Reconsidering metabolic adaptation in weight loss evidence: insights and potential limitations of tirzepatide-induced fat oxidation

References

[1] Rosenbaum M.Adaptive thermogenesis in humans.Int J Obes2010;34:S47-55 PMCID:PMC3673773

[2] Redman LM,Burton JH,Il’yasova D.Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging.Cell Metab2018;27:805-15.e4 PMCID:PMC5886711

[3] Johannsen DL,Huizenga R,Ravussin E.Metabolic slowing with massive weight loss despite preservation of fat-free mass.J Clin Endocrinol Metab2012;97:2489-96 PMCID:PMC3387402

[4] Venniyoor A.Tirzepatide once weekly for the treatment of obesity.N Engl J Med2022;387:1433-4

[5] Wadden TA,Machineni S.Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial.Nat Med2023;29:2909-18 PMCID:PMC10667099

[6] Aronne LJ, Sattar N, Horn DB, et al; SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331:38-48.

[7] Ravussin E,Martin CK.Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.Cell Metab2025;37:1060-74.e4

[8] Gabery S,Paulsen SJ.Semaglutide lowers body weight in rodents via distributed neural pathways.JCI Insight2020;5:133429 PMCID:PMC7213778

[9] Redman LM, Heilbronn LK, Martin CK, et al; Pennington CALERIE Team. Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS One. 2009;4:e4377. PMCID:PMC2634841

[10] Sumithran P,Delbridge E.Long-term persistence of hormonal adaptations to weight loss.N Engl J Med2011;365:1597-604

[11] Cummings DE,Frayo RS.Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.N Engl J Med2002;346:1623-30

[12] Ravussin E,Anderson TE,Bogardus C.Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber.J Clin Invest1986;78:1568-78 PMCID:PMC423919

[13] Fothergill E,Howard L.Persistent metabolic adaptation 6 years after “The Biggest Loser” competition.Obesity2016;24:1612-9 PMCID:PMC4989512

[14] Schoeller DA.Recent advances from application of doubly labeled water to measurement of human energy expenditure.J Nutr1999;129:1765-8

[15] Hall KD.Predicting metabolic adaptation, body weight change, and energy intake in humans.Am J Physiol Endocrinol Metab2010;298:E449-66 PMCID:PMC2838532

[16] Martins C,Hunter GR.Metabolic adaptation delays time to reach weight loss goals.Obesity2022;30:400-6 PMCID:PMC8852805

[17] Leibel RL,Hirsch J.Changes in energy expenditure resulting from altered body weight.N Engl J Med1995;332:621-8

[18] Magkos F.On adaptive thermogenesis: just another weight-loss tale?.Am J Clin Nutr2020;112:1157-9

[19] Blundell J,Axelsen M.Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.Diabetes Obes Metab2017;19:1242-51 PMCID:PMC5573908

[20] O’Neil PM,McGowan B.Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.Lancet2018;392:637-49

[21] Astrup A, Rössner S, Van Gaal L, et al; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606-16.

[22] Pi-Sunyer X, Astrup A, Fujioka K, et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22.

[23] Finan B,Ottaway N.Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.Sci Transl Med2013;5:209ra151

[24] Finan B,Ottaway N.A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.Nat Med2015;21:27-36

[25] Kim T,Holleman C.Glucagon receptor signaling regulates energy metabolism via hepatic farnesoid X receptor and fibroblast growth factor 21.Diabetes2018;67:1773-82 PMCID:PMC6110317

[26] Corbin KD,Allerton TD.Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: a randomized trial.Obesity2023;31:350-62 PMCID:PMC9881753

[27] Heise T,Urva S.Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes.Diabetes Care2023;46:998-1004 PMCID:PMC10154650