Omega-6/Omega-3 Fatty Acids and Inflammation (Vocabulary Flashcards)

Carbohydrates and Blood Glucose

• Carbohydrates digestion and absorption are relatively slow compared to simple, high glycemic carbs. This leads to a lower blood glucose response overall.
• However, when the diet includes high glycemic carbohydrates frequently (e.g., every hour or two), repeated glucose spikes occur.
  • These spikes trigger inflammatory processes, even outside of diabetes contexts.
  • A hallmark of a Western diet is carbohydrates that cause large blood glucose spikes.
• Practical takeaway: frequent high-glycemic intake can contribute to low-grade systemic inflammation over time.

Omega-6 vs Omega-3 Fatty Acids and Inflammation

• Central topic: the balance between omega-6 and omega-3 fatty acids and its impact on systemic inflammation.
• Key inflammatory mediators arise from arachidonic acid (AA), which is derived from cell membrane phospholipids.
  • In the signaling cascade, membranes release fatty acids (AA) via phospholipase A₂.
  • These fatty acids are named arachidonic acid metabolites and drive inflammatory signaling.
• AA is an omega-6 fatty acid. When released, it feeds two main enzymatic pathways:
  • Lipoxygenase pathway → leukotrienes
  • Cyclooxygenase (COX) pathway → prostaglandins and thromboxanes
• Inflammation is driven by these mediators, with stronger signals when sourced from omega-6 fatty acids.
• Anti-inflammatory medications target these pathways:
  • Corticosteroids (e.g., prednisone) largely work by preventing fatty acid release from phospholipids, shutting down downstream production.
  • Mechanism (simplified): suppress phospholipase A₂ → less AA release → fewer downstream eicosanoids.
  • Non-prescription aspirin affects prostaglandin production by interfering with COX enzymes in the downstream pathway.
  • Omega-3 fatty acids can be used by the body as an alternative substrate, shifting production toward less inflammatory mediators.
• The diet determines which mediators are produced: if the body uses omega-6 fatty acids, the signal is very strong; if omega-3 is used, the signal is weaker and counteracts omega-6 signaling.
• Simple concept: the strength of the inflammatory response depends on whether the signaling molecules are derived from omega-6 or omega-3 fatty acids.
• The two “big” families of mediators with omega-6s tend to amplify inflammation, clotting, and smooth muscle constriction when released in strong amounts.
• Omega-3-derived mediators counterbalance and suppress the omega-6-driven inflammatory response (and may directly interfere with omega-6 signaling).
• For example, cutting a finger triggers clotting; with omega-3s, the same clotting occurs but may be less aggressive; asthma-related leukotrienes may be produced but with reduced strength.
• The overall balance matters: omega-6 vs omega-3 influences not just inflammation but also cardiovascular and other inflammatory-related risks.

Arachidonic Acid Pathway and Eicosanoids (Key Details)

• AA is released from cell membrane phospholipids upon activation of immune signaling.
  • Trigger: immune cells (e.g., macrophages) signal to activate an inflammatory response.
• From AA, two main pathways produce inflammatory mediators:
  • Lipoxygenase pathway → four-series leukotrienes (four-series leukotrienes) which are extremely potent inflammatory signals.
  • Cyclooxygenase (COX) pathway → two-series eicosanoids (e.g., prostaglandins and thromboxanes).
• Important note from the material: AA-derived mediators are very powerful in driving inflammation, blood clotting, and smooth muscle constriction.
• If omega-3 fatty acids are used instead as the substrate, the same general products are formed, but they are typically far weaker in their inflammatory effects and may counteract omega-6 mediators.
• The “balance” concept: the relative availability of omega-6 vs omega-3 in tissue phospholipids is crucial for the net inflammatory response.
• Evolutionary context: humans evolved on diets with a roughly balanced ratio that supported a four-to-one signal (four strong omega-6 signals to one weaker omega-3 signal) in tissue phospholipids.
• The modern diet drastically shifts this ratio away from balance (e.g., higher omega-6 relative to omega-3), amplifying inflammatory signaling.

Evolutionary and Dietary Ratios

• Ancestral/dried diet ratio: approximately 4:1 (omega-6:omega-3) in many populations.
• Modern Western diet: roughly 50:1 (omega-6:omega-3), leading to much stronger inflammatory signaling when pathways are activated.
• Japan (historical data): around 12:1, yet with very low heart disease rates historically, partially attributed to high omega-3 intake from traditional foods.
• In some traditional Arctic diets (e.g., Inuits with whale blubber and fatty foods), very high fat intake but high omega-3 content correlated with low rates of certain inflammatory-related diseases, illustrating the protective role of omega-3s.
• Summary: a higher omega-6 to omega-3 ratio tends to increase inflammation and disease burden; a more balanced ratio (closer to the ancestral ~4:1) generally supports lower inflammatory risk.

Modern Diet, Inflammation, and Disease Burden

• Correlation: higher omega-6 to omega-3 ratio is associated with greater systemic inflammation and higher disease burden across various conditions.
• Fish oil (omega-3) supplementation is described as lowering inflammatory risk, consistent with the anti-inflammatory potential of omega-3s.
• The balance between omega-6 and omega-3 is a central mechanism linking diet to chronic inflammation and related diseases.

Other Factors Affecting Chronic Inflammation

• Stress and mental health: chronic psychological stress maintains a simmering inflammatory state.
• Sleep and circadian rhythm:
  • Sleep deprivation = pro-inflammatory state.
  • Not only total sleep, but also timing: later sleep, disrupted circadian rhythm, and irregular sleep patterns are linked to higher inflammation.
  • Sleep quality and timing are practical targets for reducing chronic inflammation.
• Environmental factors:
  • Pollution and exposure to traffic-related air pollutants are linked to increased inflammatory markers and vascular inflammation, contributing to disease risk.
  • Proximity to roads and long-term exposure to pollutants correlate with higher inflammation and disease burden.
• Social factors:
  • Social isolation is a significant risk factor for illness; humans are social animals, and belonging to a tight-knit group reduces inflammation-related risk.
  • Community and social connectedness can mitigate inflammatory processes.
  • Modern online communities can provide a sense of belonging for some individuals (e.g., gamers finding social support online), potentially reducing inflammatory risk in those contexts.

Practical Takeaways and Connections

• Dietary recommendations implied by the material:
  • Aim to balance omega-6 and omega-3 intake to approximate ancestral ratios (roughly 4:1).
  • Increase intake of omega-3-rich foods (e.g., certain fatty fish) to shift mediator production toward anti-inflammatory pathways.
  • Be mindful of high omega-6 foods that may tilt the balance toward stronger inflammatory signaling when consumed in excess.
• Pharmacological implications:
  • Corticosteroids reduce inflammation by limiting AA release, effectively shutting down the downstream production of inflammatory mediators.
  • Aspirin (an NSAID) reduces prostaglandin production by inhibiting COX enzymes, attenuating downstream inflammatory signals.
• Behavioral and lifestyle implications:
  • Manage chronic stress and improve sleep quality and circadian regularity to reduce baseline inflammation.
  • Address environmental exposures (where possible) to minimize pollution-related inflammatory activation.
  • Foster social connections and community belonging to mitigate the inflammatory consequences of isolation.

Connections to Foundational Concepts and Real-World Relevance

• Ties to basic immunology:
  • Cytokines and chemokines are signaling proteins that coordinate the immune response; the eicosanoids derived from AA are key mediators in this signaling cascade.
• Metabolic and cardiovascular relevance:
  • Eicosanoid signaling influences inflammation, clotting, and vascular tone, all of which are central to cardiovascular disease risk.
• Public health implications:
  • Diet composition (omega-6 vs omega-3) is modifiable and has broad implications for population-level inflammation-related diseases.
  • Sleep, stress, pollution, and social connectedness are actionable public health targets to reduce chronic inflammation.

Quick Reference: Key Terms and Concepts

• AA: Arachidonic acid, an omega-6 fatty acid released from phospholipids to form inflammatory mediators.
• Lipoxygenase pathway: Produces leukotrienes (eicosanoids) from AA; leukotrienes are potent inflammatory signals.
• Cyclooxygenase (COX) pathway: Produces prostaglandins and thromboxanes from AA; involved in inflammation and clotting.
• Four-series leukotrienes: A class of leukotrienes derived from omega-6 AA, noted as particularly strong inflammatory mediators.
• Two-series prostaglandins: Prostaglandins derived from AA via COX pathways, also driving inflammation and other responses.
• Omega-6 fatty acids: Tend to promote strong inflammatory signaling when converted to eicosanoids.
• Omega-3 fatty acids: Tend to promote weaker inflammatory signaling and can counteract omega-6–driven effects.
• Phospholipase A₂: Enzyme that frees fatty acids (like AA) from phospholipids in cell membranes.
• Corticosteroids: Anti-inflammatory drugs that largely prevent AA release, damping downstream eicosanoid production.
• Aspirin (NSAIDs): Anti-inflammatory drugs that inhibit COX enzymes, reducing prostaglandin synthesis.
• Circadian rhythm: The body’s internal clock; disruption increases inflammation.
• Social connectedness: A protective factor against inflammation and disease risk.
• Ratio concept: An evolutionary-anchored balance of omega-6 to omega-3 fatty acids, with modern diets often deviating from the optimum and increasing inflammatory burden.

Notes prepared to mirror the content and emphasis of the transcript, with emphasis on how dietary fats influence inflammatory signaling, and how lifestyle factors modulate chronic inflammation.