Endocrinol Metab.  2020 Sep;35(3):487-493. 10.3803/EnM.2020.301.

Metabolically Healthy and Unhealthy Normal Weight and Obesity

• Stefan N

• KMID: 2507997
• DOI: http://doi.org/10.3803/EnM.2020.301

Abstract

Increased fat mass is an established risk factor for the cardiometabolic diseases type 2 diabetes and cardiovascular disease (CVD) and is associated with increased risk of all-cause and CVD mortality. However, also very low fat mass associates with such an increased risk. Whether impaired metabolic health, characterized by hypertension, dyslipidemia, hyperglycemia, insulin resistance, and subclinical inflammation, may explain part of the elevated risk of cardiometabolic diseases that is found in many subjects with very low fat mass, as it does in many obese subjects, is unknown. An important pathomechanism of impaired metabolic health is disproportionate fat distribution. In this article the risk of cardiometabolic diseases and mortality in subjects with metabolically healthy and unhealthy normal weight and obesity is summarized. Furthermore, the change of metabolic health during a longer period of follow-up and its impact on cardiometabolic diseases is being discussed. Finally, the implementation of the concept of metabolic health in daily clinical practice is being highlighted.

Keyword

Obesity; Normal weight; Metabolic health; Fatty liver; Obesity, abdominal; Insulin resistance; Subclinical inflammation; Diabetes mellitus, type 2; Cardiovascular diseases

Figure

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  Fig. 1. Fat distribution, fatty liver and main lifestyle and genetic determinants of metabolically unhealthy normal weight and obesity. The arrows indicate whether the prevalence of fat distribution and fatty liver is increased or decreased in the metabolically unhealthy condition. Modified from Stefan et al. [8]. IRS1, insulin receptor substrate 1; GRB14, growth factor receptor-bound protein 14; PPARG, peroxisome proliferator activated receptor gamma; LYPLAL1, lysophospholipase like 1; FTO, fat mass and obesity-associated; MC4R, melanocortin-4 receptor.

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  Fig. 2. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease (CVD) risk across body mass index categories in 90,257 women of the Nurses’ Health Study. Risk of CVD in women with normal weight and obesity, stratified by metabolic health status. Hazard ratios (HRs) are adjusted for age, race, highest degree, alcohol consumption, postmenopausal status, physical examinations for screening purposes, family history of myocardial infarction and diabetes, aspirin use, smoking status change, physical activity. The data are from Eckel et al. [30], with permission from Elsevier. CI, confidence interval.

Reference

1. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet. 2016; 387:1377–96.

2. Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016; 388:776–86.

3. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017; 377:13–27.

4. Bhaskaran K, Dos-Santos-Silva I, Leon DA, Douglas IJ, Smeeth L. Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3·6 million adults in the UK. Lancet Diabetes Endocrinol. 2018; 6:944–53.

5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003; 348:1625–38.

6. Tobias DK, Hu FB. The association between BMI and mortality: implications for obesity prevention. Lancet Diabetes Endocrinol. 2018; 6:916–7.

7. Mann JP, Savage DB. What lipodystrophies teach us about the metabolic syndrome. J Clin Invest. 2019; 129:4009–21.

8. Stefan N, Schick F, Haring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017; 26:292–300.

9. Eigentler T, Lomberg D, Machann J, Stefan N. Lipodystrophic nonalcoholic fatty liver disease induced by immune checkpoint blockade. Ann Intern Med. 2020; 172:836–7.

10. Chen GC, Arthur R, Iyengar NM, Kamensky V, Xue X, Wassertheil-Smoller S, et al. Association between regional body fat and cardiovascular disease risk among postmenopausal women with normal body mass index. Eur Heart J. 2019; 40:2849–55.

11. Stefan N. Causes, consequences, and treatment of metabolically unhealthy fat distribution. Lancet Diabetes Endocrinol. 2020; 8:616–27.

12. Lotta LA, Wittemans LBL, Zuber V, Stewart ID, Sharp SJ, Luan J, et al. Association of genetic variants related to gluteofemoral vs abdominal fat distribution with type 2 diabetes, coronary disease, and cardiovascular risk factors. JAMA. 2018; 320:2553–63.

13. Loos RJ. The genetics of adiposity. Curr Opin Genet Dev. 2018; 50:86–95.

14. Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008; 168:1609–16.

15. Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, 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; 168:1617–24.

16. Stefan N, Haring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013; 1:152–62.

17. Samocha-Bonet D, Dixit VD, Kahn CR, Leibel RL, Lin X, Nieuwdorp M, et al. Metabolically healthy and unhealthy obese: the 2013 Stock Conference report. Obes Rev. 2014; 15:697–708.

18. Schulze MB. Metabolic health in normal-weight and obese individuals. Diabetologia. 2019; 62:558–66.

19. Magkos F. Metabolically healthy obesity: what’s in a name? Am J Clin Nutr. 2019; 110:533–9.

20. Smith GI, Mittendorfer B, Klein S. Metabolically healthy obesity: facts and fantasies. J Clin Invest. 2019; 129:3978–89.

21. Bluher M. Metabolically healthy obesity. Endocr Rev. 2020; 41:405–20.

22. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis. Ann Intern Med. 2013; 159:758–69.

23. Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab. 2012; 97:2482–8.

24. Eckel N, Meidtner K, Kalle-Uhlmann T, Stefan N, Schulze MB. Metabolically healthy obesity and cardiovascular events: a systematic review and meta-analysis. Eur J Prev Cardiol. 2016; 23:956–66.

25. Lassale C, Tzoulaki I, Moons KGM, Sweeting M, Boer J, Johnson L, et al. Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis. Eur Heart J. 2018; 39:397–406.

26. Yang HK, Han K, Kwon HS, Park YM, Cho JH, Yoon KH, et al. Obesity, metabolic health, and mortality in adults: a nationwide population-based study in Korea. Sci Rep. 2016; 6:30329.

27. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018; 68:268–79.

28. Stefan N, Haring HU, Hu FB, Schulze MB. Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol. 2016; 4:457–67.

29. Bell JA, Hamer M, Sabia S, Singh-Manoux A, Batty GD, Kivimaki M. The natural course of healthy obesity over 20 years. J Am Coll Cardiol. 2015; 65:101–2.

30. Eckel N, Li Y, Kuxhaus O, Stefan N, Hu FB, Schulze MB. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30 year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol. 2018; 6:714–24.

31. Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, Taylor AW, et al. Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study. Diabetes Care. 2013; 36:2388–94.

32. Lin L, Zhang J, Jiang L, Du R, Hu C, Lu J, et al. Transition of metabolic phenotypes and risk of subclinical atherosclerosis according to BMI: a prospective study. Diabetologia. 2020; 63:1312–23.

33. Lee YB, Kim DH, Kim SM, Kim NH, Choi KM, Baik SH, et al. Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study. Cardiovasc Diabetol. 2020; 19:77.

34. Morkedal B, Vatten LJ, Romundstad PR, Laugsand LE, Janszky I. Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trøndelag Health Study), Norway. J Am Coll Cardiol. 2014; 63:1071–8.

35. Lavie CJ, Milani RV, Ventura HO. Disparate effects of metabolically healthy obesity in coronary heart disease and heart failure. J Am Coll Cardiol. 2014; 63:1079–81.

36. Stefan N, Fritsche A, Haring HU. Mechanisms explaining the relationship between metabolically healthy obesity and cardiovascular risk. J Am Coll Cardiol. 2014; 63:2748–9.

37. Stefan N, Haring HU, Schulze MB. Metabolically healthy obesity: the low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol. 2018; 6:249–58.

38. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018; 24:908–22.

39. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019; 7:313–24.

40. Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017; 14:32–42.

41. Stefan N, Haring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013; 9:144–52.

42. Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012; 18:1279–85.

43. Stefan N, Haring HU. Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med. 2013; 19:394–5.

44. Stefan N, Fritsche A, Schick F, Haring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016; 4:789–98.

45. Konieczna J, Yanez A, Monino M, Babio N, Toledo E, Martinez-Gonzalez MA, et al. Longitudinal changes in Mediterranean diet and transition between different obesity phenotypes. Clin Nutr. 2020; 39:966–75.

46. Bluher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019; 15:288–98.

47. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020; 369:m1966.

48. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020; 1–16.

49. Stefan N, Birkenfeld AL, Schulze MB, Ludwig DS. Obesity and impaired metabolic health in patients with COVID-19. Nat Rev Endocrinol. 2020; 16:341–2.

50. Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 2020; 31:1068–77.

51. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2010; 375:181–3.