A New Leptin-Mediated Mechanism for Stimulating Fatty Acid Oxidation: A Pivotal Role for Sarcolemmal FAT/CD36
Open accessAbstract
Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-d-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptin-stimulated AMPK phosphorylation does not enhance fatty acid oxidation.
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Leptin-mediated activation of AMPK leads to phosphorylation and inhibition of ACC, reducing malonyl-CoA levels, which inhibits CPT1 and thereby reduces FA entry into mitochondria for β-oxidation.
“The leptin-mediated activation of AMPK leads to the phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), a rate-limiting enzyme in de novo fatty acid biosynthesis. This results in a reduction in the levels of malonyl-CoA, an inhibitor of CPT1, the enzyme responsible for shuttling FAs into mitochondria for β-oxidation”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [99]
The Results section reports that leptin increased AMPK and ACC phosphorylation, and the Figure 6 description links this pathway to increased fatty acid oxidation. Our copy does not establish the claimed reduction in malonyl-CoA. Moreover, the claim’s statement that this pathway reduces fatty-acid entry and oxidation conflicts with Figure 6’s description of increased fatty-acid uptake and oxidation; that reduction is not stated in the verbatim citing sentence. (LLM, conf=0.87)
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“This results in a reduction in the levels of malonyl-CoA, an inhibitor of CPT1, the enzyme responsible for shuttling FAs into mitochondria for β -oxidation [99].”
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- Authors
- Momken, I., Chabowski, A., Dirkx, E., Nabben, M., Jain, S. S., McFarlan, J. T., Glatz, J. F. C., Luiken, J. J. F. P., & Bonen, A.
- Affiliations
- Université d'Évry Val-d'Essonne (FR)
- Medical University of Białystok (PL)
- Maastricht University (NL)
- University of Guelph (CA)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2016-12-22
- Volume
- 474
- Issue
- 1
- Pages
- 149-162
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2556060577
- Cited by
- 30
- References
- 56
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Heart and Stroke Foundation of Canada
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (916.14.050)
- Transnationale Universiteit Limburg
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- leptin, fatty acid oxidation, FAT/CD36, AMPK, fatty acid uptake, sarcolemma, skeletal muscle, cardiomyocytes, AMPK phosphorylation, adipokine signaling
- MeSH terms
- Animals, Cell Line, Fatty Acids, Oleic Acids, Oxidation-Reduction, Phosphorylation, Sarcolemma, Succinimides, Vidarabine, Mice, Knockout, Muscle, Skeletal, CD36 Antigens, Leptin, Protein Transport, Myocytes, Cardiac, Mice, Rats, AMP-Activated Protein Kinases
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