A nutrient-sensitive CPT1C-ABHD6 axis regulates BMP homeostasis and endolysosomal function in hypothalamic neurons

The endolysosomal system is central to neuronal homeostasis, yet how nutrient sensing regulates endolysosomal lipids remains poorly understood. Bis(monoacylglycero)phosphate (BMP), a signature phospholipid of late endosomes, is required for intraluminal vesicle formation, cholesterol handling, and lysosomal function, but the mechanisms preserving neuronal BMP homeostasis are largely unknown. Here, we identify a nutrient-sensitive pathway linking metabolic state to BMP homeostasis in hypothalamic neurons. We show that the neuronal lipid sensor carnitine palmitoyltransferase 1C (CPT1C) restrains the BMP hydrolase ABHD6. Loss of CPT1C increases ABHD6 activity, lowers intracellular BMP levels, and impairs endosomal maturation, extracellular vesicle release, and lysosomal acidification and proteolytic activity. Acute ABHD6 inhibition restores BMP levels in CPT1C-deficient neurons, indicating that BMP depletion results primarily from enhanced hydrolysis. Lipid overload similarly increases ABHD6 activity and lowers BMP levels in wild-type neurons and hypothalamus, whereas CPT1C-deficient cells and mice display constitutively elevated ABHD6 activity and fail to further adapt to lipid excess. Together, these findings identify CPT1C as a nutrient-sensitive regulator of neuronal BMP homeostasis and endolysosomal function.