European Journal of Applied Physiology

, Volume 102, Issue 4, pp 381–390 | Cite as

Reduced physical activity and risk of chronic disease: the biology behind the consequences

  • Frank W. BoothEmail author
  • Matthew J. Laye
  • Simon J. Lees
  • R. Scott Rector
  • John P. Thyfault
Invited Review


This review focuses on three preserved, ancient, biological mechanisms (physical activity, insulin sensitivity, and fat storage). Genes in humans and rodents were selected in an environment of high physical activity that favored an optimization of aerobic metabolic pathways to conserve energy for a potential, future food deficiency. Today machines and other technologies have replaced much of the physical activity that selected optimal gene expression for energy metabolism. Distressingly, the negative by-product of a lack of ancient physical activity levels in our modern civilization is an increased risk of chronic disease. We have been employing a rodent wheel-lock model to approximate the reduction in physical activity in humans from the level under which genes were selected to a lower level observed in modern daily functioning. Thus far, two major changes have been identified when rats undertaking daily, natural voluntary running on wheels experience an abrupt cessation of the running (wheel lock model). First, insulin sensitivity in the epitrochlearis muscle of rats falls to sedentary values after 2 days of the cessation of running, confirming the decline to sedentary values in whole-body insulin sensitivity when physically active humans stop high levels of daily exercise. Second, visceral fat increases within 1 week after rats cease daily running, confirming the plasticity of human visceral fat. This review focuses on the supporting data for the aforementioned two outcomes. Our primary goal is to better understand how a physically inactive lifestyle initiates maladaptations that cause chronic disease.


Exercise Evolution Metabolism Adaptation Insulin sensitivity Adipose tissue 



The authors thank the University of Missouri Research Board (FB), the College of Veterinary Medicine Research Fund (FB), and the Life Sciences Predoctoral Fellowship Program (ML) for support of the reported research. The review was written while supported by Department of Veterans Affairs Career Development Grant—CDA-2 (JPT) and Department of Internal Medicine at University of Missouri (RSR).


  1. Åstrand PO, Rodahl K (1970). Textbook of work physiology. McGraw-Hill, New YorkGoogle Scholar
  2. Bassett DR, Schneider PL, Huntington GE (2004) Physical activity in an Old Order Amish community. Med Sci Sports Exerc 36:79–85PubMedCrossRefGoogle Scholar
  3. Bennett AF, Ruben JA (1979) Endothermy and activity in vertebrates. Science 206:649–654PubMedCrossRefGoogle Scholar
  4. Berlin CM, Schimke RT (1965) Influence of turnover rates on the responses of enzymes to cortisone. Mol Pharmacol 1:149–156PubMedGoogle Scholar
  5. Blair SN, Powell KE, Bazzarre TL, Early JL, Epstein LH, Green LW, Harris SS, Haskell WL, King AC, Koplan J (1993) Physical inactivity. Workshop V. AHA prevention conference III. Behavior change and compliance: keys to improving cardiovascular health. Circulation 88:1402–1405PubMedGoogle Scholar
  6. Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G (1985) Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 248:E286–E291PubMedGoogle Scholar
  7. Booth FW, Lees SJ (2007) Fundamental questions about genes, inactivity, and chronic diseases. Physiol Genomics 28:146–157PubMedGoogle Scholar
  8. Booth FW, Tseng BS (1995) America needs to exercise for health. Med Sci Sports Exerc 27:462–465PubMedGoogle Scholar
  9. Booth FW, Gordon SE, Carlson CJ, Hamilton MT (2000) Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol 88:774–787PubMedGoogle Scholar
  10. Booth FW Chakravarthy MV, Gordon SE, Spangenburg EE (2002a) Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy. J Appl Physiol 93:3–30Google Scholar
  11. Booth FW, Chakravarthy MV, Spangenburg EE (2002b) Exercise and gene expression: physiological regulation of the human genome through physical activity. J Physiol 543:399–411PubMedCrossRefGoogle Scholar
  12. Boudou P, Sobngwi E, Mauvais-Jarvis F, Vexiau P, Gautier JF (2003) Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men. Eur J Endocrinol 149:421–424PubMedCrossRefGoogle Scholar
  13. Brooks GA, Fahey TD, Baldwin KM (2005) Exercise physiology. McGraw-HIll, New YorkGoogle Scholar
  14. Burstein R, Polychronakos C, Toews CJ, MacDougall JD, Guyda HJ, Posner BI (1985) Acute reversal of the enhanced insulin action in trained athletes. Association with insulin receptor changes. Diabetes 34:756–760PubMedCrossRefGoogle Scholar
  15. Centers for Disease Control and Prevention (2007) Physical activity termsGoogle Scholar
  16. Chakravarthy MV, Booth FW (2004) Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol 96:3–10PubMedCrossRefGoogle Scholar
  17. Cordain L, Gotshall RW, Eaton SB, Eaton SB III (1998) Physical activity, energy expenditure and fitness: an evolutionary perspective. Int J Sports Med 19:328–335PubMedCrossRefGoogle Scholar
  18. Eaton SB, Konner M, Shostak M (1988) Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med 84:739–749PubMedCrossRefGoogle Scholar
  19. Eaton SB, Strassman BI, Nesse RM, NEEL JV, Ewald PW, Williams GC, Weder AB, Eaton SB III, Lindeberg S, Konner MJ, Mysterud I, Cordain L (2002) Evolutionary health promotion. Prev Med 34:109–118PubMedCrossRefGoogle Scholar
  20. Goldberg AL, Dice JF (1974) Intracellular protein degradation in mammalian and bacterial cells. Annu Rev Biochem 43:835–869PubMedCrossRefGoogle Scholar
  21. Grundy SM (1999) Primary prevention of coronary heart disease: integrating risk assessment with intervention. Circulation 100:988–998PubMedGoogle Scholar
  22. Huang B, Wu P, Bowker-Kinley MM, Harris RA (2002) Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51:276–283PubMedCrossRefGoogle Scholar
  23. International Diabetes Federation (2007) Diabetes prevalence
  24. Irwin ML, Yasui Y, Ulrich CM, Bowen D, Rudolph RE, Schwartz RS, Yukawa M, Aiello E, Potter JD, McTiernan A (2003) Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trial. JAMA 289:323–330PubMedCrossRefGoogle Scholar
  25. Kay SJ, Fiatarone Singh MA (2006) The influence of physical activity on abdominal fat: a systematic review of the literature. Obes Rev 7:183–200PubMedCrossRefGoogle Scholar
  26. Koch LG, Britton SL (2007) Evolution, atmospheric oxygen, and complex disease. Physiol Genomics 30:205–208PubMedCrossRefGoogle Scholar
  27. Kramer FM, Jeffery RW, Forster JL, Snell MK (1989) Long-term follow-up of behavioral treatment for obesity: patterns of weight regain among men and women. Int J Obes 13:123–136PubMedGoogle Scholar
  28. Kump DS, Booth FW (2005a) Alterations in insulin receptor signalling in the rat epitrochlearis muscle upon cessation of voluntary exercise. J Physiol 562:829–838PubMedCrossRefGoogle Scholar
  29. Kump DS, Booth FW (2005b) Sustained rise in triacylglycerol synthesis and increased epididymal fat mass when rats cease voluntary wheel running. J Physiol 565:911–925PubMedCrossRefGoogle Scholar
  30. Kump DS, Laye MJ, Booth FW (2006) Increased mitochondrial glycerol-3-phosphate acyltransferase protein and enzyme activity in rat epididymal fat upon cessation of wheel running. Am J Physiol Endocrinol Metab 290:E480–E489PubMedCrossRefGoogle Scholar
  31. Laye MJ, Thyfault JP, Stump CS, Booth FW (2007) Inactivity induces increases in abdominal fat. J Appl Physiol 102:1341–1347PubMedCrossRefGoogle Scholar
  32. Lipman RL, Raskin P, Love T, Triebwasser J, Lecocq FR, Schnure JJ (1972) Glucose intolerance during decreased physical activity in man. Diabetes 21:101–107PubMedGoogle Scholar
  33. Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291:1238–1245PubMedCrossRefGoogle Scholar
  34. Mourier A, Gautier JF, De KE, Bigard AX, Villette JM, Garnier JP, Duvallet A, Guezennec CY, Cathelineau G (1997) Mobilization of visceral adipose tissue related to the improvement in insulin sensitivity in response to physical training in NIDDM. Effects of branched-chain amino acid supplements. Diabetes Care 20:385–391PubMedCrossRefGoogle Scholar
  35. Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14:353–362PubMedGoogle Scholar
  36. Oshida Y, Yamanouchi K, Hayamizu S, Nagasawa J, Ohsawa I, Sato Y (1991) Effects of training and training cessation on insulin action. Int J Sports Med 12:484–486PubMedCrossRefGoogle Scholar
  37. Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, Cline GW, Befroy D, Zemany L, Kahn BB, Papademetris X, Rothman DL, Shulman GI (2007) Inaugural Article: The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci USA 104:12587–12594PubMedCrossRefGoogle Scholar
  38. Pilegaard H, Osada T, Andersen LT, Helge JW, Saltin B, Neufer PD (2005) Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise. Metabolism 54:1048–1055PubMedCrossRefGoogle Scholar
  39. Raymond J, Segre D (2006) The effect of oxygen on biochemical networks and the evolution of complex life. Science 311:1764–1767PubMedCrossRefGoogle Scholar
  40. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607PubMedCrossRefGoogle Scholar
  41. Reaven GM (2001) Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease: syndrome X revisited. In: Jefferson LS, Cherrington AD (eds) Handbook of physiology. Section 7: the endocrine system. Vol II: the endocrine pancreas and regulation of metabolism. Oxford University Press, New York, pp 1169–1197Google Scholar
  42. Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I (2000) Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 133:92–103PubMedGoogle Scholar
  43. Ross R, Janssen I, Dawson J, Kungl AM, Kuk JL, Wong SL, Nguyen-Duy TB, Lee S, Kilpatrick K, Hudson R (2004) Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 12:789–798PubMedGoogle Scholar
  44. Schimke RT (1970) Regulation of protein degradation in mammalian tissues. In: Munto HN (eds) Mammalian protein metabolism. Academic, New York, pp 177–228Google Scholar
  45. Seider MJ, Nicholson WF, Booth FW (1982) Insulin resistance for glucose metabolism in disused soleus muscle of mice. Am J Physiol 242:E12–E18PubMedGoogle Scholar
  46. Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, Tanner CJ, Duscha BD, Kraus WE (2005) Inactivity, exercise, and visceral fat. STRRIDE: a randomized, controlled study of exercise intensity and amount. J Appl Physiol 99:1613–1618PubMedCrossRefGoogle Scholar
  47. Sugden MC, Holness MJ (2006) Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem 112:139–149PubMedCrossRefGoogle Scholar
  48. US Department of Health and Human Resources (1996) Physical Activity and Health: A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GAGoogle Scholar
  49. Wadden TA, Sternberg JA, Letizia KA, Stunkard AJ, Foster GD (1989) Treatment of obesity by very low calorie diet, behavior therapy, and their combination: a five-year perspective. Int J Obes 13(Suppl 2):39–46PubMedGoogle Scholar
  50. Wadden TA, Butryn ML, Byrne KJ (2004) Efficacy of lifestyle modification for long-term weight control. Obes Res 12(Suppl):151S–162SPubMedCrossRefGoogle Scholar
  51. Weiss EP, Holloszy JO (2007) Improvements in body composition, glucose tolerance, and insulin action induced by increasing energy expenditure or decreasing energy intake. J Nutr 137:1087–1090PubMedGoogle Scholar
  52. Wendorf M, Goldfine ID (1991) Archaeology of NIDDM. Excavation of the “thrifty” genotype. Diabetes 40:161–165PubMedCrossRefGoogle Scholar
  53. Willet WC, Koplan JP, Nugent R, Dusenbury C, Puska P, Gaziano TA (2006) Prevention of chronic disease by means of diet and lifestyle changes. In: Jamison DT, Breman JG, Measham, Measham AR, Alleyne G, Evans DB, Jha P, Mills A, Musgrove P (eds) Disease control priorities in developing countries. World Bank, pp 833–850Google Scholar
  54. Williams GC, Nesse RM (1991) The dawn of Darwinian medicine. Q Rev Biol 66:1–22PubMedCrossRefGoogle Scholar
  55. Winder WW, Baldwin KM, Holloszy JO (1974) Enzymes involved in ketone utilization in different types of muscle: adaptation to exercise. Eur J Biochem 47:461–467PubMedCrossRefGoogle Scholar
  56. Wing RR, Hill JO (2001) Successful weight loss maintenance. Annu Rev Nutr 21:323–341PubMedCrossRefGoogle Scholar
  57. Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL (2006) A self-regulation program for maintenance of weight loss. N Engl J Med 355:1563–1571PubMedCrossRefGoogle Scholar
  58. Wyatt HR, Peters JC, Reed GW, Barry M, Hill JO (2005) A Colorado statewide survey of walking and its relation to excessive weight. Med Sci Sports Exerc 37:724–730PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Frank W. Booth
    • 1
    • 2
    • 5
    • 7
    Email author
  • Matthew J. Laye
    • 2
    • 7
  • Simon J. Lees
    • 1
    • 7
  • R. Scott Rector
    • 4
    • 7
  • John P. Thyfault
    • 3
    • 4
    • 6
    • 7
  1. 1.Department of Biomedical SciencesUniversity of MissouriColumbiaUSA
  2. 2.Department of Medical Pharmacology and PhysiologyUniversity of MissouriColumbiaUSA
  3. 3.Department of Nutritional SciencesUniversity of MissouriColumbiaUSA
  4. 4.Department of MedicineUniversity of MissouriColumbiaUSA
  5. 5.Dalton Cardiovascular InstituteUniversity of MissouriColumbiaUSA
  6. 6.Harry S. Truman Memorial VA HospitalColumbiaUSA
  7. 7.Health Activity CenterUniversity of MissouriColumbiaUSA

Personalised recommendations