CPT1C deficiency in SF1 neurons impairs early metabolic adaptation to dietary fats, leading to obesity

Apr 23, 2025Molecular metabolism

Lack of CPT1C in energy-regulating neurons reduces early adjustment to fatty diets, leading to obesity

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Abstract

Mice lacking CPT1C in SF1 neurons exhibit impaired caloric intake regulation during high-fat diet exposure.

SF1-Cpt1c-KO mice do not adjust their caloric intake when first exposed to a high-fat diet.
Impaired activation of the melanocortin system is observed in these mice during high-fat diet exposure.
Disrupted metabolic gene expression in the liver, muscle, and fat tissue leads to increased body fat, regardless of food intake.
Long-term high-fat diet exposure results in greater obesity and glucose intolerance in SF1-Cpt1c-KO mice compared to control mice, with males showing a more severe condition.
CPT1C deficiency in SF1 neurons is associated with increased hypothalamic endocannabinoid levels under both normal and high-fat diet conditions.

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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.

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CPT1C deficiency in SF1 neurons impairs early metabolic adaptation to dietary fats, leading to obesity

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