C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight
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Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes. However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty-acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.
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Pharmacological and genetic inhibition of hypothalamic CPT1A has been reported to reduce food intake.
“Even so, in the last decade, pharmacological and genetic inhibition of hypothalamic CPT1A has been reported to reduce the food intake ([10](#B10), [110](#B110), [127](#B127)), potentially as a result of LCFA-CoA cytoplasmic accumulation.”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [110]
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Mitochondrial fatty acid oxidation in obesity
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- Authors
- Mera, P., Bentebibel, A., López-Viñas, E., Cordente, A. G., Gurunathan, C., Sebastián, D., Vázquez, I., Herrero, L., Ariza, X., Gómez-Puertas, P., Asins, G., Serra, D., García, J., & Hegardt, F. G.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Institut de Biomedicina de la Universitat de Barcelona (ES)
- Corresponding author
- Hegardt, Fausto G.
- ORCID
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 77
- Issue
- 6
- Pages
- 1084-1095
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2150320605
- Cited by
- 57
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 9 · 2021: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 7 · 2012: 5
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- C75, carnitine palmitoyltransferase 1, fatty acid oxidation, hypothalamus, dietary intake, body weight, obesity, type 2 diabetes, hypophagia, enzyme inhibition
- MeSH terms
- Acyl Coenzyme A, Animals, Binding Sites, Body Weight, Carnitine O-Palmitoyltransferase, Eating, Female, Humans, Hypothalamus, 4-Butyrolactone, Weight Loss, Rats, Sprague-Dawley, Protein Structure, Secondary, Mice, Rats
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