CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity

Rosalía Rodríguez-Rodríguez, Cristina Miralpeix, Anna Fosch, Macarena Pozo, María Calderón-Domínguez, Xavier Perpinyà, Miquel Vellvehí, Miguel López, Laura Herrero, Dolors Serra, Núria Casals

Carnitine palmitoyltransferase 1 isoform C (CPT1C) is located in the endoplasmic reticulum of hypothalamic neurons. It is able to bind malonyl-CoA, suggesting that it could act as a sensor of this lipid intermediary. CPT1C knockout (KO) mice are more prone to become obese when chronically fed a high fat diet with a reduced peripheral fatty acid oxidation. Rodríguez-Rodríguez et al. show that the obese phenotype and metabolic inflexibility that characterizes CPT1C KO mice is related to an impaired brown adipose tissue thermogenesis. Thus, their data uncover CPT1C as a key factor in the control of brown fat thermogenesis.

Objective: Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity.

Methods: CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed.

Results: Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype.

Conclusions: CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity.