Almanac A1C

Oxidized Linoleic Acid: The Hidden Driver of Modern Metabolic Crisis

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dr. Karunia Valeriani Japar

Table of Contents
Keywords: , , , , , , ,

Introduction

The rise of metabolic disorders such as insulin resistance and type 2 diabetes (T2D) has paralleled considerable changes in dietary fat composition, especially in the ubiquity of linoleic acid (LA), the dominant n-6 polyunsaturated fatty acid (PUFA) in modern diets. Beyond its bulk presence, the role of LA and its oxidized derivatives (OXLAMs) in mediating metabolic health remains controversial, with evidence pointing to both protective and detrimental effects depending on context and downstream metabolism. The aim of this review is to comprehensively examine mechanistic, experimental, and clinical evidence linking dietary LA and OXLAMs to insulin resistance, with an emphasis on proposed biochemical models, translational gaps, and future research priorities [1,2].

In the 20th century, a major nutritional shift occurred with a large-scale replacement of animal fats with refined seed oils, driving a 20-to 30-fold increase in dietary LA intake in Western populations- from 1-2g/d in 1909 to >16g/d today. This shift was heavily influenced by public health recommendations to reduce saturated fat, resulting in LA comprising 6-8% of total daily energy intake. Largely derived from soybean, corn, and sunflower oils. LA now represents 80-90% of dietary PUFA. While initial epidemiology linked high-LA diets to lower risk of CVD, concerns have emerged over omega-6/omega-3 imbalances and the generation of pro-inflammatory OXLAMs [2,3,4,5,6].

Mechanistic Pathways: Linoleic Acid Versus It’s Oxidation Products

Cell Culture Evidence

Cell culture studies demonstrate that both LA and its oxidized metabolites exert profound effects on insulin signalling and b-cell health. LA enrichment in membrane phospholipids modulates membrane fluidity, altering the assembly of insulin receptor complexes. Chronic exposure to LA increases cellular production of OXLAMs, including 9- and 13-HODE, which trigger oxidative stress pathways (e.g., increased ROS) and active inflammatory transcription factors such as NF-KB. In b-cells, OXLAMs have been implicated in the impairment of glucose-stimulated insulin secretion (GSIS) and increased apoptosis [1,3,7].

Animal Model Evidence

Rodent models have shown both beneficial and detrimental effects of LA supplementation. Diets high in soybean oil (a rich LA source) can lead to weight gain, hyperinsulinemia, increased pro-inflammatory cytokines (e.g., TNF-a, IL-6) and impaired insulin-stimulated signalling via downregulation of IRS-1 and IRS-2 in liver and muscle. Similar findings in fish (PI3K/AKT signalling suppression) and poultry (altered adiponectin, increased PPARc) reinforce the idea that LA can disrupt central insulin signalling mechanisms. However, some interventions show neutral or modestly beneficial effects when dietary LA is not excessive [1,2].

Human Clinical Trials

Human data are complex and sometimes contradictory. Meta-analyses of randomized controlled trials (RCTs) replacing saturated fat with PUFA (primarily LA) have shown improvements in fasting insulin and HOMA-IR, but these designs often fail to isolate the effects of LA from those of total PUFA or dietary pattern changes. Direct intervention studies report both beneficial and adverse changes in insulin sensitivity markers, with some revealing increased plasma resistin and apolipoprotein B with high-LA diets. Mendelian randomization analyses and prospective cohort studies generally indicate an inverse association between plasma LA and T2D risk, though causality remains in question and some studies identify a subpopulation at increased risk, possibly related to individual OXLAM formation [1,2,8].

Proposed Unifying Theory

Contemporary models of insulin resistance increasingly focus on how dietary fats, especially saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) such as linoleic acid (LA), differentially influence cellular energetics and insulin signalling through unique biochemical pathways [9].

Saturated Fat Pathway

Saturated fats, abundant in animal products, have classically been associated with the development of insulin resistance and metabolic syndrome. Mechanistically:

Lipid Intermediates: High intake of saturated fat leads to the accumulation of bioactive lipid intermediates in the liver and muscle, particularly diacylglycerols (DAG) and ceramides. These molecules activate protein kinase C epsilon (PKCe), which inhibits insulin receptor substrate (IRS)-2 phosphorylation and impairs downstream PI3K-Akt signalling-reducing insulin-stimulated glucose uptake [10].

Immune Activation/ Inflammation: Saturated fatty acids can also activate toll-like receptor 4 (TLR-4) signalling, increasing pro-inflammatory cytokines (e.g., TNF-a, IL-6), further blunting insulin action. However, some evidence suggests that insulin resistance induced by saturated fat can arise independently of TLR-4, with DAG-PKCe as a central effector [10].

Mitochondrial Overload: Sustained SFA oxidation can impinge on mitochondrial function, elevating reactive oxygen species (ROS) and ultimately promoting cellular stress and apoptosis [10].

Linoleic Acid Pathway

The energy model of insulin resistance posits that excess dietary LA, mainly from refined seed oils, presents a distinct pathway involving oxidative stress and cellular fuel adaptation [9].

PUFA incorporation/ Oxidative Stress: High intake of LA shifts adipose composition toward a higher PUFA fraction. Cells metabolizing these LA-rich fats experience enhanced oxidative stress, as PUFA are more readily oxidized than SFA, depleting intracellular antioxidant capacity [9].

OXLAM Formation: LA is easily oxidized, generating oxidized linoleic acid metabolites (OXLAMs) that impair mitochondrial function and stimulate inflammatory pathways [9].

Aerobic Glycolysis (“Warburg Effect”): Persistently elevated oxidative stress drives a compensatory metabolic shift-increased aerobic glycolysis at the cellular level, known as the Warburg effect. Cells become reliant on increased glucose import to mitigate further fat oxidation and ROS production, disturbing whole-body glucose homeostasis and ultimately elevating insulin and counter-regulatory hormones [9].

Consequences: These shifts disrupt mitochondrial substrate selection, elevate redox imbalance, and foster a systemic environment favourable to metabolic inflexibility and insulin resistance. The metabolic demand for glucose, rather than simple impaired insulin sensitivity, is hypothesized as a core defect according to this model [9].

Schemic Integration

In summary, both saturated fat and LA-rich PUFA may converge on mitochondrial dysfunction and impaired insulin signalling, but through distinct molecular triggers:

  • SFA: DAG/Ceramide-PKCe activation, inflammation, and ER/mitochondrial stress.
  • LA: Enhanced oxidative stress from OXLAMs, redox depletion, metabolic reprogramming (aerobic glycolysis), and chronic glucose demand [9].

Biochemical Mechanisms Linking Oxidized Linoleic Acid to Insulin Resistance

OXLAMs, produced via both enzymatic and non-enzymatic oxidation of LA, are potent metabolic disruptors:

  • Mitochondrial Dysfunction: OXLAMs increase mitochondrial ROS, impairing ATP production and activating kinase that inhibit insulin signalling [11,12].
  • Insulin Signalling Disruption: OXLAMs interfere with GLUT4 translocation and alter insulin receptor substrate phosphorylation, impairing glucose uptake in muscle and adipose tissue [11].
  • Inflammation: Activation of NF-kB and other pro-inflammatory pathways by OXLAMs fosters local and systemic insulin resistance, and their presence in plasma is correlated with inflammation and b-cell dysfunction [11,12].
  • Lipotoxicity: Chronic OXLAM exposure increases ceramide synthesis and endoplasmic reticulum stress, both of which are established contributors to b-cell failure and whole-body insulin resistance [11].

Clinical and Dietary Implications

The clinical significance of LA and its oxidized metabolites in insulin resistance is nuanced. At intakes near 2-4% of calories, LA is essential for membrane structure and signalling. At intakes near 2-4% of calories, LA is essential for membrane structure and signalling. Adverse effects appear most clearly at higher intakes, especially in the context of pro-oxidant dietary patterns. Key implications include [1,5,13]:

Beneficial Effects at Physiological intake

  • Reduced Type 2 Diabetes Risk: Mendelian randomization and cohort meta-analyses demonstrate that higher circulating and dietary LA are associated with a lower risk of type 2 diabetes (T2D), lower fasting glucose, and improved glycated hemoglobin (HbA1c) levels, though effects on fasting insulin are less consistent. This inverse association holds across diverse populations and is reflected in improvement in HOMA-IR and glycemic markers in prospective studies [2,14,15].
  • Improvement in Adipokinesis and Lipids: Supplementation and biomarker studies- especially in metabolic syndrome- suggest LA can beneficially modulate adiponectin and leptin, resulting in impaired glucose metabolism and lipoprotein profiles [14,16].
  • Essential Fatty Acid Role: As an essential n-6 PUFA, LA is required for healthy cell membrane structure, signal transduction, and development. Deficiency states are rare but severe, highlighting the necessity of modest dietary intake [5,14].

Risk of Excess intake and OXLAM Formation

  • Adverse Effects of Excess and Oxidation Products: High or excessive LA intake, prevalent in modern Western diets (often exceeding 10%total energy), increases tissue incorporation and production of oxidized linoleic acid metabolites (OXLAMs). These OXLAMs are implicated in mitochondrial dysfunction, increased oxidative stress, and progression of chronic diseases- including insulin resistance, metabolic syndrome, and atherosclerosis [1,5,17,18].
  • Dose-Dependent Effects: While moderate LA reduces T2D risk, high intakes (particularly when omega-3 is low) may increase OXLAMs, promoting insulin resistance in genetically or metabolically susceptible individuals. Animal and clinical studies document worsened insulin sensitivity after prolonged high-LA diets, linked to increased resistin and atherogenic lipoproteins [5,17,18].
  • Pediatric and Genetic Concerns: In obese children/adolescents, higher circulating OXLAMs strongly correlate with metabolic syndrome and a more proatherogenic lipoprotein profile. Generic variants (e.g., FADS genotypes) and gut microbiota modulate individual OXLAM burden and metabolic risk, suggesting heightened caution for certain groups [18].

As for dietary implications, these are the keys:

  • Practical Recommendations
    • Moderation, Not Elimination: Evidence supports maintaining LA intake at moderate levels (2-4% of calories) , avoiding excess from industrial seed oils, fried foods, and ultra0processed products. Overcorrection or complete avoidance is not supported and may risk deficiency [8,19].
    • Omega -6/Omega-3 Balance: A lower n-6:n-3 ratio (closer to 4:1 or below) is advisable, increasing marine omega-3 (EPA/DHA) to offset pro-inflammatory signals from LA [19,20].
    • Source Matters: Favor LA from whole food sources (nuts, seeds, modest unrefined oils) rather than concentrated, repeatedly heated seed oils prone to oxidation [5].
    • Minimizing OXLAM Formation: Reduce high-heat cooking and processed foods high in oxidized LA. Select cold-pressed oils and improve dietary antioxidants (e.g., polyphenols, vitamin E) [17,19].
  • Special Populations
    • Metabolic Syndrome & Diabetes: These individuals may benefit from a targeted reduction of dietary LA to lower OXLAM production, especially if omega-3 intake is low or oxidative stress is high. Monitoring and individualized counselling are recommended [3,5,18].
    • Pediatric, Genetic, and Microbiome Factors: Pediatrics, those with unfavourable FADS genotypes, or disrupted microbiota may need extra attention to both LA/OXLAMs and omega-3 status [18].
FactorModerate LA IntakeExcess LA/OXLAMs
T2D RiskDecreasedIncreased (esp. with low omega-3) [1,3,18,19]
Insulin SensitivityImproved / neutralWorsened, more oxidative stress [5,18,19,21]
Adiponectin/LipidsElevated, beneficial modulationImpaired,  ↑resistin/ApoB, dyslipidemia [16,18,19,21]
OXLAM FormationMinimalMarked, tissue-damaging [3,5,19,21,23]
Dietary Advice5-10% energy (whole foods , n6:n3- 4:1)Avoid processed oils, minimize oxidation [17,19,22]
At Risk GroupsMost healthy adultsMetabolic syndrome, children, genetic [1,3,5,19]
Table 1. Summary Table: Clinical and Dietary Implications of LA & OXLAMs

Research Gaps and Future Directions

Significant uncertainties remain:

  • Optimal safe upper and lower thresholds for dietary LA in different populations.
  • Specific mechanisms and tissue targets of OXLAMs in humans; the role of the microbiome and individualized redox state in modulating risk.
  • Large, long-term RCTs and mechanistic studies comparing low-LA versus high-LA, with and without antioxidant co-interventions, are urgently needed.
  • Strengthening metabolic phenotyping to identify responders and non-responders in dietary LA trials.

Conclusion

The metabolic effects of linoleic acid and it oxidized metabolites on insulin resistance are context-dependent and multifaceted. While dietary LA is an essential nutrient and may prove beneficial at moderate intake, high intakes can, particularly through increased generation of OXLAMs, promote oxidative stress, inflammation, and insulin resistance insusceptible individuals. Future research should refine dietary guidelines and explore personalized nutrition strategies to optimize LA intake for metabolic health.

References

  1. Hamilton JS, Klett EL. Linoleic acid and the regulation of glucose homeostasis: A review of the evidence. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2021 Dec;175:102366.
  2. Liang H, Mu HB, Zhang FH, Li WQ, Li GC, Li WD, et al. Causal relationship between linoleic acid and type 2 diabetes and glycemic traits: a bidirectional Mendelian randomization study. Frontiers in Endocrinology. 2023 Nov 21;14.
  3. Santoro N, Feldstein AE. The role of oxidized lipid species in insulin resistance and NASH in children. Frontiers in Endocrinology [Internet]. 2022 Oct 3 [cited 2025 Sep 9];13. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9573982/
  4. Raatz SK, Conrad Z, Jahns L. Trends in linoleic acid intake in the United States adult population: NHANES 1999–2014. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2018 Jun;133:23–8.
  5. Mercola J, D’Adamo CR. Linoleic Acid: A Narrative Review of the Effects of Increased Intake in the Standard American Diet and Associations with Chronic Disease. Nutrients [Internet]. 2023 Jan 1;15(14):3129. Available from: https://www.mdpi.com/2072-6643/15/14/3129
  6. Jandacek RJ. Linoleic Acid: A Nutritional Quandary. Healthcare [Internet]. 2017 May 20;5(2):25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492028/
  7. Martemucci G, Fracchiolla G, Muraglia M, Tardugno R, Dibenedetto RS, D’Alessandro AG. Metabolic Syndrome: A Narrative Review from the Oxidative Stress to the Management of Related Diseases. Antioxidants [Internet]. 2023 Dec 1 [cited 2024 Feb 15];12(12):2091. Available from: https://www.mdpi.com/2076-3921/12/12/2091
  8. Mousavi SM, Jalilpiran Y, Karimi E, Aune D, Larijani B, Mozaffarian D, et al. Dietary Intake of Linoleic Acid, Its Concentrations, and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies. Diabetes Care. 2021 Aug 20;44(9):2173–81.
  9. López-Moreno M. Commentary: The energy model of insulin resistance: a unifying theory linking seed oils to metabolic disease and cancer. Frontiers in Nutrition. 2025 Aug 5;12.
  10. Galbo T, Perry RJ, Jurczak MJ, Joao Paulo Camporez, Tiago Marcos Alves, Kahn M, et al. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo. 2013 Jul 30;110(31):12780–5.
  11. Simopoulos AP. Metabolic Syndrome: A Narrative Review from the International Diabetes Federation. Nutrients. 2023;15(12):2489.
  12. Zhao Y, et al. The role of oxidized lipid species in insulin resistance and metabolic diseases. Front Endocrinol (Lausanne). 2022;13:9573982.
  13. Santoro N, Feldstein AE. The role of oxidized lipid species in insulin resistance and NASH in children. Frontiers in Endocrinology [Internet]. 2022 Oct 3;13. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9573982/
  14. Belury MA. Linoleic acid, an omega-6 fatty acid that reduces risk for cardiometabolic diseases: premise, promise and practical implications. Current Opinion in Clinical Nutrition and Metabolic Care [Internet]. 2023 May 1 [cited 2023 Nov 29];26(3):288–92. Available from: https://pubmed.ncbi.nlm.nih.gov/37017716/#:~:text=Summary%3A%20Unraveling%20the%20cellular%20mechanism
  15. Mousavi SM, Jalilpiran Y, Karimi E, Aune D, Larijani B, Mozaffarian D, et al. Dietary Intake of Linoleic Acid, Its Concentrations, and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies. Diabetes Care. 2021 Aug 20;44(9):2173–81.
  16. Cole RM, Puchala S, Ke JY, Abdel-Rasoul M, Harlow K, O’Donnell B, et al. Linoleic Acid–Rich Oil Supplementation Increases Total and High-Molecular-Weight Adiponectin and Alters Plasma Oxylipins in Postmenopausal Women with Metabolic Syndrome. Current Developments in Nutrition [Internet]. 2020 Aug 21;4(9):nzaa136. Available from: https://www.sciencedirect.com/science/article/pii/S2475299122120688
  17. Ramsden CE, Ringel A, Feldstein AE, Taha AY, MacIntosh BA, Hibbeln JR, et al. Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2012 Oct;87(4-5):135–41.
  18. Domenico Tricò, Anna Di Sessa, Caprio S, Chalasani N, Liu W, Liang T, et al. Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxidants & Redox Signaling. 2019 Jan 10;30(2):241–50.
  19. Jackson KH, Harris WS, Belury MA, Kris-Etherton PM, Calder PC. Beneficial effects of linoleic acid on cardiometabolic health: an update. Lipids in Health and Disease. 2024 Sep 12;23(1).
  20. Maral Bishehkolaei, Pathak Y. Influence of Omega n-6/n-3 Ratio on Cardiovascular Disease and Nutritional interventions. Human Nutrition & Metabolism. 2024 Jun 11;37:200275–5.
  21. Ulf Risérus, Basu S, Jovinge S, Gunilla Nordin Fredrikson, Johan Ärnlöv, Bengt Vessby. Supplementation With Conjugated Linoleic Acid Causes Isomer-Dependent Oxidative Stress and Elevated C-Reactive Protein. 2002 Oct 8;106(15):1925–9.
  22. Marangoni F, Agostoni C, Borghi C, Catapano AL, Cena H, Ghiselli A, et al. Dietary linoleic acid and human health: Focus on cardiovascular and cardiometabolic effects. Atherosclerosis [Internet]. 2020 Jan 1;292:90–8. Available from: https://pubmed.ncbi.nlm.nih.gov/31785494/
  23. Shanahan C. The energy model of insulin resistance: a unifying theory linking metabolic disease and cancer. Frontiers in Nutrition. 2025 Apr 29;12.