Abstract
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been suggested to play a key role in insulin resistance development. Reactive oxygen species (ROS) production and lipid accumulation due to mitochondrial dysfunction seemed to be important mechanisms leading to cellular insulin resistance. Moreover, mitochondria are functionally and structurally linked to ER, which undergoes stress in conditions of chronic overnutrition, activating the unfolded protein response, which in turn activates the principal inflammatory pathways that impair insulin action. Among the nutrients, dietary fats are believed to play key roles in insulin resistance onset. However, not all dietary fats exert the same effects on cellular energy metabolism. Dietary omega 3 polyunsaturated fatty acids (PUFA) have been suggested to counteract insulin resistance development by modulating mitochondrial bioenergetics and ER stress. In the current review, we summarized current knowledge on the role played by mitochondrial and ER stress in inflammation and insulin resistance onset, focusing on the modulation role of omega 3 PUFA on these stress pathways. Understanding the mechanisms by which omega 3 PUFA modulates cellular metabolism and insulin resistance in peripheral tissues may provide additional details on the potential impact of omega 3 PUFA on metabolic function and the management of insulin resistance in humans.
Highlights
Insulin resistance is a condition in which the response of peripheral tissue to insulin is attenuated and precedes by several years the development of type 2 diabetes mellitus
Tubbs et al demonstrated that mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signalling by performing experiments on cyclophilin D (CypD), a mitochondrial protein that interacts with the Ca2+ -channelling complex at the MAM interface
Insulin resistance is strictly linked to inflammatory pathways which in turn is associated with endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production and mitochondrial function/dynamic behaviour impairment
Summary
Insulin resistance is a condition in which the response of peripheral tissue to insulin is attenuated and precedes by several years the development of type 2 diabetes mellitus. Nutrients 2018, 10, 350 by insulin resistance leads to a pro-inflammatory state, which in turn has detrimental effects on other metabolic tissues [6]. The “lipotoxicity theory” suggests that cytosolic ectopic accumulation of fatty acid metabolites, such as diacylglycerols (DAG) and/or ceramides, underlies insulin resistance development in peripheral metabolic tissues—namely skeletal muscle and liver (reviewed in Lark et al [3]). Mitochondria are functionally and structurally linked to ER, which in condition of chronic overnutrition undergoes stress, which activates the unfolded protein response (UPR) which in turn activates the principal inflammatory pathways that impair insulin action. In the first part of the review, we summarized the current hypothesis on the role played by mitochondrial and ER stress and inflammation in insulin resistance onset, whereas in the second part we focused on the modulatory role of omega 3 PUFA on these pathways. Understanding the mechanisms by which omega 3 PUFA modulate cellular metabolism and inflammatory pathways, may provide additional details to the potential impact of omega 3 PUFA on metabolic function and management of insulin resistance in humans
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