Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism

Abstract

Metabolic disorders, particularly aberrations in lipid homeostasis, such as obesity, type 2 diabetes mellitus, and hypertriglyceridemia often manifest together as the metabolic syndrome (MetS). Despite major advances in our understanding of the pathogenesis of these disorders, the prevalence of the MetS continues to rise. It is becoming increasingly apparent that intermediary metabolism within the central nervous system is a major contributor to the regulation of systemic metabolism. In particular, lipid metabolism within the brain is tightly regulated to maintain neuronal structure and function and may signal nutrient status to modulate metabolism in key peripheral tissues such as the liver. There is now a growing body of evidence to suggest that fatty acid (FA) sensing in hypothalamic neurons via accumulation of FAs or FA metabolites may signal nutritional sufficiency and may decrease hepatic glucose production, lipogenesis, and VLDL-TG secretion. In addition, recent studies have highlighted the existence of liver-related neurons that have the potential to direct such signals through parasympathetic and sympathetic nervous system activity. However, to date whether these liver-related neurons are FA sensitive remain to be determined. The findings discussed in this review underscore the importance of the autonomic nervous system in the regulation of systemic metabolism and highlight the need for further research to determine the key features of FA neurons, which may serve as novel therapeutic targets for the treatment of metabolic disorders.

Keywords: brain; energy homeostasis; hypothalamus; lipid metabolism; liver.

Figure 1

Schematic representation of the neuronal regulation of hepatic carbohydrate and lipid metabolism. Neurons of discrete hypothalamic nuclei including the paraventricular nucleus (PVN) and arcuate nucleus (ARC) within the mediobasal hypothalamus respond to neuronal inputs to regulate hepatic glucose and very low density lipoprotein (VLDL-TG) metabolism. The accumulation or application of long-chain fatty acids (LCFAs), such as oleic acid (OA), glucose, and melanocortin (MC) signaling act through the autonomic nervous system to signal nutritional plenty a reduced requirement for energy substrate mobilization, by inhibiting VLDL-TG secretion and hepatic glucose production (HGP). This is at least in part due to reduced stearol-CoA desatrate-1 (SCD1) expression. In contrast, hypothalamic NPY is indicative of hunger and nutritional deficiency and can increase energy substrate mobilization via an increase in VLDL-TG and SCD1 expression and HGP. The features of these fatty acid and nutritionally sensitive neurons are unclear; however, pseudorabies virus-152 labeling supports the notion that liver-related neurons in the PVN exist and may be involved in this autonomic regulation of hepatic metabolism.