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Cited by 233Fatty Acid Research and HealthMitochondrial Function and PathologyAdipose Tissue and Metabolism

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

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Lepretti, Marilena, Martucciello, Stefania, Burgos Aceves, Mario, Putti, Rosalba, Lionetti, Lillà·2018·Nutrients
DOI 10.3390/nu10030350PMC PMC5872768
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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.

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Crossref · 10.3390/nu10030350

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Figure 1 Overview of possible routes of lipid oversupply-induced insulin resistances associated with mitochondrial and endoplasmic reticulum (ER) stress. (Orange arrow) Mitochondrial dysfunction and lipotoxicity theory: lipid oversupply elicits reduction in mitochondrial β-oxidation that induces cytosolic ectopic accumulation of fatty acid metabolites, such as diacylglycerol and ceramides. These lipid metabolites impair insulin signalling pathways, directly or indirectly, through the activation of an inflammasome/pro-inflammatory pathway. (Blue arrow) ROS implication: lipid overload induces an increase in mitochondrial β-oxidation that stimulates ROS production. ROS can directly target protein involved in the glucose uptake process or activate the inflammasome, which initiates a series of inflammatory reactions in response to stress. ROS production may be also induced by excessive mitochondrial Ca2+ influx from ER. (Black arrow) ER stress induced by lipid oversupply directly actives inflammatory pathways and impairs insulin action. On the other hand, ER stress also trigger Ca2+ mobilization towards mitochondria through mitochondria-associated endoplasmic reticulum membrane (MAM), where Mfn2 play a regulatory role. The subsequent opening of the mitochondrial transition pore leads to activation of inflammasome and inflammatory pathways.
Figure 1 Overview of possible routes of lipid oversupply-induced insulin resistances associated with mitochondrial and endoplasmic reticulum (ER) stress. (Orange arrow) Mitochondrial dysfunction and lipotoxicity theory: lipid oversupply elicits reduction in mitochondrial β-oxidation that induces cytosolic ectopic accumulation of fatty acid metabolites, such as diacylglycerol and ceramides. These lipid metabolites impair insulin signalling pathways, directly or indirectly, through the activation of an inflammasome/pro-inflammatory pathway. (Blue arrow) ROS implication: lipid overload induces an increase in mitochondrial β-oxidation that stimulates ROS production. ROS can directly target protein involved in the glucose uptake process or activate the inflammasome, which initiates a series of inflammatory reactions in response to stress. ROS production may be also induced by excessive mitochondrial Ca2+ influx from ER. (Black arrow) ER stress induced by lipid oversupply directly actives inflammatory pathways and impairs insulin action. On the other hand, ER stress also trigger Ca2+ mobilization towards mitochondria through mitochondria-associated endoplasmic reticulum membrane (MAM), where Mfn2 play a regulatory role. The subsequent opening of the mitochondrial transition pore leads to activation of inflammasome and inflammatory pathways.CC BY · PubMed Central
Figure 2 Proposal mechanism of omega 3 PUFA effects on insulin sensitivity. Omega-3 PUFA attenuate ER stress and increase mitochondrial fatty acid β-oxidation and mitochondrial uncoupling with subsequent decrease in lipid accumulation and ROS production. Therefore, inflammasome/inflammatory processes are downregulated improving insulin sensitivity. Omega 3 PUFA have also positive effects on Mfn2 involved in maintenance of mitochondrial dynamics homeostasis and MAM integrity. Mitochondrial fusion phenotype and MAM integrity contribute to maintain insulin sensitivity under condition of cellular stress.
Figure 2 Proposal mechanism of omega 3 PUFA effects on insulin sensitivity. Omega-3 PUFA attenuate ER stress and increase mitochondrial fatty acid β-oxidation and mitochondrial uncoupling with subsequent decrease in lipid accumulation and ROS production. Therefore, inflammasome/inflammatory processes are downregulated improving insulin sensitivity. Omega 3 PUFA have also positive effects on Mfn2 involved in maintenance of mitochondrial dynamics homeostasis and MAM integrity. Mitochondrial fusion phenotype and MAM integrity contribute to maintain insulin sensitivity under condition of cellular stress.CC BY · PubMed Central

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Metadata

Authors
Lepretti, M., Martucciello, S., Burgos Aceves, M., Putti, R., & Lionetti, L.
Affiliations
  • University of Salerno (IT)
  • Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II, 132, Fisciano 84084, Italy
  • University of Naples Federico II (IT)
Corresponding author
Lionetti, Lillà
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2018-03-14
Volume
10
Issue
3
Pages
350
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu10030350
PMC
PMC5872768
OpenAlex
W2790337766
Cited by
232
References
122
Citations by year
2026: 18 · 2025: 30 · 2024: 38 · 2023: 41 · 2022: 19 · 2021: 25 · 2020: 33 · 2019: 21 · 2018: 7
FWCI
2.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Keywords
omega-3 fatty acids, insulin resistance, mitochondrial dysfunction, endoplasmic reticulum stress, reactive oxygen species, lipid accumulation, unfolded protein response, inflammation, dietary fat, polyunsaturated fatty acids, mitochondrial bioenergetics, energy metabolism, overnutrition
MeSH terms
Animals, Humans, Insulin Resistance, Mitochondria, Fatty Acids, Omega-3, Endoplasmic Reticulum Stress

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