CPT1C deficiency in SF1 neurons impairs early metabolic adaptation to dietary fats, leading to obesity
Molecular Metabolism. 2025-06-01; 96: 102155
DOI: 10.1016/j.molmet.2025.102155
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Fosch A(1), Pizarro DS(1), Zagmutt S(1), Reguera AC(1), Batallé G(1),
Rodríguez-García M(1), García-Chica J(1), Freire-Agulleiro O(2), Miralpeix C(3),
Zizzari P(4), Serra D(5), Herrero L(5), López M(6), Cota D(4),
Rodríguez-Rodríguez R(7), Casals N(8).
Author information:
(1)Department of Biomedical Sciences, Faculty of Medicine and Health Sciences,
Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain.
(2)Department of Physiology, CIMUS, University of Santiago de
Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782,
Spain.
(3)Department of Biomedical Sciences, Faculty of Medicine and Health Sciences,
Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain;
INSERM, Neurocentre Magendie, U1215, University of Bordeaux, 3300 Bordeaux,
France.
(4)INSERM, Neurocentre Magendie, U1215, University of Bordeaux, 3300 Bordeaux,
France.
(5)Department of Biochemistry and Physiology, School of Pharmacy and Food
Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB),
Universitat de Barcelona, Barcelona, 08028 Spain; Centro de Investigación
Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN),
Instituto de Salud Carlos III, 28029 Madrid, Spain.
(6)Department of Physiology, CIMUS, University of Santiago de
Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782,
Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad
y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.
(7)Department of Biomedical Sciences, Faculty of Medicine and Health Sciences,
Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain;
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la
Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Electronic address: .
(8)Department of Biomedical Sciences, Faculty of Medicine and Health Sciences,
Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain;
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la
Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Electronic address: .
OBJECTIVES: SF1 neurons of the ventromedial hypothalamus (VMH) play a pivotal
role in regulating body weight and adiposity, particularly in response to a
high-fat diet (HFD), as well as in the recovery from insulin-induced
hypoglycemia. While the brain-specific CPT1C isoform is well known for its role
in controlling food intake and energy homeostasis, its function within specific
hypothalamic neuronal populations remains largely unexplored. Here, we explore
the role of CPT1C in SF1 neurons.
METHODS: Mice deficient in CPT1C within SF1 neurons were generated, and their
response to a HFD was investigated.
RESULTS: SF1-Cpt1c-KO mice fail to adjust their caloric intake during initial
HFD exposure, which is associated with impaired activation of the melanocortin
system. Furthermore, these mice exhibit disrupted metabolic gene expression in
the liver, muscle, and adipose tissue, leading to increased adiposity
independently of food intake. In contrast, their response to glucose or insulin
challenges remains intact. After long-term HFD exposure, SF1-Cpt1c-KO mice are
more prone to developing obesity and glucose intolerance than control
littermates, with males exhibiting a more severe phenotype. Interestingly, CPT1C
deficiency in SF1 neurons also results in elevated hypothalamic endocannabinoid
(eCB) levels under both chow and HFD conditions. We propose that this sustained
eCB elevation reduces VMH activation by fatty acids and impairs the SF1-POMC
drive upon fat intake.
CONCLUSION: Our findings establish CPT1C in SF1 neurons as essential for
VMH-driven dietary fat sensing, satiety, and lipid metabolic adaptation.
Copyright © 2025 The Author(s). Published by Elsevier GmbH.. All rights
reserved.
DOI: 10.1016/j.molmet.2025.102155
PMID: 40268191
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.