The central nervous system in metabolic syndrome

Abstract

In the last decades obesity and its related metabolic disorders have increased at an epidemic rate in the developed and developing world. Lipid accumulation in peripheral tissues, such as heart, skeletal muscle, liver, and pancreatic β cells leads to lipotoxicity. It is an important factor contributing to type 2 diabetes, steatotic liver disease, insulin resistance and heart failure, disorders that are usually known as the Metabolic Syndrome (MetS). Recent work has demonstrated that hypothalamic sensing of circulating lipids and modulation of hypothalamic endogenous fatty acid and lipid metabolism are mechanisms modulating energy homeostasis at the whole body level. Enzymes, such as AMP-activated protein kinase (AMPK) and fatty acid synthase (FAS), plus intermediate metabolites, such as malonyl-CoA and long chain fatty acid-CoAs (LCFA-CoAs), have a key role in this neuronal network, integrating peripheral signals with classical neuropeptide-based mechanisms. One major point that needs to be addressed is whether impairment of lipid metabolism and accumulation of specific lipid species in the hypothalamus, leading to lipotoxicity, has deleterious effects on hypothalamic neurons that may contribute to MetS. In this chapter, we discuss data about hypothalamic lipid metabolism, with emphasis on the events typically associated to lipotoxicity such as endoplasmic reticulum (ER) stress. More extensive knowledge about these molecular mechanisms will be of great relevance for the treatment of obesity and metabolic syndrome.