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

Lepretti, Marilena; Martucciello, Stefania; Burgos Aceves, Mario; Putti, Rosalba; Lionetti, Lillà

doi:10.3390/nu10030350

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

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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Unsaturated fats, particularly omega-3 fatty acids, exhibit anti-inflammatory and insulin-sensitizing effects.
“Dietary fat quality also has a significant influence, with unsaturated fats, particularly omega-3 fatty acids, exhibiting anti-inflammatory and insulin-sensitizing effects [19].”
From Nutritional and herbal interventions for polycystic ovary syndrome (PCOS): a comprehensive review of dietary approaches, macronutrient impact, and herbal medicine in management (2025) · cites this paper as [19]
Section 5 describes omega-3 fatty acids’ anti-inflammatory action as established, but says their effect on insulin action remains controversial. It also reports that human intervention studies have not shown an insulin-sensitivity benefit in people with type 2 diabetes or insulin resistance. The claim presents insulin sensitization more generally and confidently than the review supports. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In diabetic MASLD patients, severe insulin resistance, chronic inflammation, and oxidative stress may impair the pathways through which omega-3 lowers TG, leading to failure of omega-3 therapy.
“However, in diabetic MASLD patients, severe insulin resistance, chronic inflammation, and oxidative stress may impair these pathways, leading to the failure of omega-3 therapy.39”
From The Impact of Omega-3 Fatty Acids on Triglyceride Levels in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis of Randomized Controlled Trials with Subgroup Analysis by Diabetes Status (2026) · cites this paper as [39]
Section 5 describes omega-3’s triglyceride-lowering and anti-inflammatory effects, while Sections 1 and 8 link insulin resistance with inflammation and oxidative stress. The paper does not say that these conditions impair omega-3’s triglyceride-lowering pathways or cause therapy to fail in diabetic MASLD patients. Its report of no insulin-sensitivity benefit in some human intervention studies concerns a different outcome. (LLM, conf=0.86)
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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: Lepretti, Marilena
Martucciello, Stefania
Burgos Aceves, Mario
Lionetti, Lillà
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: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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 › 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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Omega-3 Fatty Acids and Insulin Resistance: Focus on the Regulation of Mitochondria and Endoplasmic Reticulum Stress

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