January 2017 Issue

Metabolically Healthy Obesity — An Oxymoron or Medical Reality?
By Carrie Dennett, MPH, RDN, CD
Today's Dietitian
Vol. 19, No. 1, P. 30

Obesity has long been associated with risk of various chronic health conditions, including type 2 diabetes, cardiovascular disease (CVD), and several cancers, as well as premature death from these and all causes.1-3

In August, the Lancet published a study by the Global BMI Mortality Collaboration that pooled data from about 10.5 million individuals. The findings showed that both overweight (BMI over 25 kg/m2) and obesity (BMI over 30 mg/k2) were associated with increased all-cause mortality.4

However, a commentary in the same issue points out that it's challenging to address factors such as disease history, diet, and physical activity in large studies that pool data, and difficult at best to infer a cause-and-effect relationship between BMI and mortality from any observational study.5 Unfortunately, these details got lost in translation, as evidenced by headlines like "Study Finds Fat Kills, Casting Doubt on 'Obesity Paradox'"6 or "Being Obese Can Kill You."7

In fact, there's ongoing debate about whether being obese directly causes or contributes to chronic disease, or if it's simply that obesity and chronic disease often coexist. Both obesity and metabolic syndrome are associated with increased risk of CVD and type 2 diabetes, but obesity and metabolic syndrome don't always occur in the same individuals. Some people are obese but metabolically healthy, while others are metabolically unhealthy even at a "normal" weight.

What Is Metabolically Healthy Obesity?
The phenomenon that some individuals are metabolically healthy despite long-standing obesity—even morbid obesity—was first described in the early 1980s, challenging the paradigm that obesity leads to metabolic and cardiovascular risks.8,9 In basic terms, metabolically healthy obesity is defined as having a BMI of more than 30 kg/m2 without having metabolic syndrome, which in turn is generally defined as the presence of two or more of these criteria: high triglycerides, low HDL cholesterol, high blood pressure, and high fasting blood glucose.10 In the research literature, however, scientists have defined a metabolically healthy phenotype at least 30 different ways.11

So how many people with an obese BMI are metabolically healthy? According to Jennifer Kuk, PhD, an associate professor and researcher in the York University School of Kinesiology & Health Science in Toronto, Canada, that depends on how you define metabolic abnormalities and the population you look at.12,13 "If you define it as multiple factors present in the same individuals with higher risk cut-points, the proportion of individuals with obesity but are 'healthy' can be more than 50% and as much as 75% in younger populations," she says.14 However, if you use lower risk cut-points (eg, borderline hypertension) and require no risk factors to be considered healthy, we show that the prevalence can be as low at 6%."15,16

While there's disagreement, overall the research suggests that metabolically healthy obese adults have a higher risk of CVD and type 2 diabetes compared with metabolically healthy individuals of normal weight, but a lower risk than metabolically unhealthy obese adults.1,8,17-19 A 2014 meta-analysis found that metabolically healthy obese adults had a substantially increased risk of developing type 2 diabetes compared with healthy normal-weight adults, although their risk was lower than that of metabolically unhealthy adults of any BMI.20 In addition, a large prospective cohort study of Korean adults found that being metabolically unhealthy contributed more to risk of death from CVD and all causes than did BMI.21

Metabolically healthy obesity may be the result of genetic predisposition, diet and lifestyle factors, or both.22 It's known that genetic factors contribute to metabolic disorders,23 so it's possible that some people are genetically predisposed to be metabolically healthy even at higher weights.8 Birth weight also plays a role. Large babies who become large adults are less likely to develop certain health problems, compared with small babies who become large adults.24 Being a metabolically healthy obese child is a common trait among metabolically healthy obese adults, which suggests they may have traits that preserve metabolic health.23

Ayra Sharma, MD, DSc, FRCPC, a professor of medicine and chair of obesity research and management at the University of Alberta, Edmonton, Canada, has argued that there's no such thing as healthy obesity25—if you use the World Health Organization's (WHO) definition of obesity: abnormal or excessive fat accumulation that presents a risk to health.26 "If it's excess body fat that impairs health, and your body fat is not affecting your health, then maybe you don't have obesity," he says. "Maybe you're at risk of obesity, but being at risk of something is not the same as having something."

Beyond BMI: The Role of Body Composition
Even in the early 1990s, when the WHO adopted the BMI tables, scientists pointed out that BMI—a mathematical calculation—can't accurately distinguish between body fat and lean muscle.17,27 A person can have a high BMI but low fat mass, or vice versa, and an unhealthy metabolic state can exist at body weights within any BMI range.17,18 Since BMI lumps metabolically healthy and unhealthy people together, studying the relationship between BMI and health outcomes is misleading.17,18,27

"The reason BMI is not a strong predictor of health risk is that it's a measure of size, not body composition," Sharma says. "It doesn't tell us anything about the composition of that fat tissue. It doesn't tell us anything about your genetic risk."

Body weight is the sum of muscle, bone, organs, and tissue. The amount of muscle and fat someone has and where their fat is located matter. Subcutaneous fat (fat directly under the skin) appears to not increase metabolic risk, while visceral fat (fat deep within the abdominal cavity) might, but fat deposits in the liver, heart, and skeletal muscle are most concerning.23,28,29

Fat, or adipose, tissue isn't just storage for fat cells. It functions as an endocrine organ, secreting a variety of hormones and inflammation-promoting cytokines that promote the development of insulin resistance, type 2 diabetes, and other metabolic complications.13,30,31 Chronic, low-grade inflammation of fat tissue may explain differences in metabolic health among individuals of all BMI categories.8,30-32 A 2016 study published in the Journal of the American Heart Association found that metabolically healthy obese individuals who had low levels of C-reactive protein had a heart disease risk comparable to that of metabolically healthy nonobese individuals.33

One theory is that metabolically healthy obese adults have fat tissue that hasn't become dysfunctional. Another is that their bodies aren't vulnerable to inflammatory cytokines.13,30,34,35 Metabolically healthy obese individuals tend to have better insulin sensitivity, low levels of visceral fat and fat deposits in the liver and skeletal muscles (compared with overall subcutaneous fat), smaller fat cells, and less inflammation of fat tissue.23,36 This could be due to genetics or lifestyle. A 2016 clinical study found that metabolically healthy participants had a greater ability to burn (oxidize) fat than those with metabolic syndrome or type 2 diabetes, noting that an unhealthy lifestyle with low physical activity and a high-fat diet also impairs fat oxidation, leading to cellular damage.37

Research suggests that metabolic health is associated with being younger and female and with higher physical activity and smaller waist circumference.9,13,38 Metabolically healthy obese young women tend to have more healthful lifestyle habits than their metabolically unhealthy peers, including less sedentary time, more time spent doing light physical activity, and a diet with more fiber and vegetables and healthful types of fat.39 Women are more likely to use health services than men and may receive more preventive health counseling.38

Physical Activity
Metabolically healthy people of all weights spend more time being physically active and less time being sedentary.29 Most evidence supports the role of cardiorespiratory fitness,28 but there's even support for light activity. A 2015 study that measured activity using an accelerometer to capture "incidental" physical activity as well as planned activity found that overall physical activity is higher among metabolically healthy obese individuals compared with metabolically unhealthy obese individuals, but found almost no difference in the amount of moderate-to-vigorous activity.40

"Some research indicates that physical fitness is more strongly related with mortality risk than BMI," Kuk says. "Physical activity is beneficial for not only improving fitness, but also improving many aspects of physical and mental health. Furthermore, the amount of physical activity needed to attain health benefits is much less than what is typically associated with weight loss."

Even though physical activity is known to improve health and help prevent type 2 diabetes and CVD, most studies don't factor it in.18,20 One study that did, published in 2013 in European Heart Journal, found that metabolically healthy obese individuals had an elevated risk of CVD—until the researchers accounted for fitness.24

It's possible that regular physical activity is a marker for a healthier lifestyle overall, rather than the major mechanism defining metabolic health,36 but we do know that exercise helps to improve body composition by reducing visceral fat and preserving muscle while promoting insulin sensitivity, lower blood pressure, and better lipid levels.22,23,27,40

Transitory State?
The vast body of research on metabolic health in obesity has raised an important question: Do metabolically healthy obese individuals have some specific phenotypic or genetic traits that protect them, or are they simply experiencing "delayed onset" of obesity-related metabolic diseases?23,36 Long-term studies have found that one-third to two-thirds of these individuals become metabolically unhealthy over time, especially with age.8,10-13,28,41,42 It's also worth noting that even within the normal BMI range, a percentage of metabolically healthy individuals become metabolically unhealthy over time.34

Data from the Multi-Ethnic Study of Atherosclerosis suggest that greater severity and duration of obesity are associated with development of metabolic syndrome, leading the authors to conclude that metabolically healthy obesity is a temporary state.10 However, these researchers noted that resistance to the metabolic effects of obesity differed on an individual basis, possibly due to the presence—or absence—of inflammation and variations in body fat distribution.10

Changing body composition may be one explanation why some people maintain metabolic health and others don't. Adults lose about 1.5 kg of fat-free mass per decade,11 so if weight remains stable, that means fat tissue has increased. Another theory is that the loss of metabolic health may be a natural consequence of stopping or reducing physical activity,1 partly because of the importance of cardiorespiratory fitness, but also because regular physical activity is critical for retaining lean muscle with age.

If metabolic health is transitory, then it's possible that appropriate treatment may help individuals with metabolically unhealthy obesity remain in or return to a healthy state.36 Data from the Coronary Artery Risk Development in Young Adults Study found that over 20 years of follow-up limiting weight gain and maintaining or improving cardiorespiratory fitness were associated with sustaining metabolically healthy obesity.43

"I think the biggest question is, 'Why are these individuals with obesity able to remain healthy, and how do we keep people with obesity from developing other chronic diseases such as diabetes or hypertension?'" Kuk says.

Are Interventions Helpful?
Research shows that weight loss is associated with metabolic improvements in individuals who are both metabolically unhealthy and obese,8,11 but few sufficiently sized randomized trials have been done to assess whether weight loss interventions protect health. Researchers ended one trial after about 10 years of follow-up because they found no association between weight loss and cardiovascular events.44

Overall, research to date suggests that metabolically healthy obese individuals may not significantly reduce their risk of future cardiometabolic health problems through weight loss or other obesity interventions.36 One meta-analysis of clinical studies published in Nutrients found that a calorie-restricted diet resulted in weight loss as well as improvement in blood pressure and triglyceride levels but no other beneficial changes.9 Other studies have found no improvement in individual metabolic risk factors in response to diet- and/or exercise-based interventions,45 and some have even found adverse effects, such as decreased insulin sensitivity.46 In fact, one study found that weight loss in postmenopausal women who are metabolically healthy may be not just unnecessary, but harmful.46 Another study suggested that metabolically healthy obese people are resistant to the adverse effects of weight gain.47

"Most individuals are unable to sustain their weight loss over long periods of time. Thus, the question should be whether we should require individuals with obesity to continually fail at losing weight and whether that is worse for their health than simply trying to adopt healthier sustainable lifestyles," Kuk says. "In fact, I think that all of us, regardless of our body weight, could probably work on some aspect of our lifestyle to be healthier."

In the future, using a standardized definition of the metabolically healthy obese phenotype may allow for risk stratification to better guide treatment decisions. For example, the Edmonton Obesity Staging System,48 which Sharma helped develop, has five stages, with Stage 0 representing an individual with obesity who has no sign of related risk factors, no physical or psychological symptoms, and no physical limitations.

Pending clear data about genetic predisposition, lifestyle modifications aimed at minimizing visceral fat accumulation are the best hope.22 Lifestyle modifications may be beneficial for improving metabolic health even if a clinically relevant weight loss of 5% of starting weight isn't achieved.16 A prudent intervention is regular physical activity, reduced sedentary activity, along with a balanced diet that limits sugar and refined carbs.22 Replacing even 30 minutes of sedentary activity per day with an equal amount of light physical activity—or 10 minutes of moderate-to-vigorous physical activity for 10 minutes of sedentary time—has been shown to improve health.39

"Physical activity is a behavior that you can prescribe in concrete amounts, whereas weight loss is a result of various behaviors, environmental exposures, physiology, and many other conditions that may be outside of the individual's control," Kuk says.

Weight Stigma, Stress, and Socioeconomic Status
Another avenue of intervention is on a societal level, addressing the effects of weight stigma and low socioeconomic status. Stress contributes to metabolic abnormalities, and both weight stigma and lower socioeconomic status can be profound sources of stress.49 Higher educational level also is associated with metabolic health, and educational status impacts socioeconomic status, which influences living conditions and opportunities to live a healthful lifestyle.38,50,51

Chronic stress contributes to elevation of the same proinflammatory cytokines that have been observed to be higher in people with obesity.49 Secretion of the stress hormone cortisol contributes to further weight gain and metabolic risk by driving both overeating and accumulation of visceral fat.52 It's well established that weight stigma and discrimination impair mood and mental health, but there's growing evidence that weight stigma also is associated with increased blood pressure, chronic inflammation, and greater disease and mortality risk.53,54

The Big Picture
It's important for dietitians to remember that people are not statistics. What large-scale epidemiologic studies show about trends in a population doesn't necessarily apply to the patient sitting across from you. Weight has become a handy, but inaccurate, shorthand for health by health care providers and the public, even though research suggests it's not that simple. Help patients of all body weights make changes in nutrition and lifestyle that they can sustain for the long term to help protect metabolic health.

"I think the problem is we think you can step on a scale and measure your health, and that's not true," Sharma says. "The exception might be if there are changes in weight, weight gain, or weight loss. You have to look at that in the context of what else is going on."

— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times and speaks frequently on nutrition-related topics. She also provides nutrition counseling via the Menu for Change program in Seattle.

 

References
1. Roberson LL, Aneni EC, Maziak W, et al. Beyond BMI: The "metabolically healthy obese" phenotype & its association with clinical/subclinical cardiovascular disease and all-cause mortality — a systematic review. BMC Public Health. 2014;14:14.

2. Aune D, Sen A, Prasad M, et al. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. BMJ. 2016;353:i2156.

3. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309(1):71-82.

4. Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388(10046):776-786.

5. Berrigan D, Troiano RP, Graubard BI. BMI and mortality: the limits of epidemiological evidence. Lancet. 2016;388(10046):734-736.

6. Kelland K. Study finds fat kills, casting doubt on 'obesity paradox.' Reuters website. http://www.reuters.com/article/us-health-obesity-idUSKCN0ZT2SX. Published July 13, 2016. Accessed September 4, 2016.

7. Associated Press. Being obese can kill you, study finds. NBC News website. http://www.nbcnews.com/health/health-news/being-obese-can-kill-you-study-finds-n609601. Published July 14, 2016. Accessed September 4, 2016.

8. Muñoz-Garach A, Cornejo-Pareja I, Tinahones FJ. Does metabolically healthy obesity exist? Nutrients. 2016;8(6):E320.

9. Stelmach-Mardas M, Walkowiak J. Dietary interventions and changes in cardio-metabolic parameters in metabolically healthy obese subjects: a systematic review with meta-analysis. Nutrients. 2016;8(8):E455.

10. Mongraw-Chaffin M, Foster MC, Kalyani RR, et al. Obesity severity and duration are associated with incident metabolic syndrome: evidence against metabolically healthy obesity from the Multi-Ethnic Study of Atherosclerosis. J Clin Endocrinol Metab. 2016;101(11):4117-4124.

11. Zheng R, Liu C, Wang C, et al. Natural course of metabolically healthy overweight/obese subjects and the impact of weight change. Nutrients. 2016;8(7):E430.

12. van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, et al. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord. 2014;14:9.

13. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med. 2008;160(15):1617-1624.

14. Heinzle S, Ball GD, Kuk JL. Variations in the prevalence and predictors of prevalent metabolically healthy obesity in adolescents. Pediatr Obes. 2016;11(5):425-433.

15. Kuk JL, Ardern CI. Are metabolically normal but obese individuals at lower risk for all-cause mortality? Diabetes Care. 2009;32(12):2297-2299.

16. Liu RH, Wharton S, Sharma AM, Ardern CI, Kuk JL. Influence of a clinical lifestyle-based weight loss program on the metabolic risk profile of metabolically normal and abnormal obese adults. Obesity (Silver Spring). 2013;21(8):1533-1539.

17. Müller MJ, Lagerpusch M, Enderle J, Schautz B, Heller M, Bosy-Westphal A. Beyond the body mass index: tracking body composition in the pathogenesis of obesity and the metabolic syndrome. Obes Rev. 2012;13(Suppl 2):6-13.

18. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta analysis. Ann Intern Med. 2013;159(11):758-769.

19. Hinnouho GM, Czernichow S, Dugravot A, et al. Metabolically healthy obesity and the risk of cardiovascular disease and type 2 diabetes: the Whitehall II cohort study. Eur Heart J. 2015;36(9):551-559.

20. Bell JA, Kivimaki M, Hamer M. Metabolically healthy obesity and risk of incident type 2 diabetes: a meta-analysis of prospective cohort studies. Obes Rev. 2014;15(6):504-515.

21. Yang HK, Han K, Kwon HS, et al. Obesity, metabolic health, and mortality in adults: a nationwide population-based study in Korea. Sci Rep. 2016;6:30329.

22. Gonçalves CG, Glade MJ, Meguid MM. Metabolically healthy obese individuals: key protective factors. Nutrition. 2016;32(1):14-20.

23. Berezina A, Belyaeva O, Berkovich O, et al. Prevalence, risk factors, and genetic traits in metabolically healthy and unhealthy obese individuals. Biomed Res Int. 2015;2015:548734.

24. Ortega FB, Lee DC, Katzmarzyk PT, et al. The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness. Eur Heart J. 2013;34(5):389-397.

25. Sharma AM. There is no "healthy" obesity. Dr. Sharma's Obesity Notes website. http://www.drsharma.ca/there-is-no-healthy-obesity. Published September 27, 2016. Accessed October 12, 2016.

26. Obesity. World Health Organization website. http://www.who.int/topics/obesity/en/. Accessed October 20, 2016.

27. Nuttall FQ. Body mass index: obesity, BMI, and health: a critical review. Nutr Today. 2015;50(3):117-128.

28. Phillips CM. Metabolically healthy obesity across the life course: epidemiology, determinants, and implications [published online October 10, 2016]. Ann N Y Acad Sci. doi: 10.1111/nyas.13230.

29. de Rooij BH, van der Berg JD, van der Kallen CJ, et al. Physical activity and sedentary behavior in metabolically healthy versus unhealthy obese and non-obese individuals — The Maastricht Study. PLoS One. 2016;11(5):e0154358.

30. Goran MI, Alderete TL. Targeting adipose tissue inflammation to treat the underlying basis of the metabolic complications of obesity. Nestle Nutr Inst Workshop Ser. 2012;73:49-60.

31. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184-6223.

32. Doumatey AP, Zhou J, Zhou M, Prieto D, Rotimi CN, Adeyemo A. Proinflammatory and lipid biomarkers mediate metabolically healthy obesity: a proteomics study. Obesity (Silver Spring). 2016;24(6):1257-1265.

33. van Wijk DF, Boekholdt SM, Arsenault BJ, et al. C-reactive protein identifies low-risk metabolically healthy obese persons: the European Prospective Investigation of Cancer–Norfolk Prospective Population Study. J Am Heart Assoc. 2016;5(6):e002823.

34. Zhao L, Ni Y, Ma X, et al. A panel of free fatty acid ratios to predict the development of metabolic abnormalities in healthy obese individuals. Sci Rep. 2016;6:28418.

35. Mittendorfer B. Origins of metabolic complications in obesity: adipose tissue and free fatty acid trafficking. Curr Opin Clin Nutr Metab Care. 2011;14(6):535-541.

36. Blüher M. Are metabolically healthy obese individuals really healthy? Eur J Endocrinol. 2014;171(6):R209-R219.

37. Pujia A, Gazzaruso C, Ferro Y, et al. Individuals with metabolically healthy overweight/obesity have higher fat utilization than metabolically unhealthy individuals. Nutrients. 2016;8(1):E2.

38. Diniz Mde F, Beleigoli AM, Ribeiro AL, et al. Factors associated with metabolically healthy status in obesity, overweight, and normal weight at baseline of ELSA-Brasil. Medicine (Baltimore). 2016;95(27):e4010.

39. Camhi SM, Crouter SE, Hayman LL, Must A, Lichtenstein AH. Lifestyle behaviors in metabolically healthy and unhealthy overweight and obese women: a preliminary study. PLoS One. 2015;10(9):e0138548.

40. Bell JA, Hamer M, van Hees VT, Singh-Manoux A, Kivimäki M, Sabia S. Healthy obesity and objective physical activity. Am J Clin Nutr. 2015;102(2):268-275.

41. Schröder H, Ramos R, Baena-Díez JM, et al. Determinants of the transition from a cardiometabolic normal to abnormal overweight/obese phenotype in a Spanish population. Eur J Nutr. 2014;53(6):1345-1353.

42. Appleton SL, Seaborn CJ, Visvanathan R, et al. Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study. Diabetes Care. 2013;36(8):2388-2394.

43. Fung MD, Canning KL, Mirdamadi P, Ardern CI, Kuk JL. Lifestyle and weight predictors of a healthy overweight profile over a 20-year follow-up. Obesity (Silver Spring). 2015;23(6):1320-1325.

44. Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145-154.

45. Shin MJ, Hyun YJ, Kim OY, Kim JY, Jang Y, Lee JH. Weight loss effect on inflammation and LDL oxidation in metabolically healthy but obese (MHO) individuals: low inflammation and LDL oxidation in MHO women. Int J Obes (Lond). 2006;30(10):1529-1534.

46. Karelis AD, Messier V, Brochu M, Rabasa-Lhoret R. Metabolically healthy but obese women: effect of an energy-restricted diet. Diabetologia. 2008;51(9):1752-1754.

47. Fabbrini E, Yoshino J, Yoshino M, et al. Metabolically normal obese people are protected from adverse effects following weight gain. J Clin Invest. 2015;125(2):787-795.

48. Sharma AM, Kushner RF. A proposed clinical staging system for obesity. Int J Obes (Lond). 2009;33(3):289-295.

49. Muennig P. The body politic: the relationship between stigma and obesity-associated disease. BMC Public Health. 2008;8:128.

50. Social determinants of health: know what affects health. Centers for Disease Control and Prevention website. http://www.cdc.gov/socialdeterminants/. Updated October 13, 2016.

51. Woolf SH, Braveman P. Where health disparities begin: the role of social and economic determinants — and why current policies may make matters worse. Health Aff (Millwood). 2011;30(10):1852-1859.

52. Himmelstein MS, Incollingo Belsky AC, Tomiyama AJ. The weight of stigma: cortisol reactivity to manipulated weight stigma. Obesity (Silver Spring). 2015;23(2):368-374.

53. Jackson SE. Obesity, weight stigma and discrimination. J Obes Eat Disord. 2016;2(1):1-3.

54. Sutin AR, Terracciano A. Perceived weight discrimination and obesity. PLoS One. 2013;8(7):e70048.

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