Omega-3 Fatty Acids and Insulin Resistance: Focus on the Regulation of Mitochondria and Endoplasmic Reticulum Stress

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.

Resveratrol metabolites ameliorate insulin resistance in HepG2 hepatocytes by modulating IRS-1/AMPK

“…Like, the study by Marilena Lepretti et al showed that dietary omega 3 polyunsaturated fatty acids were able to recover insulin resistance by modulating ROS production and endoplasmic reticulum stress. 37 Similarly, Hoehn et al also showed that manganese(III) tetrakis (4-benzoic acid) porphyrin, a broad-spectrum antioxidant, was capable of scavenging not only O 2 À and H 2 O 2 , but also reactive nitrogen species, and improved glucose tolerance in HFD-fed C57BL/6JSlc mice. 38 Thus, it was important to highlight that R3G and R4G were also able to reduce cellular ROS levels in insulin-resistant HepG2 cells.…”

Could Omega 3 Fatty Acids Preserve Muscle Health in Rheumatoid Arthritis?

“…This effect was probably related to an increased expression of the mitochondrial uncoupling protein 3 (UCP3) [119]. Moreover, the dietary supplementation with omega 3 FA increased CPT-1 expression and activity in rat skeletal muscle, indicating an increase in FA β-oxidation ( Figure 2) [77,120]. Thus, omega 3 FA could increase lipid oxidation to limit or prevent the production of lipotoxic mediators implicated in the development of CVD and sarcopenia.…”

“…The decline in mitochondrial FA β-oxidation could also contribute to ectopic lipid accumulation and the RA-related increase in adiposity and metabolic disorders. These events will contribute to further aggravate all the mentioned alterations, amplifying the accumulation of ectopic fat and the progression of anabolic resistance [77,78]. However, the links between mitochondrial dysfunctions in skeletal muscle, lipitoxicity, IL-17 and RA remain unexplored.…”

Adjuvant Therapies in Diabetic Retinopathy as an Early Approach to Delay Its Progression: The Importance of Oxidative Stress and Inflammation

“…Preclinical studies have demonstrated that a flaxseed oil diet, another natural source of omega-3 fatty acid, does increase the expression of G-protein-coupled receptor 120 (GPR120), a receptor of omega-3, but not GPR40 [194] (see Table 2). Remarkably, omega-3 PUFAs suppress ER stress in adipocytes by AMPK activation, and resolvin D1, a family derived from eicosapentaenoic and docosahexaenoic acids, attenuates ER stress-induced apoptosis and decreases caspase-3 activity [195].…”