Abstract
A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.
Highlights
The number of obese and elderly people is constantly growing in industrialized countries
The purpose of this review is to summarize and discuss the most recent studies supporting a causal role of DAGs and ceramides in the development of Insulin resistance (IR), with a special attention given to transgenic mouse models influencing either the total pool or specific species and their association with insulin sensitivity
Many studies using pharmacological inhibitors and transgenic mouse models have, in our opinion, supported the growing interest for ceramides in the pathogenesis of Type 2 diabetes (T2D). They incriminated short-chain ceramides (C16–C18) in all metabolic tissues. They evidenced that ceramides could interfere with insulin sensitivity, through direct targeting of insulin signal transduction, and by modulating mitochondrial activity and membrane biophysical properties
Summary
The number of obese and elderly people is constantly growing in industrialized countries. One prevailing hypothesis is the emergence of ectopic lipid storage in lean tissues, so-called lipotoxicity, caused by fatty acid (FA) overflow out of adipose tissue (AT) in periods of positive energy balance [9] This phenomenon typically occurs when excess dietary lipids cannot be adequately buffered within AT stores. Excess FA delivery and uptake in peripheral tissues such as the liver and skeletal muscle will lead to excess intracellular FA flux These FA will first be activated to form fatty acyl-CoA and further converted into triacylglycerols (TAG) within lipid droplets [10,11] or give rise to diacylglycerols (DAGs) and ceramides through specific metabolic pathways that will be detailed in the following chapters of this review. The purpose of this review is to summarize and discuss the most recent studies supporting a causal role of DAGs and ceramides in the development of IR, with a special attention given to transgenic mouse models influencing either the total pool or specific species and their association with insulin sensitivity
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