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

Highlights

• CPT1C deficiency in VMH-SF1 neurons disrupts metabolic adaptation of peripheral tissues to dietary fats.
• SF1-Cpt1c-KO mice exhibit transitory hyperphagia upon a consumption of a HFD.
• CPT1C deficiency in VMH-SF1 neurons elevates hypothalamic eCBs.
• Fatty acid-driven VMH activation is abolished in CPT1C-deficient SF1 neurons.

Abstract

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.