Advertisement

Obesity: Genetics, Pathogenesis, and Therapy

  • Hannah Mathew
  • Stavroula A. PaschouEmail author
  • Kalliopi M. Aramapatzi
  • William Hsu
  • Christos S. Mantzoros
Reference work entry

Abstract

The increasing prevalence of obesity is a major public health concern. The present epidemic is distributed across sociodemographic groups in both industrialized and developing countries. This poses tremendous clinical challenges, as obesity makes notable contributions to morbidity and mortality and carries a staggering economic cost. In this chapter, we discuss the definition, classification, and epidemiology of obesity. Furthermore, we review the genetics and pathogenesis of obesity, as well as the evaluation of the patient with obesity and the current available treatments.

Keywords

Obesity Pathogenesis Adipose tissue Metabolic syndrome Genetics Therapy 

References

  1. 1.
    Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults–the evidence report. National Institutes of Health. Obes Res 1998;6(Suppl 2):51S–209S.Google Scholar
  2. 2.
    World Health Organization. Obesity: preventing and managing the global epidemic. Geneva: World Health Organization; 1998.Google Scholar
  3. 3.
    Fact sheet on overweight and obesity. World Health Organization. 2015.Google Scholar
  4. 4.
    Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311:806–14.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Johnson NB, Hayes LD, Brown K, Hoo EC, Ethier KA. Centers for Disease Control and Prevention (CDC). CDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors – United States, 2005–2013. MMWR Surveill Summ. 2014;63 Suppl 4:3–27.Google Scholar
  6. 6.
    Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med. 1995;122:481–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Withrow D, Alter DA. The economic burden of obesity worldwide: a systematic review of the direct costs of obesity. Obes Rev. 2011;12:131–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997;27:325–51.CrossRefPubMedGoogle Scholar
  10. 10.
    van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161:119–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–47.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085–95.CrossRefPubMedGoogle Scholar
  13. 13.
    Hampton T. Common gene variant linked to obesity. JAMA. 2007;297:2063–4.PubMedGoogle Scholar
  14. 14.
    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–94.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Locke AE, Kahali B, Berndt SI, Justic AE, Pers TH, Day FR, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Group, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, et al. International Endogene Consortium. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S, Garg S, et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet. 2013;45:513–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gusev A, Lee SH, Trynka G, Finucane H, Vilhjálmsson BJ, Xu H, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am J Hum Genet. 2014;95:535–52.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Falchi M, El-Sayed Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-Assarsson JC, et al. Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet. 2014;46:492–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med. 2007;357:370–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Williamson DF, Madans J, Anda RF, Kleinman JC, Kahn HS, Byers T. Recreational physical activity and ten-year weight change in a US national cohort. Int J Obes Relat Metab Disord. 1993;17:279–86.PubMedGoogle Scholar
  21. 21.
    Williamson DF, Madans J, Anda RF, Kleinman JC, Giovino GA, Byers T. Smoking cessation and severity of weight gain in a national cohort. N Engl J Med. 1991;324:739–45.CrossRefPubMedGoogle Scholar
  22. 22.
    Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686–96.PubMedGoogle Scholar
  23. 23.
    Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68:20–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Gale SM, Castracane VD, Mantzoros CS. Energy homeostasis, obesity and eating disorders: recent advances in endocrinology. J Nutr. 2004;134:295–8.PubMedGoogle Scholar
  26. 26.
    Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263–307.CrossRefPubMedGoogle Scholar
  27. 27.
    Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med. 1999;130:671–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature. 2000;404:652–60.PubMedGoogle Scholar
  29. 29.
    Kajimura S, Spiegelman BM, Seale P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 2015;22:546–59.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Choi HY, Kim S, Park JW, Lee NS, Hwang SY, Huh JY, Hong HC, Yoo HJ, Baik SH, Youn BS, Mantzoros CS, Choi KM. Implication of circulating irisin levels with brown adipose tissue and sarcopenia in humans. J Clin Endocrinol Metab. 2014;99:2778–85.CrossRefPubMedGoogle Scholar
  31. 31.
    Farooqi IS. Defining the neural basis of appetite and obesity: from genes to behaviour. Clin Med. 2014;14:286–9.CrossRefGoogle Scholar
  32. 32.
    Seoane-Collazo P, Fernø J, Gonzalez F, Diéguez C, Leis R, Nogueiras R, López M. Hypothalamic-autonomic control of energy homeostasis. Endocrine. 2015;50:276 [Epub ahead of print].CrossRefPubMedGoogle Scholar
  33. 33.
    Ahima RS, Antwi DA. Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am. 2008;37:811–23.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep. 2007;7:1–2.CrossRefPubMedGoogle Scholar
  35. 35.
    Berridge KC. Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev. 1996;20:1–25.CrossRefPubMedGoogle Scholar
  36. 36.
    Peciña S, Cagniard B, Berridge KC, Aldridge JW, Zhuang X. Hyperdopaminergic mutant mice have higher “wanting” but not “liking” for sweet rewards. J Neurosci. 2003;23:9395–402.PubMedGoogle Scholar
  37. 37.
    Browning LM, Hsieh SD, Ashwell M. A systematic review of waist-to-height ratio as a screening tool for the prediction of cardiovascular disease and diabetes: 0.5 could be a suitable global boundary value. Nutr Res Rev. 2010;23:247–69.CrossRefPubMedGoogle Scholar
  38. 38.
    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.CrossRefPubMedGoogle Scholar
  39. 39.
    Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63:2985–3023.CrossRefPubMedGoogle Scholar
  40. 40.
    Bray G, Ryan D. Medical approaches to treatment of the obese patient. In: Mantzoros C, editor. Obesity and diabetes. Totowa: Humana Press; 2006. p. 57–469.Google Scholar
  41. 41.
    Tsai AG, Wadden TA. The evolution of very-low-calorie diets: an update and meta-analysis. Obesity (Silver Spring). 2006;14:1283–93.CrossRefGoogle Scholar
  42. 42.
    Look AHEAD Research Group, Wadden TA, West DS, Delahanty L, Jakicic J, Rejeski J, et al. The Look AHEAD Study: A Description of the Lifestyle Intervention and the Evidence Supporting It. Obesity. 2006;14:737–52.CrossRefGoogle Scholar
  43. 43.
    Dutton GR, Lewis CE. The look AHEAD trial: implications for lifestyle intervention in type 2 diabetes mellitus. Prog Cardiovasc Dis. 2015;58:69–75.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Thompson WG, Cook DA, Clark MM, Bardia A, Levine JA. Treatment of obesity. Mayo Clin Proc. 2007;82:93–101.CrossRefPubMedGoogle Scholar
  45. 45.
    Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998;352:167–72.CrossRefPubMedGoogle Scholar
  46. 46.
    Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155–61.CrossRefPubMedGoogle Scholar
  47. 47.
    Kushner RF, Apovian CM, Fujioka K. Obesity consults – comprehensive obesity management in 2013: understanding the shifting paradigm. Obesity (Silver Spring). 2013;21 Suppl 2:S3–13; quiz S14–5.Google Scholar
  48. 48.
    Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity. J Hypertens. 2014;32:1178–88.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bray GA, Ryan DH. Update on obesity pharmacotherapy. Ann N Y Acad Sci. 2014;1311:1–13.CrossRefPubMedGoogle Scholar
  50. 50.
    Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341–52.CrossRefPubMedGoogle Scholar
  51. 51.
    Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330–42.CrossRefGoogle Scholar
  52. 52.
    Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297–308.CrossRefPubMedGoogle Scholar
  53. 53.
    Pucci A, Finer N. New medications for treatment of obesity: metabolic and cardiovascular effects. Can J Cardiol. 2015;31:142–52.CrossRefPubMedGoogle Scholar
  54. 54.
    VICTOZA (liraglutide injection) prescribing information. Plainsboro: Novo Nordisk Inc. 2013.Google Scholar
  55. 55.
    FDA approves weight-management drug Saxenda. Food and drug administration website. 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.html. Accessed Oct 15 2015.
  56. 56.
    Saxenda Risk Evaluation and Mitigation Strategy (REMS). Plainsboro: Novo Nordisk Inc. 2014.Google Scholar
  57. 57.
    Clinicaltrials.gov website. Effect of liraglutide on body weight in overweight or obese subjects with type 2 diabetes: SCALE™ – diabetes. 2014. https://clinicaltrials.gov/ct2/show/NCT01557166
  58. 58.
    Bray GA. Medical treatment of obesity: the past, the present and the future. Best Pract Res Clin Gastroenterol. 2014;28:665–84.CrossRefPubMedGoogle Scholar
  59. 59.
    Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care. 2015;38:1161–72.CrossRefPubMedGoogle Scholar
  60. 60.
    Blackburn GL, Mun EC. Therapy insight: weight-loss surgery and major cardiovascular risk factors. Nat Clin Pract Cardiovasc Med. 2005;2:585–91.CrossRefPubMedGoogle Scholar
  61. 61.
    Gagner M, Matteotti R. Laparoscopic biliopancreatic diversion with duodenal switch. Surg Clin North Am. 2005;85:141–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Kelly J, Tarnoff M, Shikora S, Thayer B, Jones DB, Forse RA. Best practice recommendations for surgical care in weight loss surgery. Obes Res. 2005;13:227–33.CrossRefPubMedGoogle Scholar
  63. 63.
    Puzziferri N, Roshek 3rd TB, Mayo HG, Gallagher R, Belle SH, Livingston EH. Long-term follow-up after bariatric surgery: a systematic review. JAMA. 2014;312:934–42.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kwok CS, Pradhan A, Khan MA, Anderson SG, Keavney BD, Myint PK. Bariatric surgery and its impact on cardiovascular disease and mortality: a systematic review and meta-analysis. Int J Cardiol. 2014;173:20–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Pontiroli AE, Morabito A. Long-term prevention of mortality in morbid obesity through bariatric surgery. A systematic review and meta-analysis of trials performed with gastric banding and gastric bypass. Ann Surg. 2011;253:484–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Boido A, Ceriani V, Cetta F, Lombardi F, Pontiroli AE. Bariatric surgery and prevention of cardiovascular events and mortality in morbid obesity: mechanisms of action and choice of surgery. Nutr Metab Cardiovasc Dis. 2015;25:437–43.CrossRefPubMedGoogle Scholar
  67. 67.
    Sarwe DB, Wadden TA, Fabricatore AN. Psychosocial and behavioral aspects of bariatric surgery. Obes Res. 2005;13:639–48.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Hannah Mathew
    • 1
  • Stavroula A. Paschou
    • 1
    Email author
  • Kalliopi M. Aramapatzi
    • 1
  • William Hsu
    • 1
  • Christos S. Mantzoros
    • 1
  1. 1.Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations