Hypothalamic lipids and the regulation of energy homeostasis

Abstract

The hypothalamus is a specialised area in the brain that integrates the control of energy homeostasis, regulating both food intake and energy expenditure. The classical theory for hypothalamic feeding control is mainly based on the relationship between peripheral signals and neurotransmitters/neuromodulators in the central nervous system. Thus, hypothalamic neurons respond to peripheral signals, such as hormones and nutrients, by modifying the synthesis of neuropeptides. Despite the well-established role of these hypothalamic networks, increasing evidence indicates that the modulation of lipid metabolism in the hypothalamus plays a critical role in feeding control. In fact, the pharmacologic and genetic targeting of key enzymes from these pathways, such as AMP-activated protein kinase, acetyl-CoA carboxylase, carnitine palmitoyltransferase 1, fatty acid synthase, and malonyl-CoA decarboxylase, has a profound effect on food intake and body weight. Here, we review what is currently known about the relationship between hypothalamic lipid metabolism and whole body energy homeostasis. Defining these novel mechanisms may offer new therapeutic targets for the treatment of obesity and its associated pathologies.

Fig. 1

Fatty acid synthesis pathway: Excess glucose in the cell is first converted to pyruvate via glycolysis in the cytoplasm. Pyruvate enters the mitochondria and is converted to acetyl-CoA and transported as citrate from mitochondria to the cytoplasm. ATP citrate lyase (ACL) then reconverts citrate to acetyl-CoA. Acetyl-CoA carboxylase (ACC) catalyses the carboxylation of acetyl-CoA to malonyl-CoA. Both acetyl-CoA and malonyl-CoA are then used as the substrates for the production of palmitate catalysed by fatty acid synthase (FAS). Malonyl-CoA decarboxylase (MCD) converts malonyl-CoA back to acetyl-CoA. Carnitine palmitoyltransferase 1 (CPT1) is the enzyme importing long-chain fatty acyl-CoA into mitochondria for β-oxidation; CPT1 activity is allosterically inhibited by malonyl-CoA. The resulting saturated fatty acid molecule produced by FAS can be further metabolised depending on requirements, desaturated to form unsaturated fatty acids, derived to triglyceride molecules, or channelled to a range of phospholipids and derivatives for membrane and signalling functions.

Fig. 2

Hypothalamic fatty acid metabolism integrates peripheral signals with neuropeptide systems: Peripheral hormonal and nutrient/metabolic signals operate on the different components of the fatty acid metabolic pathway, modulating the cytoplasmatic pool of malonyl-CoA and palmitoyl-CoA. This effect elicits changes in neuropeptide expression, such as agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine and amphetamine-regulated transcript (CART), and proopiomelanocortin (POMC) by still undefined mechanisms (represented as ?) which ultimately regulates feeding. In addition, current evidence has demonstrated that ghrelin-induced carnitine palmitoyltransferase 1 (CPT1) activation promotes the generation of reactive oxygen species (ROS). Fatty acids and ROS increase uncoupling protein 2(UCP2)-dependent uncoupling activity and UCP2 gene expression which subsequently decreases ROS in a feedback manner, allowing appropriate ghrelin-induced gene transcription. Further work is necessary to demonstrate whether this mechanism (labelled in blue), besides ghrelin, is extensive to other peripheral signals modulating food intake. NrF1 = Nuclear respiratory factor 1.