Modification of hypothalamic
fatty acid (FA) metabolism can improve energy homeostasis and prevent
hyperphagia and excessive
weight gain in diet-induced
obesity (DIO) from a diet high in
saturated fatty acids. We have shown previously that C75, a stimulator of
carnitine palmitoyl transferase-1 (CPT-1) and
fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate
acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during
lipid excess with
palmitate. Both compounds enhanced
palmitate oxidation, increased
ATP, and inactivated
AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased
palmitate availability and prevented the production of fatty
acylglycerols,
ceramides, and
cholesterol esters,
lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of
reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and
inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess
lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal
ATP and lead to decreased food intake and
body weight to improve systemic metabolism.