Intermittent Fasting: Is the Wait Worth the Weight?

Abstract

Purpose of Review

We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models and recent clinical trials.

Recent Findings

Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition, and delays aging. Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio varies by model, IF protocol, age at initiation, and duration.

Summary

We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More rigorous research is needed.

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Fig. 1

Abbreviations

IF:

Intermittent fasting

CR:

Calorie restriction

ICR:

Intermittent calorie restriction

ER:

Energy restriction

TRF:

Time-restricted feeding

PF:

Prolonged fasting

ADER:

Alternate-day energy restriction

CER:

Continuous energy restriction

RCT:

Randomized controlled trial

GIR:

Glucose infusion rate

Si:

Insulin sensitivity

ROS:

Reactive oxygen species

ad lib:

Ad libitum

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Flegal KMK, Kruszon-Moran D, Carroll MDM, Fryar CDC, Ogden CCL, et al. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. American Medical Association. 2016;315:2284–91. https://doi.org/10.1001/jama.2016.6458.

    Article  CAS  Google Scholar 

  2. 2.

    Collier R. Intermittent fasting: the next big weight loss fad. CMAJ. 2013;185:E321–2. https://doi.org/10.1503/cmaj.109-4437.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    • Golbidi S, Daiber A, Korac B, Li H, Essop MF, Laher I. Health benefits of fasting and caloric restriction. Curr Diab Rep. 2017;17:123. This recent review summarizes some of the cellular mechanisms underlying the benefits of fasting and caloric restriction

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    •• St-Onge M-P, Ard J, Baskin ML, Chiuve SE, Johnson HM, Kris-Etherton P, et al. Meal timing and frequency: implications for cardiovascular disease prevention: a scientific statement from the American Heart Association. Circulation. 2017;135:e96–121. https://doi.org/10.1161/CIR.0000000000000476. This statement provides an up-to-date review of the effects of meal timing on cardiovascular disease risk.

  5. 5.

    Varady KA, Bhutani S, Church EC, Klempel MC. Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults. Am J Clin Nutr. 2009;90:1138–43. https://doi.org/10.3945/ajcn.2009.28380.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Collier R. Intermittent fasting: the science of going without. CMAJ Canadian Medical Association. 2013;185:E363–4.

    Article  Google Scholar 

  7. 7.

    Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. Elsevier. 1963;281:785–9. https://doi.org/10.1016/S0140-6736(63)91500-9.

    Article  Google Scholar 

  8. 8.

    Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am. J. Physiol. Metab. Am Physiological Soc. 2009;297:E578–91. https://doi.org/10.1152/ajpendo.00093.2009.

    CAS  Article  Google Scholar 

  9. 9.

    Gropper S, Smith J. Integration and regulation of metabolism and the impact of exercise and sport. In: Feldman E, Cronin S, Myers M, editors. Advanced nutrition and human metabolism. Wadsworth, Cengage Learning. 2013. p. 256–9.

  10. 10.

    Unger RHH. Roth MGG. A new biology of diabetes revealed by leptin. Cell Metab. Elsevier. 2015;21:15–20. https://doi.org/10.1016/j.cmet.2014.10.011.

    Article  CAS  Google Scholar 

  11. 11.

    Azzout B, Bois-Joyeux B, Chanez M, Peret J. Development of gluconeogenesis from various precursors in isolated rat hepatocytes during starvation or after feeding a high protein, carbohydrate-free diet. J Nutr. 1987;117:164–9. Available from: http://jn.nutrition.org/content/117/1/164.short.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22. https://doi.org/10.1146/annurev.nutr.26.061505.111258.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Wasserman DH. Four grams of glucose. Am. J. Physiol. Metab.. American Physiological Society. 2009;296:E11–21. https://doi.org/10.1152/ajpendo.90563.2008.

    CAS  Article  Google Scholar 

  14. 14.

    Stannard SR, Thompson MW, Fairbairn K, Huard B, Sachinwalla T, Thompson CH, et al. Fasting for 72 h increases intramyocellular lipid content in nondiabetic, physically fit men. Am. J. Physiol. Metab.. American Physiological Society. 2002;283:E1185–91. https://doi.org/10.1152/ajpendo.00108.2002.

    CAS  Article  Google Scholar 

  15. 15.

    • Anton SD, Moehl K, Donahoo WT, Marosi K, Lee SA, Mainous AG, et al. Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity. 2017. This review synthesizes the animal and human data on the metabolic benefits of fasting.

  16. 16.

    Bass J, Lazar MA. Circadian time signatures of fitness and disease. Science. 2016;354(80):994–9. Available from: http://science.sciencemag.org/content/354/6315/994.abstract.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Nørrelund H. The metabolic role of growth hormone in humans with particular reference to fasting. Growth Horm. IGF Res. Elsevier. 2005;15:95–122. https://doi.org/10.1016/j.ghir.2005.02.005.

    Article  CAS  Google Scholar 

  18. 18.

    Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005;81:69–73. Available from: http://ajcn.nutrition.org/content/81/1/69.full.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    • Byrne NMM, Sainsbury A, King NA, Hills AP, Wood RE. Intermittent energy restriction improves weight loss efficiency in obese men: the MATADOR study. Int. J. Obes.. 2017;42(2):129–8. https://doi.org/10.1038/ijo.2017.206 This recent RCT of ICR and CER in males found that REE decreased to a greater extent in the ICR group, suggesting that IF without CR may lead to weight gain.

  20. 20.

    Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, et al. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br. J. Nutr. 2013;110:1534–47. Available from: https://www.cambridge.org/core/article/effect-of-intermittent-energy-and-carbohydrate-restriction-v-daily-energy-restriction-on-weight-loss-and-metabolic-disease-risk-markers-in-overweight-women/BC03063A5D8E9446D5090DB083A4B226.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes. 2011;35:714–27.

  22. 22.

    Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Varady KA. Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans. Obesity. 2013;21:1370–9. https://doi.org/10.1002/oby.20353.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    •• Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults. JAMA Intern Med. 2017;177:930–8. https://doi.org/10.1001/jamainternmed.2017.0936 This study showed minimal between group differences, though dropout rate in the ADF group (38%) was one of the highest observed in this review.

  24. 24.

    Trepanowski JF, Kroeger CM, Barnosky A, Klempel M, Bhutani S, Hoddy KK, et al. Effects of alternate-day fasting or daily calorie restriction on body composition, fat distribution, and circulating adipokines: Secondary analysis of a randomized controlled trial. Clin. Nutr. Elsevier; 2017.

  25. 25.

    Teng NIMFN, Shahar S, Rajab NFN, Manaf ZA, Johari MHM, Ngah WZWW. Improvement of metabolic parameters in healthy older adult men following a fasting calorie restriction intervention. Aging Male. 2013;16:177–83. https://doi.org/10.3109/13685538.2013.832191.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Varady KA, Bhutani S, Klempel MC, Kroeger CM. Comparison of effects of diet versus exercise weight loss regimens on LDL and HDL particle size in obese adults. Lipids Health Dis. 2011;10:119.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Keogh JB, Pedersen E, Petersen KS, Clifton PM. Effects of intermittent compared to continuous energy restriction on short-term weight loss and long-term weight loss maintenance. Clin Obes. 2014;4:150–6. https://doi.org/10.1111/cob.12052.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Hussin NM, Shahar S, Teng NIMF, Ngah WZW, Das SK. Efficacy of fasting and calorie restriction (FCR) on mood and depression among ageing men. J Nutr Heal Aging. 2013;17:674–80.

    Article  CAS  Google Scholar 

  29. 29.

    Varady KA, Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Haus JM, et al. Alternate day fasting for weight loss in normal weight and overweight subjects: a randomized controlled trial. Nutr J. 2013;12:146.

  30. 30.

    Teng NIMF, Shahar S, Manaf ZA, Das SK, Taha CSC, Ngah WZW. Efficacy of fasting calorie restriction on quality of life among aging men. Physiol Behav. 2011;104:1059–64.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    • Catenacci VA, Pan Z, Ostendorf D, Brannon S, Gozansky WS, Mattson MP, et al. A randomized pilot study comparing zero-calorie alternate-day fasting to daily caloric restriction in adults with obesity. 2016;24:1874–83. Changes in fat mass and FFM were more favorable in the ADF group than in the CR group.

  32. 32.

    Harder-Lauridsen NM, Nielsen ST, Mann SP, Lyngbæk MP, Benatti FB, Langkilde AR, et al. The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: a randomized trial. J Appl Physiol. 2017;122:230–41. https://doi.org/10.1152/japplphysiol.00846.2016.

  33. 33.

    Eshghinia S, Mohammadzadeh F. The effects of modified alternate-day fasting diet on weight loss and CAD risk factors in overweight and obese women. J Diabetes Metab Disord. 2013;12:4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Klempel MC, Kroeger CM, Varady KA. Alternate day fasting (ADF) with a high-fat diet produces similar weight loss and cardio-protection as ADF with a low-fat diet. Metabolism. 2013;62:137–43.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    • Barnosky AR, Kroeger CM, Trepanowski JF, Bhutani S, Hoddy KK, Gabel K, et al. Effect of alternate day fasting on markers of bone metabolism: an exploratory analysis of a 6-month randomized controlled trial. Nutr Heal Aging2 IOS Press. 2017;4:255–63. Insulin resistance decreased to a greater extent, independent of a change in lean mass, in the ADF group over the CR group.

    Article  Google Scholar 

  36. 36.

    Gutch M, Kumar S, Razi S, Gupta K, Gupta A. Assessment of insulin sensitivity/resistance. Indian J Endocrinol Metab. 2015;19:160. Available from: http://www.ijem.in/text.asp?2015/19/1/160/146874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Halberg N, Henriksen M, Söderhamn N, Stallknecht B, Ploug T, Schjerling P, et al. Effect of intermittent fasting and refeeding on insulin action in healthy men. J. Appl. Physiol. American Physiological Society. 2005;99:2128–36. https://doi.org/10.1152/japplphysiol.00683.2005.

    Article  CAS  Google Scholar 

  38. 38.

    Soeters MR, Lammers NM, Dubbelhuis PF, Ackermans MT, Jonkers-Schuitema CF, Fliers E, et al. Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism. Am J Clin Nutr. 2009;90:1244–51.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Heilbronn LK, Civitarese AE, Bogacka I, Smith SR, Hulver M, Ravussin E. Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obes Res. 2005;13:574–81.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Wegman MP, Shankar MN, Guo MH, Bennion DM, Chrzanowski SM, Goldberg LA, et al. Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. Rejuvenation Res. 2015;18:162–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007;42:665–74. https://doi.org/10.1016/j.freeradbiomed.2006.12.005.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 2017;39:46–58. Available from: http://www.sciencedirect.com/science/article/pii/S1568163716302513.

    Article  PubMed  Google Scholar 

  43. 43.

    Wan R, Ahmet I, Brown M, Cheng A, Kamimura N, Talan M, et al. Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. J Nutr Biochem. 2010;21:413–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2854256&tool=pmcentrez&rendertype=abstract.

  44. 44.

    Varady KA, Hudak CS, Hellerstein MK. Modified alternate-day fasting and cardioprotection: relation to adipose tissue dynamics and dietary fat intake. Metabolism Elsevier Inc. 2009;58:803–11. https://doi.org/10.1016/j.metabol.2009.01.018.

    CAS  Article  Google Scholar 

  45. 45.

    • Antoni R, Johnston KL, Collins AL, Robertson MD. Investigation into the acute effects of total and partial energy restriction on postprandial metabolism among overweight/obese participants. Br J Nutr. 2016;115:951–9. This study suggests that CER could alter cardiometabolic risk independent of weight change.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Horne BD, Muhlestein JB, May HT, Carlquist JF, Lappé DL, Bair TL, et al. Relation of routine, periodic fasting to risk of diabetes mellitus, and coronary artery disease in patients undergoing coronary angiography. Am J Cardiol. 2012;109:1558–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22425331%5Cn, http://www.sciencedirect.com/science/article/pii/S0002914912005954.

  47. 47.

    Gomez-Pinilla F. The influences of diet and exercise on mental health through hormesis. Ageing Res. Rev. 2008;7(1):49–62. https://doi.org/10.1016/j.arr.2007.04.003.

  48. 48.

    Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16:129–37.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev. 2006;5:332–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Betteridge D. What is oxidative stress? Metabolism. 2000;49:3–8.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci. 2003;100:6216–20. https://doi.org/10.1073/pnas.1035720100.

  52. 52.

    Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech Ageing Dev. 1990;55:69–87. Available from: http://www.sciencedirect.com/science/article/pii/004763749090107Q.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and Sirtuin 3: physiological modulators of metabolism. Physiol Rev. 2012;92:1479–514. https://doi.org/10.1152/physrev.00022.2011.

  54. 54.

    Allard JS, Heilbronn LK, Smith C, Hunt ND, Ingram DK, Ravussin E, et al. In vitro cellular adaptations of indicators of longevity in response to treatment with serum collected from humans on calorie restricted diets. PLoS one. Public Libr Sci. 2008;3:e3211. https://doi.org/10.1371/journal.pone.0003211.

  55. 55.

    Pull CB. Binge eating disorder. Curr Opin Psychiatry. 2004;17:43–8.

    Article  Google Scholar 

  56. 56.

    Vocks S, Tuschen-Caffier B, Pietrowsky R, Rustenbach SJ, Kersting A, Herpertz S. Meta-analysis of the effectiveness of psychological and pharmacological treatments for binge eating disorder. Int J Eat Disord. 2010;43:205–17.

    PubMed  Google Scholar 

  57. 57.

    •• Hoddy KK, Kroeger CM, Trepanowski JF, Barnosky AR, Bhutani S, Varady KA. Safety of alternate day fasting and effect on disordered eating behaviors. Nutr J. 2015;14:44. This study found that depression and binge eating scores decreased after 8 weeks of ADF.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ridaura VK, Faith JJ, Rey FE, Cheng J, Alexis E, Kau AL, et al. Cultured gut microbiota from twins discordant for obesity modulate adiposity and metabolic phenotypes in mice. Science (80-. ). 2013;341.

  59. 59.

    Li G, Xie C, Lu S, Nichols RGG, Tian Y, Li L, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab Cell Metab. 2017;26:672–85. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695033/pdf/nihms917439.pdf

    Article  PubMed  CAS  Google Scholar 

  60. 60.

    Shen R, Wang B, Giribaldi MG, Ayres J, Thomas JB, Montminy M. Neuronal energy-sensing pathway promotes energy balance by modulating disease tolerance. Proc. Natl. Acad. Sci.. 2016;113:E3307–14. Available from: http://www.pnas.org/content/113/23/E3307.abstract

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. 61.

    Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 2014;25(1):42–52. https://doi.org/10.1016/j.tem.2013.09.002

  62. 62.

    Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(80):211–4.

    Article  PubMed  CAS  Google Scholar 

  63. 63.

    Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2015;21:263–9.

  64. 64.

    Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, et al. The β-hydroxybutyrate receptor HCA 2 activates a neuroprotective subset of macrophages. Nat Commun Nature Publishing Group. 2014;5:3944.

    CAS  Article  Google Scholar 

  65. 65.

    Lanza IR, Zabielski P, Klaus KA, Morse DM, Heppelmann CJ, Bergen HR, et al. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. Cell Metab. 2012;16:777–88. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544078/.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. 66.

    Kowaltowski AJ. Caloric restriction and redox state: does this diet increase or decrease oxidant production? Redox Rep. Taylor & Francis. 2011;16:237–41. https://doi.org/10.1179/1351000211Y.0000000014.

    Article  CAS  Google Scholar 

  67. 67.

    Walsh ME, Shi Y, Van Remmen H. The effects of dietary restriction on oxidative stress in rodents. Free Radic Biol Med. 2014;66:88–99. Available from: http://www.sciencedirect.com/science/article/pii/S0891584913002475.

    Article  PubMed  CAS  Google Scholar 

  68. 68.

    Mattson MP. Hormesis defined. Ageing Res Rev. 2008;7:1–7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248601/.

    Article  PubMed  CAS  Google Scholar 

  69. 69.

    Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014;12:288–341. https://doi.org/10.2203/dose-response.13-035.Ristow.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. 70.

    Descamps O, Riondel J, Ducros V, Roussel A-M. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech Ageing Dev Elsevier. 2005;126:1185–91.

    Article  CAS  Google Scholar 

  71. 71.

    Cerqueira FM, Chausse B, Kowaltowski AJ. Intermittent fasting effects on the central nervous system: how hunger modulates brain function. In: Preedy V, Patel VB, editors. Handb. Famine, Starvation, Nutr. Deprivation. Cham: Springer; 2017. p. 1–18. https://doi.org/10.1007/978-3-319-40007-5_29-1.

  72. 72.

    Chausse B, Vieira-Lara MA, Sanchez AB, Medeiros MHG, Kowaltowski J, Kowaltowski AJ. Intermittent fasting results in tissue-specific changes in bioenergetics and redox state. PLoS one. Public Libr Sci. 2015;10:e0120413. https://doi.org/10.1371/journal.pone.0120413.

    Article  CAS  Google Scholar 

  73. 73.

    Lee JM, Wagner M, Xiao R, Kim KH, Feng D, Lazar MA, et al. Nutrient-sensing nuclear receptors coordinate autophagy. Nature. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2014;516:112. doi:https://doi.org/10.1038/nature13961.

  74. 74.

    Liu H-Y, Han J, Cao SY, Hong T, Zhuo D, Shi J, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FOXO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284:31484–92. Available from: http://www.jbc.org/content/284/45/31484.abstract.

  75. 75.

    Liu H, Javaheri A, Godar RJ, Murphy J, Ma X, Rohatgi N, et al. Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway. Autophagy. Taylor & Francis. 2017;13:1952–68. https://doi.org/10.1080/15548627.2017.1368596.

  76. 76.

    • Harvie MN, Sims AH, Pegington M, Spence K, Mitchell A, Vaughan AA, et al. Intermittent energy restriction induces changes in breast gene expression and systemic metabolism. Breast Cancer Res. 2016;18:57. https://doi.org/10.1186/s13058-016-0714-4. This study compared the effects of CER and ICR on serum and urine metabolites as well as breast tissue gene expression.

  77. 77.

    Ong KR, Sims AH, Harvie M, Chapman M, Dunn WB, Broadhurst D, et al. Biomarkers of dietary energy restriction in women at increased risk of breast cancer. Cancer Prev Res. 2009;2:720–31. Available from: http://cancerpreventionresearch.aacrjournals.org/content/2/8/720.abstract

  78. 78.

    •• Kim K-H, Kim YH, Son JE, Lee JH, Kim S, Choe MS, et al. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage. Cell Res The Author(s). 2017;27:1309–26. https://doi.org/10.1038/cr.2017.126 This study demonstrated a new mechanism for IF involving changes in AT inflammation in mice and evaluated correlations between genes involved in this pathway in human AT.

  79. 79.

    Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007. p. 819–26.

  80. 80.

    Homko CJ, Cheung P, Boden G. Effects of free fatty acids on glucose uptake and utilization in healthy women. Diabetes. 2003;52:487–91.

    Article  PubMed  CAS  Google Scholar 

  81. 81.

    Dichlberger A, Schlager S, Maaninka K, Schneider WJ, Kovanen PT. Adipose triglyceride lipase regulates eicosanoid production in activated human mast cells. J Lipid Res. 2014;55:2471–8. https://doi.org/10.1194/jlr.M048553.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. 82.

    Thomas D, Apovian C. Macrophage functions in lean and obese adipose tissue. Metab. - Clin. Exp. Elsevier. 2017;72:120–43.

    Article  CAS  Google Scholar 

  83. 83.

    Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest Am Soc Clin Investig. 2010;120:3466–79.

  84. 84.

    Schreiber R, Zechner R. Lipolysis meets inflammation-arachidonic acid mobilization from fat. J Lipid Res ASBMB. 2014;55:2447–9.

    Article  CAS  Google Scholar 

  85. 85.

    Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic and clinical implications. Hepatology. 2010;51:679–89. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575093/.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. 86.

    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. Wiley Subscription Services, Inc., A Wiley Company. 2012;55:2005–23. https://doi.org/10.1002/hep.25762.

  87. 87.

    Hoeks J, van Herpen NA, Mensink M, Moonen-kornips E, van Beurden D, Hesselink MKC, et al. Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance. Diabetes. 2010;59:2117 LP-2125. Available from: http://diabetes.diabetesjournals.org/content/59/9/2117.abstract.

  88. 88.

    Larter CZ, Chitturi S, Heydet D, Farrell GC. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J. Gastroenterol. Hepatol.. Blackwell Publishing Asia. 2010;25:672–90. https://doi.org/10.1111/j.1440-1746.2010.06253.x.

    Article  CAS  Google Scholar 

  89. 89.

    Li G, Brocker CN, Yan T, Xie C, Krausz KW, Xiang R, Gonzalez FJ Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha. Mol Metab. 2018;7:80–9. Available from: http://www.sciencedirect.com/science/article/pii/S2212877817306440.

  90. 90.

    Cotter DG, Ercal B, Huang X, Leid JM, d’Avignon DA, Graham MJ, et al. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J. Clin. Invest. The American Society for Clinical Investigation. 2014;124:5175–90. https://doi.org/10.1172/JCI76388.

    Article  Google Scholar 

  91. 91.

    Stote KS, Baer DJ, Spears K, Paul DR, Harris GK, Rumpler WV, et al. A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults. Am J Clin Nutr. 2007;85:981–8.

  92. 92.

    Varady KA. Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss? Obes Rev. 2011;12:e593–601.

    Article  PubMed  CAS  Google Scholar 

  93. 93.

    Intermittent fasting trials. 2018 [cited 2018 Jan 3]. Available from: clinicaltrials.gov.

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Funding Sources

This work was supported in part by the National Institutes of Health [UL1TR001430, P30DK046200, T32DK007201].

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Correspondence to Mary-Catherine Stockman.

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Mary-Catherine Stockman declares that she has no conflict of interest.

Dylan Thomas declares that he has no conflict of interest.

Jacquelyn Burke declares that she has no conflict of interest.

Caroline M. Apovian has received research funding through grants from Sanofi-Aventis, Orexigen, Aspire Bariatrics, GI Dynamics, MYOS, Takeda, Gelesis, Vela Foundation, Dr. Robert C. and Veronica Atkins Foundation, Coherence Lab, Energesis, Patient-Centered Outcomes Research Institute (PCORI), the National Institutes of Health (NIH), Eli Lilly, and MetaPrteomics LLC; has received compensation from Nutrisystem, Zafgen, Sanofi-Aventis, Orexigen, Novo Nordisk, GI Dynamics, Takeda, Scientific Intake, Gelesis, Merck, Johnson & Johnson, Amylin, EnteroMedics, Arena Pharmaceuticals, Rhythm Pharmaceuticals, and Xeno Biosciences for service on advisory boards; and owns stock in Science-Smart LLC.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Obesity Treatment

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Stockman, M., Thomas, D., Burke, J. et al. Intermittent Fasting: Is the Wait Worth the Weight?. Curr Obes Rep 7, 172–185 (2018). https://doi.org/10.1007/s13679-018-0308-9

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Keywords

  • Intermittent fasting
  • Fasting
  • Obesity
  • Calorie restriction
  • Metabolism
  • Insulin resistance
  • Weight loss