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Clinical Trial
. 2025 May 6;37(5):1060-1074.e4.
doi: 10.1016/j.cmet.2025.03.011. Epub 2025 Apr 8.

Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation

Eric Ravussin  1 , Guillermo Sanchez-Delgado  2 , Corby K Martin  1 , Robbie A Beyl  1 , Frank L Greenway  1 , Libbey S O'Farrell  3 , William C Roell  3 , Hui-Rong Qian  3 , Jing Li  3 , Hiroshi Nishiyama  3 , Axel Haupt  3 , Edward J Pratt  3 , Shweta Urva  3 , Zvonko Milicevic  4 , Tamer Coskun  5
Affiliations
Clinical Trial

Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation

Eric Ravussin et al. Cell Metab. .

Abstract

Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.

Keywords: GIP; GLP-1; adaptive thermogenesis; energy balance; energy expenditure; energy intake; fat oxidation; obesity; sleeping metabolic rate; weight loss.

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Conflict of interest statement

Declaration of interests L.S.O., W.C.R., H.-R.Q., J.L., H.N., A.H., E.J.P., S.U., Z.M., and T.C. are employees and shareholders of Eli Lilly and Company. E.R. has received grants or contracts from Amazon, Eli Lilly and Company, ICON, Novartis, and Sanofi; has received consulting fees from Altimmune, Amway (Nutrilite Health), Eli Lilly and Company, Energesis Pharmaceuticals, Generian, Kintai Therapeutics, Merck, Novo Nordisk, and YSOPIA Bioscience (LNC Therapeutics); has received honoraria from National Institutes of Health (NORC Review) and Open Academy of Medicine; and has received support for attending meetings from Aegean Conference on Precision Nutrition, American Association of Clinical Endocrinology, Clermont Auvergne University, Eli Lilly and Company Obesity Working Group, Frontiers in Obesity, Diabetes, and Metabolism Seminar, Les Journées Françaises de Nutrition, Lipedema Foundation Retreat, National Institutes of Health (NORC Review), New York University Grand Rounds, The Obesity Society, Quebec Society of Lipidology, Nutrition and Metabolism, RACMEM, Société Francophone du Diabète, and Tulane Personalized Health Institute. G.S.-D. has received support for attending meetings and travel from Eli Lilly and Company. C.K.M. serves on advisory boards for EHE Health and Wondr Health; receives compensation to facilitate continuing education events for Commission on Dietetic Registration; receives royalties from ABGIL (paid to his institution); receives research support from Eli Lilly and Company, Foundation for Food & Agriculture Research, Henry M. Jackson Foundation for the Advancement of Military Medicine, Leona M. and Harry B. Helmsley Charitable Trust, National Institute for Health and Care Research, National Institutes of Health National Science Foundation, State of Louisiana Federal American Rescue Plan, United States Department of Agriculture, and WW International; and receives honoraria and/or travel reimbursement for giving presentations and other academic activities from Bray Course Planning Committee, Brigham Young University, Duke University, Indiana University Bloomington, University of Alabama at Birmingham, University of Kansas Medical Center, and University of Nebraska-Lincoln. F.L.G. has received grants or contracts from Eli Lilly and Company; has received consulting fees from Altimmune, Dexcom, Basic Research, and NovMetaPharma; has received support for attending meetings and/or travel from Biohaven; and has stock or stock options in Pep-10, Slim Health Nutrition Inc., Rejuvenate Bio, Energesis Pharmaceuticals, Ketogenic Health System, GATC Health, and Uplifting Results Labs Inc.

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