Origins of metabolic complications in obesity: ectopic fat accumulation. The importance of the qualitative aspect of lipotoxicity

Purpose of review This study highlights two aspects of the concept of lipotoxicity. First, the metabolic consequences following ectopic fat accumulation are not only determined by the amount of lipid accumulated, but also the quality of lipid species. Second, the existence of allostatic mechanisms operating at cellular and tissue levels, which counterbalance the negative effects of lipid overload. Recent findings The development of lipidomics has allowed the isolation and identification of a wide range of lipid species. Some are highly reactive and capable of inducing undesirable toxic effects. Here we focus on recent information related to pathways involved in the production of these reactive lipid species, their sites of generation and tropism for specific organelles and the molecular mechanisms through which they exert toxic effects. We describe how cell membranes and the lipid species forming their bilayer constitute the main platform from which reactive lipid species are generated. We propose that strategies aimed at maintaining membrane lipid homeostasis are fundamental to preventing the initiation of metabolically relevant lipotoxicity. Summary It is essential to understand the qualitative component of lipid species involved in cellular toxicity and the molecular mechanisms mediating these toxic effects to identify new therapeutic targets.