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.