Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice
Open accessAbstract
The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether “lead-in” calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care. • Combining lifestyle interventions with drug treatments presents untapped potential for obesity management. • Lead–in calorie restriction enhances the maximal achievable weight loss with semaglutide and tirzepatide in mice. • The amplified weight loss is reflected in loss of fat mass and preserved energy expenditure. • Calorie restriction prior to treatment with the MC4R agonist setmelanotide has no additional weight loss benefits.
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In DIO mice, 7 or 14 days of calorie restriction prior to commencement of semaglutide or tirzepatide treatment lowered the weight loss plateau of these drugs.
“showing that 7 or 14 days of calorie restriction in DIO mice prior to commencement of semaglutide or tirzepatude treatment lowered the weight loss plateau of these drugs (126).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [126]
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GLP-1 and the Neurobiology of Eating Control: Recent Advances
Jones, L. A., & Brierley, D. I. (2025) · Endocrinology · doi:10.1210/endocr/bqae167 · Cited by 43 · see citing works
- Authors
- Petersen, J., Merrild, C., Lund, J., Holm, S., & Clemmensen, C.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Clemmensen, Christoffer
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 89
- Pages
- 102027
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC11424796
- OpenAlex
- W4402509701
- Cited by
- 13
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 1
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Københavns Universitet (NNF23SA0084103)
- Novo Nordisk Foundation (NNF22OC0073778, NNF17SA0031406, NNF18CC0034900)
- Danish Diabetes and Endocrine Academy (NNF20SA0064340)
- Lundbeck Foundation
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- caloric restriction, obesity treatment, pharmacological weight loss, incretin-based therapy, semaglutide, tirzepatide, setmelanotide, GLP-1 receptor agonists, GIP receptor agonist, melanocortin-4 receptor agonist, diet-induced obesity, energy expenditure, energy intake, fat mass, weight loss plateau, lifestyle intervention
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-2 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Semaglutide, alpha-MSH, Animals, Energy Metabolism, Glucagon-Like Peptides, Gastric Inhibitory Polypeptide, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Receptors, Gastrointestinal Hormone, Weight Loss, Caloric Restriction, Receptor, Melanocortin, Type 4, Mice, Incretins
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