LIPID SENSING BY CPT1C REGULATES BMP-DEPENDENT ENDOLYSOSOMAL HOMEOSTASIS IN HYPOTHALAMIC NEURONS

The neuronal endolysosomal system is essential for maintaining metabolic and cellular homeostasis. Bis(monoacylglycerol)phosphate (BMP), a phospholipid enriched in late endosome intraluminal vesicles, plays a central role in endosomal maturation, lysosomal activity, and extracellular vesicle (EV) biogenesis, yet how nutrient availability and metabolic stress regulate BMP metabolism and endolysosomal lipid homeostasis in neurons remains poorly understood. The enzyme ABHD6 has emerged as an important BMP hydrolase in the brain, and our recent work demonstrates that the neuron-specific carnitine-palmitoyltransferase-1C (CPT1C) negatively regulates alpha/beta-Hydrolase-domain-6 (ABHD6) enzyme activity in a nutrient-dependent manner. Here, we investigated whether CPT1C regulates BMP metabolism and endolysosomal homeostasis through modulation of ABHD6 activity. We generated a CPT1C-deficient hypothalamic neuronal model using CRISPR-Cas9 and examined the consequences of CPT1C loss on BMP metabolism and endolysosomal homeostasis under basal and fatty acid–exposure conditions. Our results showed that loss of CPT1C selectively increased ABHD6 activity, leading to enhanced BMP degradation. CPT1C deficiency resulted in smaller and less mature endosomes, impaired lysosomal acidification and proteolytic activity, and a marked reduction in EV secretion. Exposure to saturated or unsaturated long-chain fatty acids increased ABHD6 activity and reduced BMP levels in wild-type neurons, whereas CPT1C-deficient neurons were unaffected. Consistent with these observations, high-fat diet selectively reduced BMP levels and increased ABHD6 activity in the hypothalamus of wild-type but not CPT1C-knockout mice, indicating loss of nutrient-dependent regulation. Overall, this study identifies a novel nutrient-sensitive regulatory axis linking metabolic state to BMP metabolism and endolysosomal function in hypothalamic neurons, with potential implications for neuronal homeostasis.