, p38MAPK, and NF-κB that phosphorylate IRS-1 and IRS-2 insulin response proteins [21,23,24,25][20][22][23][24]. While Nrf2, a master antioxidant transcription factor, would normally be activated by enhanced ROS production, excess activation of NF-κB may downregulate or blunt the endogenous Nrf2 response by upregulating Nrf2 constitutive repressor Keap1 via p65 under non-autophagic conditions (excessive glucose) [24][23]. Excessive processed carbohydrate consumption in the East, typically from white rice and white flour or instant noodles, may thus be causative in driving the pathogenesis of ROS-induced damage through chronic upregulation of Nrf2-repressing factors under hyperglycemic conditions. In East Asia: While browning of WAT into a calorie-metabolizing, “beige,” BAT-like phenotype can occur through the mineralocorticoid receptor, ERK1/2, MAPK, and AKT, the long-term implications of this shift are not clear and the effect of beige fat in East Asian phenotypes with regard to MHO has not been detailed in sufficient studies [22][21]. However, studies in China, Japan, and South Korea have found solid links between ROS and obesogenesis, even in children, that may result in eventual MUHO pathogenesis [39,40,41][25][26][27].

2.4. Environmental Pollution

Associations of air and water pollution with obesity may stem from immune-mediated reactions to particles in the air (asthma, COPD) or interactions between chemicals and gut flora as has been observed in animal studies [42,43][28][29]. A 2016 systematic review of 35 human cohort studies found that 46% reported positive links between environmental pollution and obesity, similar to a study in 98 people with obesity and 47 normal weight volunteers which found at least some associations between liquid organic pollutants (i.e., pesticides/herbicides) and obesity-relevant biomarkers, such as insulin resistance [44,45][30][31]. In East Asia: The BPA-obesity link was mirrored in a Korean study of 10,021 volunteers in which obese adults had significantly higher BPA levels in their urine and another Korean study of 3782 adults that found additional correlations between paraben levels and type 2 diabetes/obesity risks [48,49][32][33]. Clearly, ground/water-borne pollutants, preservatives, and plasticizers may bioaccumulate in lipid tissue, but parabens have been found to concentrate in fingernails, especially those of women, and the sequestration of such products may have an endocrine or immune-disrupting effect that has yet to be fully determined in Asians, especially with regard to the MHO to MUHO shift [50][34]. Air particulate matter (pm), as defined by size in microns (e.g., pm2.5, pm10), may have a more solid connection to obesity through multiple factors. First, air pollution prevents outdoor exercise, especially in asthmatics or those with allergies (who are already at increased risk of obesity). Second, ROS generated by infiltration of fine particulate matter into the body could promote cumulative damage to the mitochondria and, by extension, the overall energy metabolism [51][35]. Finally, damage to the cardiopulmonary system by pm2.5 could reduce exercise capacity crucial in maintaining MHO status by increased fibrotic damage [52][36]. In East Asia: A study using Chinese data from 13,741 adults over a 26-year-period determined that every microgram of pm2.5 increase resulted in a 0.27% rise in BMI via a lack of outdoor exercise [53][37]. Another Chinese study of 91,121 adults similarly found that each 10-microgram increment of pm2.5 pollution resulted in an 8% increase to the obesity risk [54][38]. This was mirrored in an Asian study that found, over 9 years, significant associations between airborne sulfur dioxide levels, high blood pressure, and type 2 diabetes [55][39].

2.5. Seed Oils and Allergies

Traditional use of unrefined animal fats (e.g., butter or lard) has given way over the past 70 years to the use of highly refined, easily oxidized seed oils (rapeseed, safflower, sunflower, and soybean) chosen for their high smoke point and neutral taste. However, animal studies have reported that linoleic acid in refined soy oil causes both fatty liver and obesity while black seed oil (cold-pressed and unrefined) has been shown to reduce this effect via upregulation of antioxidant master transcription factor Nrf2 [57,58,59][40][41][42]. Unrefined oils (especially fish oil) high in polyunsaturated omega 3 long-chain fatty acids (e.g., EPA/DHA), inversely to seed-based cooking oils, have been repeatedly shown to reduce cardiovascular disease (CVD) risk, chronic inflammation, and obesity risk in animals and humans alike [60][43]. Cumulative intake of oxidized oils may thus increase metabolic damage and spur progression of MHO to MUHO in populations that rely on such high-heat methods of cooking. In East Asia: High-heat seed oils may not be causative for all Asian obesity trends since only the Chinese cooking styles features foods fried in excessive oil at high temperatures, which could introduce ROS or other oxidized oil byproducts into the body [61][44]. A study of 15,022 Chinese adults over 14 years found positive associations between refined lard, peanut oil, canola oil, and sesame oils and type 2 diabetes, indicative of metabolic damage while, conversely, Korean traditional cooking features addition of oil after preparation and would not be a source of ROS from oxidized oils [62,63][45][46]. Japanese traditional cooking similarly relies on low oil use but recent increases in animal product consumption and the popularity of Western/Chinese cuisine featuring heavy seed oil use in both Japan and South Korea may be of concern in preventing MUHO pathogenesis. Obesity, often associated with allergies (even in children), mediates allergic pathogenesis due to activation of chronic inflammatory mechanisms and generation of ROS via sustained hyperglycemia. Another putative mechanism elucidated in animal studies is the breakdown in the intestinal barrier system via the PPARγ/NF-κB pathway and also a higher circulating IgE level [64,65][47][48]. The sustained inflammation caused by repeated allergen challenge and immune dysregulation may, thus, synergistically increase the risks associated with obesity under conditions of hyperglycemia and subsequent ROS generation. In East Asia: A study of 1772 Japanese children found that girls with overweight status were more likely to self-report food allergies and a Chinese study of 3327 children in Wuhan, China found a link between obesity and allergic rhinitis [66,67][49][50]. A Korean mental health study of 703,869 children found that, of 440,411 enrolled participants with some form of allergic disease (atopic dermatitis, rhinitis, or asthma), 21,836 (~5.0%) had comorbid obesity [68][51]. Specific links between MHO, the East Asian phenotype, and allergies are scarce in the literature.

2.6. Hormonal Changes, Age, and Menopause

Hormones, as a comparatively slower but wide-reaching chemical messenger system, play a key role in obesogenesis and maintenance of excessive fat stores. In general, the hunger and fat management mechanism is currently known to consist of extensively reviewed hormones, such as glucagon-like peptide 1 (GLP-1), visfatin, ghrelin, cholecystokinin (CCK), leptin, and enterostatin, that reside in the digestive tract and fat to control satiety and peristalsis in concert with the hypothalamus via vagus nerve signaling (Figure 21) [69,70][52][53].

/media/item_content/202209/632bf416b9c88medicina-58-01271-g002.png
Figure 21. Hormonal Effects in MHO vs. MUHO. A delicate biochemical homeostasis between leptin, ghrelin, and adiponectin controls energy intake in addition to the action of insulin. Resistance to leptin signaling increases hunger by upregulating ghrelin while adiponectin may be increased in MHO vs. MUHO [75][54]. Created in BioRender.com.
In East Asia: Increases in perceived stress from the industrialization of East Asia, work, finances, and the fragmentation of families due to employment migration might exacerbate levels of obesity-related stress hormones. As numerous studies have reported similar results with regard to Asians, BMI, and leptin resistance, further exploration of resistance pathogenesis might give new insights on therapies to prevent the MHO to MUHO shift in East Asia.

2.7. Immune Factors

The immune system is a complex population of organs, biochemistry, and interplay between specialized effector and somatic cells. Obesity, as a chronic inflammatory condition, has been well reported to maintain increased systemic interleukin (IL)-2, IL-4, IL-6, TNFα, IFNγ, and GM-CSF levels in a manner modulated by physical activity [98][55]. These cytokines are secreted by effector cells (e.g., polarized M1-type macrophages), as well as lipid cells, and activation of fatty acid-sensitive Toll-like receptors (TLR), such as TLR-2 and TLR-4, are reported to play a central role in obesogenic, chronic immune dysregulation [99,100][56][57]. Interplay between hormones and cytokines may also be important as TNFα, which reduces insulin sensitivity and has been shown to be overexpressed in people with obesity, is partially mediated by leptin in addition to IL-2, and IL-6 cytokines that increase T-cell expansion and liver disorders [101,102,103][58][59][60].
In East Asia: Asian studies, such as a study of 217 adults, found elevated IL-33 (Th2, pro-allergic factor) in obese patients while a study linked IL-6 polymorphisms, obesity, and osteoporosis risk in elderly Chinese women [111,112][61][62]. The effect of immune dysfunction in lipid tissue on obesogenesis in children has been extensively summarevieweized by Asian authorscholars [113][63].

2.8. The Microbiome

Only within the last 40 years has the importance of the microbiome to human health conditions (such as obesity) been intensely studied. Studies have shown that imbalances in the gut flora, especially with regard to high Firmicutes to Bacteroidetes ratios, are indicative of obesity but the complete effect of stable microbes in the human digestive system have not been fully elucidated [114,115][64][65]. Additional studies have reported that microbial maintenance of the mucous barrier within the intestines, bolstered by mucinogens such as Akkermansia muciniphilia, reduces systemic inflammation by reducing allergen ingress from digesting food while Lactobacillus reuterii, Clostridium butyricum, and other potentially transient species may contribute to barrier function and lipid/glucose homeostasis by regulation of IL-10, GLP1, GLUT2, and TLR2/AMPK pathways (Figure 32) [115,116][65][66]. In addition, the epithelium of the small intestine has tight junctions to prevent ingress of particles into the bloodstream, a function mediated by MyD88 secreted by Paneth cells (Figure 32) [117][67].  /media/item_content/202209/632bf480b17famedicina-58-01271-g003.png
Medicina 58 01271 g003 550
Figure 32. Importance of barrier function in preventing obesity. Diverse symbiotic species of bacteria protect the digestive tract by crowding out pathogens as well as maintaining the mucus barrier and promoting immune tolerance by dendritic sampling. Pathogens, antibiotics, and loss of the mucus layer degrades the integrity of the epithelial barrier via lowered MyD88 and immune recruitment creates sustained inflammation that may promote obesity [115,117][65][67]. Created in BioRender.com.
In East Asia: In Japan, a study of 100 adult men with obesity and prediabetes found that L. casei strain Shirota-fermented milk administration resulted in glycoalbumin and HbA1c reductions after 8 weeks even though blood sugar reductions were not seen [121][68]. Other trials in East Asia featuring probiotic interventions for MHO maintenance are scarce in the literature.

2.9. Social Aspect

Bullying and social pressure during childhood have been associated with lifelong obesity in multiple reports. Chronic psychosocial stress, especially bullying that causes hopelessness, estrangement, and anxiety, has been repeatedly shown to engender compensatory binge eating as well as increased pro-inflammatory cytokine environments (e.g., TNFα, IL-6, IL-1β) that can serve as a foundation for rapid and persistent fat gain [122,123][69][70]. A study of 4781 11–15-year-old children in Denmark found that boys and girls with overweight/obese statuses were subjected to about twice the risk of bullying, an effect pronounced among girls with obesity (OR 2.74) [124][71].
In East Asia: Additional psychosocial stress has also been associated with lower income levels, sedentary lifestyle (excessive TV or screen viewing), excessive study time, and bullying issues in Japan and China [125,126][72][73]. A global health survey of 41 low-to-middle-income countries (including SE Asia) found that girls and boys with overweight/obese statuses were 3.4× and 2.48×, respectively, more likely to be bullied [127][74]. The higher population densities in some Asian cities, coupled with cultural expectations of emotional subjugation, may contribute to higher social stress that could exacerbate obesity or create chronic stress leading to metabolic syndrome in the already overweight [128][75].

2.10. Vitamin and Micronutrient Deficiencies

A lack of vitamins or other micronutrients has been implicated in obesogenesis and animal studies have shown that obesity features a lack of Vitamins A and D, with Vitamin A regulating metabolism through RBP3 and ALDH1A1 and Vitamin D playing key roles in adipokine synthesis, calcium balance, and glucose metabolism [129,130,131][76][77][78]. Vitamin D, shown to be sequestered in fat tissue and, therefore, of low bioavailability in the obese, additionally regulates the immune system through the Vitamin D receptor on T cells, reducing the effect of chronic inflammation on obesogenesis [131,132][78][79].

In East Asia: With regard to MHO and vitamins, a study of 16,190 Korean adults found that MHO sufferers had lower AST/ALT liver enzyme levels and that, while Vitamin D deficiency was related to insulin resistance, there were no significant differences between MHO and MUHO with regard to Vitamin D levels [138][80]. In spite of possible antioxidant and immune-regulating benefits, studies have not shown a clear link between vitamin deficiencies and the MHO to MUHO phenotypic shift, especially in Asian populations.

2.11. Weight Fluctuation and Rebound Effect

In East Asia: Although studies on rebound are scarce, several small studies in Japan and China implicated a return to previous overfeeding patterns due to social contact or post-surgical pain that limited activity [141,142][81][82]. A large Korean study of 3678 adults, among whom half experienced high weight variability, found increased risk of death and rebound was attributed to homeostatic feedback after weight loss that creates a biochemical milieu favorable to weight gain [140][83].

2.12. Genetic Factors

In East Asia: A study of 1213 Chinese children found that KCNQ1-rs2237897 is associated with cardiovascular and KCNQ1-rs2237892 is associated with insulin resistance risk in MHO while another Chinese study of 1790 MHO children found FTO-rs9939609 or CYP17A1-rs11191548 predictive of cardiovascular risk in addition to GNPDA2-rs10938397 or KCTD15-rs29941 being predictive for insulin resistance [145,146][84][85]. A separate Chinese study did find that adiponectin-related gene polymorphisms, especially rs6773957, were related to diet and MUHO, in line with a similar Russian study of 503 obese patients that found similar connections to polymorphisms such as G45G [147,148][86][87]. A genome-wide association study of 49,915 Koreans found that LPL, APOA5, CETP, GCKR, CDKAL1, and CDKN2B (all lipid metabolism genes) were associated with MHO, thus lending weight to the concept that the MHO condition is a discrete genetic phenotype and that shifts to MUHO may involve epigenetic regulation from synergistic internal (reactive oxygen species, stress, hormones, etc.) and/or external (pollution, diet, etc.) sources [149][88].

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