The causes of obesity relapse after weight loss

The main problem of obesity treatment is the difficulty of long-term weight maintenance. From one point of view, it can easily be explained by patients’ low compliance and absence of self-control. From another point of view, body weight is regulated not only by persons will, but also by multiple physiological mechanisms. Moreover, studies demonstrate that the attempts to reduce body weight stimulate the activation of adaptive biological process that block weight reduction.

Despite the variety of obesity treatment methods, only few patients are able to achieve significant (at least 5–7%) weight loss and maintain the result. In most cases people return to the initial weight in about 3–5 years. Therefore it is relevant to study weight regain mechanisms in order to identify new effective obesity treatment strategies.

The objective of this review is to summarize the information about the main issues of central, peripheral and behavioral pathogenic mechanisms which lead to disease relapse after obesity treatment and ideas for future strategies to resolve them.

1. McGuire MT, Wing RR, Hill JO. The prevalence of weight loss maintenance among American adults. Int J Obes Relat Metab Disord. 1999;23(12):1314-1319. doi: https://doi.org/10.1038/sj.ijo.0801075

2. AG, Jacquet J, Girardier L. Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues. Am J Clin Nutr. 1997;65(3):717-723. doi: https://doi.org/10.1093/ajcn/65.3.717

3. Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr. 2001;74(5):579-584. doi: https://doi.org/10.1093/ajcn/74.5.579

4. Leibel RL, Rosenbaum M, Hirsch J. Changes in Energy Expenditure Resulting from Altered Body Weight. N Engl J Med. 1995;332(10):621-628. doi: https://doi.org/10.1056/NEJM199503093321001

5. Dulloo A, Jacquet J, Girardier L. Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues. Am J Clin Nutr. 1997;65(3):717-723. doi: https://doi.org/10.1093/ajcn/65.3.717

6. Zitting KM, Vujovic N, Yuan RK, et al. Human Resting Energy Expenditure Varies with Circadian Phase. Curr Biol. 2018;28(22):3685-3690.e3. doi: https://doi.org/10.1016/j.cub.2018.10.005

7. Окороков П.Л., Васюкова О.В., Ширяева Т.Ю. Скорость основного обмена в покое и факторы его вариабельности у подростков с простым ожирением // Вопросы детской диетологии. — 2019. — Т. 17. — №3. — 5–9. doi: https://doi.org/10.20953/1727-5784-2019-3-5-9

8. Дедов И.И. Болезни жировой ткани / Под общ. ред. Дедова И.И. — М.: ГЭОТАР-Медиа, 2020. — 224 с.

9. Crujeiras AB, Goyenechea E, Abete I, et al. Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. J Clin Endocrinol Metab. 2010; 95:pp. 5037-5044. doi: https://doi.org/10.1210/jc.2009-2566

10. Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J Endocrinol. 2016;174(6):775-784. doi: https://doi.org/10.1530/EJE-15-1116

11. Knerr PJ, Finan B, Gelfanov V, Perez-Tilve D, Tschöp MH, DiMarchi RD. Optimization of peptide-based polyagonists for treatment of diabetes and obesity. Bioorg Med Chem. 2018;26(10):2873-2881. doi: https://doi.org/10.1016/j.bmc.2017.10.047

12. Crujeiras AB, Goyenechea E, Abete I, et al. Weight Regain after a Diet-Induced Loss Is Predicted by Higher Baseline Leptin and Lower Ghrelin Plasma Levels. J Clin Endocrinol Metab. 2010;95(11):5037-5044. doi: https://doi.org/10.1210/jc.2009-2566 7.

13. Hinkle W, Cordell M, Leibel R, et al. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One. 2013;8:e59114. doi: https://doi.org/10.1371/journal.pone.0059114. 8

14. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. doi: https://doi.org/10.1056/NEJMoa1105816

15. Jensen SBK, Janus C, Lundgren JR, et al. Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment. Nat Commun. 2022;13(1):4770. doi: https://doi.org/10.1038/s41467-022-32307-y

16. Johnson AW. Eating beyond metabolic need: how environmental cues influence feeding behavior. Trends Neurosci. 2013;36(2):101-109. doi: https://doi.org/10.1016/j.tins.2013.01.002

17. Hall KD. Did the Food Environment Cause the Obesity Epidemic? Obesity. 2018;26(1):11-13. doi: https://doi.org/10.1002/oby.22073

18. Massey A, Hill AJ. Dieting and food craving. A descriptive, quasi-prospective study. Appetite. 2012;58(3):781-785. doi: https://doi.org/10.1016/j.appet.2012.01.020

19. Blundell JE, Cooling J. Routes to obesity: Phenotypes, food choices and activity. In: British Journal of Nutrition. 2000. doi: https://doi.org/10.1017/s0007114500000933

20. Bolotova NV, Kurdiyan MS, Filina NYu. Neuroendocrine mechanisms of regulation of eating behavior (review). Saratovskii nauchno-meditsinskii zhurnal. 2020;16(3):707-13 (in Russian)

21. Dedov II, Troshina EA, Mazurina NV, et al. The role of neurotransmitters in regulation of energy homeostasis and possibility of drug correction of its disturbances in obesity. Obesity and metabolism. 2016;13(1):9-15 (in Russian). doi: https://doi.org/10.14341/OMET201619-15

22. Berezina MV, Mihaleva OG, Bardymova TP. The obesity: mechanisms of development. Sibirskii meditsinskii zhurnal. 2012(7):15-8 (in Russian)

23. Anikina NV, Smirnova EN. The value of blood serotonin for effective weight loss in obese women. Obesity and metabolism. 2015;12(3):31-5 (in Russian). doi: https://doi.org/10.14341/OMET2015331-35

24. Turenius CI, Htut MM, Prodon DA, et al. GABA(A) receptors in the lateral hypothalamus as mediators of satiety and body weight regulation. Brain Res. 2009;1262:16-24. doi: https://doi.org/10.1016/j.brainres.2009.01.016

25. Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3–36. Eur J Endocrinol. 2016;174(6):775-784. doi: https://doi.org/10.1530/EJE-15-1116

26. DeBenedictis JN, Nymo S, Ollestad KH, et al. Changes in the Homeostatic Appetite System After Weight Loss Reflect a Normalization Toward a Lower Body Weight. J Clin Endocrinol Metab. 2020;105(7):e2538-e2546. doi: https://doi.org/10.1210/clinem/dgaa202

27. Knerr PJ, Mowery SA, Finan B, Perez-Tilve D, Tschöp MH, DiMarchi RD. Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates. Peptides. 2020;125:170225. doi: https://doi.org/10.1016/j.peptides.2019.170225

28. Gadde KM, Allison DB, Ryan DH, 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(9774):1341-1352. doi: https://doi.org/10.1016/S0140-6736(11)60205-5

29. Yavuz S, Salgado Nunez del Prado S, Celi FS. Thyroid Hormone Action and Energy Expenditure. J Endocr Soc. 2019;3(7):1345-1356. doi: https://doi.org/10.1210/js.2018-00423

30. Bitar A, Fellmann N, Vernet J, et al. Variations and determinants of energy expenditure as measured by whole-body indirect calorimetry during puberty and adolescence. Am J Clin Nutr. 1999;69(6):1209-1216. doi: https://doi.org/10.1093/ajcn/69.6.1209

31. Rosenbaum M, Vandenborne K, Goldsmith R, et al. Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects. Am J Physiol Regul Integr Comp Physiol. 2003;285(1):R183-92. doi: https://doi.org/10.1152/ajpregu.00474.2002

32. Müller MJ, Enderle J, Bosy-Westphal A. Changes in Energy Expenditure with Weight Gain and Weight Loss in Humans. CurrObes Rep. 2016;5(4):413-423. doi: https://doi.org/10.1007/s13679-016-0237-4

33. Weinsier RL, Nagy TR, Hunter GR, et al. Do adaptive changes in metabolic rate favor weight regain in weight-reduced individuals? An examination of the set-point theory. Am J Clin Nutr. 2000;72(5):1088–94

34. Weinsier RL, Hunter GR, Zuckerman PA, Darnell BE. Low resting and sleeping energy expenditure and fat use do not contribute to obesity in women. Obes Res. 2003;11(8):937–44

35. Flatt JP. Exaggerated claim about adaptive thermogenesis. Int J Obes. 2007;31(10):1626; author reply 1627–8.

36. Wyatt HR, Grunwald GK, Seagle HM, et al. Resting energy expenditure in reduced-obese subjects in the National Weight Control Registry. Am J Clin Nutr. 1999;69(6):1189–93

37. Larson DE, Ferraro RT, Robertson DS, Ravussin E. Energy metabolism in weight-stable postobese individuals. Am J Clin Nutr. 1995;62(4):735–9

38. Fothergill E, Guo J, Howard L, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity. 2016;24(8):1612–19

39. Choi KM. Sarcopenia and sarcopenic obesity. Korean J Intern Med. 2016;31(6):1054-1060. doi: https://doi.org/10.3904/kjim.2016.193

40. Dulloo AG, Jacquet J, Montani JP, Schutz Y. Adaptive thermogenesis in human body weight regulation: more of a concept than a measurable entity? Obes Rev. 2012;13(Suppl 2):105–21

41. Burke LE, Wang J, Sevick MA. Self-monitoring in weight loss: a systematic review of the literature. J Am Diet Assoc. 2011;111(1):92–102

42. Milsom VA, Middleton KM, Perri MG. Successful long-term weight loss maintenance in a rural population. Clin Interv Aging. 2011;6:303–9.

43. Peterson ND, Middleton KR, Nackers LM, et al. Dietary self-monitoring and long-term success with weight management. Obesity. 2014;22(9):1962–7

44. Laitner MH, Minski SA, Perri MG. The role of self-monitoring in the maintenance of weight loss success. Eat Behav. 2016;21:193–7

45. Piya MK, Chimoriya R, Yu W, et al. Improvement in Eating Disorder Risk and Psychological Health in People with Class 3 Obesity: Effects of a Multidisciplinary Weight Management Program. Nutrients. 2021; 13(5):1425. doi: https://doi.org/10.3390/nu13051425

46. Forman EM, Schumacher LM, Crosby R, et al. Ecological momentary assessment of dietary lapses across behavioral weight loss treatment: characteristics, predictors, and relationships with weight change. Ann Behav Med. 2017;51(5):741–53

47. Kaliyan A, Kumaran VS, Prasanna S, Ethirajan N, Manjunath R, Jeganathan S. Impact of a Multidisciplinary Lifestyle Intervention on Weight Reduction in Overweight and Obese Adolescents- A Longitudinal Study. J Clin DIAGNOSTIC Res. 2021. doi: https://doi.org/10.7860/JCDR/2021/50887.15362

48. Zhang Y, Liu J, Yao J, Ji G, et al. Obesity: pathophysiology and intervention. Nutrients. 2014; 186(11):5153-83

49. Beck AT, Haigh EA. Advances in cognitive theory and therapy: the generic cognitive model. Annu Rev Clin Psychol. 2014;10:1-24. doi: https://doi.org/10.1146/annurev-clinpsy-032813-153734