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Cited by 32Adipose Tissue and MetabolismMitochondrial Function and PathologyMetabolism, Diabetes, and Cancer

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle

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Choi, Ran Hee, Karasawa, Takuya, Meza, Cesar A., Maschek, J. Alan, Manuel, Allison M., Nikolova, Linda S., Fisher‐Wellman, Kelsey H., Cox, James E. +2 more·2025·Obesity
DOI 10.1002/oby.24274PMC PMC12015655

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Abstract

Objective: Glucagon‐like peptide‐1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity‐related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet‐mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency. Methods: C57BL/6J mice were fed a high‐fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rates of ATP production and oxygen (O 2 ) consumption were measured via high‐resolution respirometry and fluorometry to determine OXPHOS efficiency in muscle at these two time points. Results: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O 2 consumed in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (LYRM7 and TTC19; p < 0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits. Conclusions: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

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  • GLP-1RAs can directly influence skeletal muscle function.

    “Emerging research also indicates that GLP-1RAs can directly influence skeletal muscle function.”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [41]

    The Discussion (page not provided) reports increased skeletal muscle mitochondrial efficiency after semaglutide treatment in mice, supporting an influence on muscle function. But the paper frames this as an effect of semaglutide-induced weight loss; it does not establish that GLP-1 receptor agonists act directly on skeletal muscle. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The findings on GLP-1RA effects on skeletal muscle are very limited and presented in animal and in vitro models.

    “It is important to emphasize that these findings are very limited and presented in animal and in vitro models.”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [41]

    The study reports semaglutide findings in mice, with mitochondrial measurements in permeabilized muscle fibers and isolated mitochondria (Abstract, Conclusions; Methods, High-resolution respirometry and fluorometry; no page numbers supplied). This supports caution about applying its findings to humans, but the paper does not establish that the broader evidence on GLP-1RA effects on skeletal muscle is 'very limited' or confined to animal and in vitro models. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In obese mice, semaglutide treatment, despite reducing lean mass, improved skeletal muscle oxidative phosphorylation (OXPHOS) efficiency and ameliorated mitochondrial morphology reducing swelling.

    “Moreover, in obese mice model, semaglutide treatment, despite reducing lean mass, improved skeletal muscle oxidative phosphorylation (OXPHOS) efficiency (41) and ameliorated mitochondrial morphology reducing swelling (42).”

    From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [41]

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Authors
Choi, R. H., Karasawa, T., Meza, C. A., Maschek, J. A., Manuel, A. M., Nikolova, L. S., Fisher‐Wellman, K. H., Cox, J. E., Chaix, A., & Funai, K.
Affiliations
  • University of Utah (US)
  • Atrium Health Wake Forest Baptist (US)
Corresponding author
  • Choi, Ran Hee
  • Karasawa, Takuya
  • Funai, Katsuhiko
ORCID
Venue
Obesity
Publisher
Wiley
Published
2025-04-20
Volume
33
Issue
5
Pages
974-985
ISSN
  • 1930-7381 (ISSN-L)
  • 1930-739X
DOI
10.1002/oby.24274
PMC
PMC12015655
OpenAlex
W4409651701
Cited by
32
References
43
Citations by year
2026: 19 · 2025: 13
FWCI
20.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Obesity (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of General Medical Sciences (GM144613)
  • Japan Society for the Promotion of Science (24KJ2039)
  • National Institute on Aging (AG065993, AG074535)
  • National Cancer Institute (CA278826)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK107397, DK110858, DK127979)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
semaglutide, GLP-1 receptor agonists, weight loss, weight regain, skeletal muscle, oxidative phosphorylation, ATP production, oxygen consumption, high-fat diet, mitochondrial proteomics

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