Increasing Fatty Acid Oxidation Remodels the Hypothalamic Neurometabolome to Mitigate Stress and Inflammation

Abstract

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.

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

“…Ceramides (and other lipotoxic species such as diacylglycerol, cholesterol esters, and dihexosylceramide) are increased in the hypothalamus of HFD versus low-fat diet mice [214] , as well as in the brain of streptozocin-induced diabetic rats [215] . In line with this, increments in hypothalamic fatty acid oxidation preventing the production of fatty acylglycerols, ceramides, and cholesterol esters can revert ER stress levels, and this reduction in lipotoxicity leads to decreased food intake and body weight, improving systemic metabolism [216] . Mechanistically, it was described in cellular models that ceramides induce ER calcium depletion through SERCA (sarco/endoplasmic reticulum Ca 2+ -ATPase) inhibition, leading to disrupted ER Ca 2+ homeostasis and triggering a UPR [217,218] .…”

“…In fact, it is now clear that hypothalamic lipotoxicity is able to disrupt energy balance. Specifically, some lipid species like palmitate and ceramides have been associated with hypothalamic inflammation and ER stress, which in turn promotes resistance to anorexigenic signals and decreases energy expenditure through impairment of the sympathetic control of brown fat [96,99,187,189,216] . Despite a growing understanding of how hypothalamic ER stress may lead to metabolic dysfunction, a deeper understanding of the molecular mechanism mediating hypothalamic lipotoxicity is warranted in order to develop therapeutic strategies useful against obesity and related comorbidities.…”

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

“…Saturated fatty acids have been shown to increase hypothalamic inflammation via TLR4 (149). In contrast, increasing fatty acid oxidation in hypothalamic neurons can decrease palmitate-induced inflammation and toxicity (155). These observations highlight the need for more research to understand the mechanism of lipotoxic inflammation in the CNS leading to metabolic dysregulation.…”

Inflammation and Oxidative Stress: Critical Role for Metabolic Syndrome

“…Enhancing of the ROS production in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and endoplasmatic reticulum (ER) stress responses [31].…”