Essential Fatty Acids (Omega-3 & Omega-6) are direct building blocks for the skin's lipid bilayers, reducing transepidermal water loss (TEWL).

AlphaZance

To ensure that Gamma-Linolenic Acid (GLA) yields its powerful anti-inflammatory benefits, you must control the specific enzymes that act like traffic cops at this metabolic crossroads. [1]
The primary goal is to maximize the conversion of DGLA into PGE1 while blocking the Delta-5-Desaturase (D5D) enzyme, which shifts DGLA down the highly inflammatory Arachidonic Acid (AA) pathway. [2, 3]

1. Nutrients and Cofactors for the PGE1 Pathway

Once GLA is converted into Dihomo-Gamma-Linolenic Acid (DGLA) via an elongase enzyme, it needs specific cofactors to downstream into anti-inflammatory PGE1 and prevent toxic lipid breakdown. [1, 4, 5]

Zinc & Magnesium: Essential trace elements that act as direct enzymatic cofactors. They optimize cellular signaling, allowing the Cyclooxygenase (COX) enzymes to cleanly process DGLA into the 1-series prostaglandins (PGE1) rather than stalling the process. [2, 6]
Vitamin B6 (Pyridoxine): Works in tandem with zinc and magnesium to support upstream fatty acid metabolism and maintain proper cell membrane phospholipid composition. [6, 7, 8]
Vitamins A, C, E, & Selenium: These potent antioxidants protect fragile polyunsaturated fatty acids (like GLA and DGLA) from oxidation. If these fats undergo lipid peroxidation, they cannot be converted into PGE1. [6, 9]

2. How Omega-3s Block the Inflammatory AA Pathway

To stop DGLA from slipping down into the inflammatory PGE2 pathway, you must inhibit the enzyme Delta-5-Desaturase (D5D). Long-chain Omega-3 fatty acids—specifically Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA)—are the most effective natural tools for this task. [3, 5, 9, 10, 11]

            [ GLA ] 
               │
               ▼ (Elongase)
            [ DGLA ] ───(COX Enzymes + Zinc/Mg/B6)───► [ PGE1 ] (Anti-inflammatory)
               │
               X ◄─── [ BLOCKED BY OMEGA-3s (EPA/DHA) ]
               │
               ▼ (Delta-5-Desaturase / D5D)
      [ Arachidonic Acid (AA) ] ─────────────────────► [ PGE2 ] (Pro-inflammatory)

Competitive Enzymatic Inhibition: The D5D enzyme is responsible for converting DGLA into Arachidonic Acid (AA). However, D5D also acts on Omega-3 fatty acids. When you consume EPA and DHA, they have a significantly higher binding affinity for the D5D enzyme than DGLA does. [3, 5]
The "Traffic Jam" Effect: EPA and DHA essentially flood the engine, hogging the D5D enzymes. Because the enzyme is busy processing the Omega-3s, it is completely unavailable to convert DGLA into AA. [5]
The Net Result: This biochemical traffic jam causes DGLA to pool up in the cell membranes. With nowhere else to go, the accumulated DGLA is forced into the alternative COX pathway, successfully generating vast amounts of anti-inflammatory PGE1. [1, 2, 12]

Summary Strategy
If you are taking a GLA supplement (such as borage oil or evening primrose oil), always pair it with a high-quality Omega-3 fish oil (to block AA production) and ensure your baseline levels of Zinc, Magnesium, and B6 are topped off to smoothly synthesize PGE1. [5, 6, 9, 13, 14]

Combining GLA and EPA:

To stop DGLA from converting into pro-inflammatory Arachidonic Acid (AA), your biochemical target is the Delta-5 Desaturase (Delta5D) enzyme.

Both the omega-6 pathway (DGLA to AA) and the omega-3 pathway (ETA to EPA) rely on this exact same enzyme. Because Delta5D has a limited processing capacity, you can intentionally throttle it via competitive inhibition.

However, because you are dealing with enzyme kinetics rather than a simple mechanical valve, there is no single "extra dose" number. Instead, blocking this conversion relies on maintaining a specific molecular ratio in your system.

The Target Ratio: 1:1 or 2:1 (EPA to GLA)

To aggressively block DGLA from flipping over to AA, you want the incoming EPA to match or slightly outcompete the incoming GLA at the enzyme site.

The Rule of Thumb: Aim for an EPA-to-GLA ratio between 1:1 and 2:1.
The Math: If you are taking a therapeutic skin-repair dose of 300 mg of pure GLA, you want to pair it with roughly 300 mg to 600 mg of pure EPA.

Why EPA is the Specific Blocker (Not DHA)

When choosing your omega-3 tool for this specific job, look exclusively at the EPA content, not the total omega-3 or DHA content.

EPA (omega-3) is a structural look-alike to DGLA (20:3 omega-6). They are both 20-carbon molecules vying for the same slot on the Delta5D enzyme. DHA (22:6 omega-3) has already passed this stage of elongation and does not compete for the Delta5D enzyme. Therefore, a high-DHA oil will completely fail to block the DGLA-to-AA shift.

How to Build the Combined Stack

If we apply this to the 60% rich EPA/DHA softgels (which typically provide around 400 mg EPA per 1 g capsule) alongside a standard high-GLA Borage oil:

The GLA Input: 1 softgel of Borage Oil yielding ~200 mg of pure GLA.
The EPA Blocker: 1 softgel of your 60% fish oil yielding ~400 mg of pure EPA.

This creates a clean 2:1 EPA-to-GLA ratio. The 400 mg of EPA acts as an elegant competitive buffer, keeping the Delta5D enzyme highly occupied. This forces the 200 mg of GLA to back up in the tissue pool as DGLA, where it is safely diverted by COX enzymes into anti-inflammatory Prostaglandin E1 (PGE1) instead of downstream AA.

The Synergy

By pairing them this way, you fulfill your ultimate target of fluidity and balance. You get the targeted skin barrier benefits of the GLA without letting it degrade into unwanted inflammation, and you keep the daily fish oil dose locked at just a single capsule—providing enough systemic EPA to manage the enzyme traffic without oversaturating your mitochondria or triggering rampant lipid peroxidation.

sunsunsun

@AlphaZance interdasting…

LucH

@alphazance
Ya, fine and great job.
I cite an explanation from IA:
[With a high intake EPA] The Net Result [is]: This biochemical traffic jam causes DGLA to pool up in the cell membranes. With nowhere else to go, the accumulated DGLA is forced into the alternative COX pathway, successfully generating vast amounts of anti-inflammatory PGE1.
My comment (LucH):
I won’t say it so but I’m going to cut hair in four parts (French expression, meaning: I'm splitting hairs, meaning I'm exaggerating one side of the problem).
“This biochemical traffic jam causes DGLA to pool up in the cell membranes”
=> However, it has been modulated by next sentence:
“With nowhere else to go, the accumulated DGLA is forced into the alternative COX pathway, successfully generating vast amounts of anti-inflammatory PGE1”
=> Right. GLA has been used up when and only when it takes the COX pathway (anti-inflammatory), in an appropriate low amount.

For other readers
Just keep in mind, that what is not used in this enzymatic pathway, is going to be kept in several additional takes. Not a real problem with one gram fish oil high in EPA/ DHA (60%). Only in cure if higher (often advised 2.5-3 g EPA in studies to fight painful arthrosis but only when pain is under control).
Why to moderate?
Inhibition of metabolism by accumulation of PUFA, with a high take.

Unsaturated oils block the secretion of thyroid hormones, their circulation and tissue response. This leads to an increase in estrogen levels.
Efraim Racker observed that released unsaturated fatty acids (PUFA) inhibit mitochondrial respiration. (1)
In addition to inhibiting the thyroid gland, unsaturated fats impair intercellular communication (2) suppress several cancer-related immune functions, and are present in high concentrations in cancer cells, where their anti-proteolytic action would be expected to interfere with proteolytic enzymes and to shift/boost the balance towards growth/proliferation.

Borst, P., J. A. Loos, E. J. Christ, & E. C. Slater, “Uncoupling action of long chain fatty acids,” Biochem. Bioph. Acta. 62, 509-18, 1962.
Aylsworth, C.F., C.W. Welsch, J.J. Kabora, J.E. Trosko, Effect of fatty acids on junctional communication, possible role in tumor promotion by dietary fat, Lipids 22 (6) 1987).

Let us first clarify: at 0.6–1 g of EPA+DHA per day (equivalent to one gram of 60% oil), the intake level is comparable to consuming fatty fish two to three times a week, as already mentioned. White fish and no haddock / aiglefin (predator). And of course, you get enough Mg (350-420 mg), B6 (20-25 mg) and Se (100 mcg), which is not quite sure. By the way, remember you used up B6 when you suffer from an immune reaction or from inflammation. Exhaustion.

Now, if we suppose here you take a softgel (no liquid), with Vit E and rosmarinus extract to stabilize the oil, it could do the job regarding pain from osteoarthritis (with a HM certificate: less than 0.01 ppm per heavy metal).
At this dosage level (0.6–1 g), the real technical issue / problem could be “product stability”, not metabolism: "concentrated" or "triple-strength" oils almost always come in the form of ethyl esters (rather than triglycerides)—a form that is structurally less stable against oxidation. Furthermore, the concentration process removes a significant portion of the natural tocopherols (vitamin E) that protected the crude oil.

On caveat for chips eaters, very rich in sunflower (with 80% LA omega-6): You can't just "burn off" an excess bad type of fat the next day. It stays in your system, influencing your inflammatory markers for years. This is why a small amount of "bad" fat is more disruptive long-term than a large amount of "good" fat. And remind moreover that Ray Peat has advised to eat some SFA (coconut oil / butter) to stabilize membranes. Eating at the same meal.
Note too that I eat chips from time to time (once a month, since nobody is perfect) but I try to limit PUFA then to 1/5 (ratio W3/W6). We’re surrounded by linoleic acid (LA omega-6).

Additional info if you want to counteract inflammation with a high level of EPA
Excerpt from: Unsaturated Vegetable Oils: Toxic (Ray PEAT)
http://www.raypeat.com/articles/articles/unsaturated-oils.shtml

To defend the seeds from the animals that would eat them, the [PUFA]-oils block the digestive enzymes in the animals' stomachs.
Their tendency to oxidize is very great. These oxidative processes can damage enzymes and other parts of cells, and especially their ability to produce energy.
The enzymes which break down proteins are inhibited by unsaturated fats, and these enzymes are needed not only for digestion, but also for production of thyroid hormones, clot removal, immunity, and the general adaptability of cells. The risks of abnormal blood clotting, inflammation, immune deficiency, shock, aging, obesity, and cancer are increased. Thyroid and progesterone are decreased. Since the unsaturated oils block protein digestion in the stomach, we can be malnourished even while "eating well."
=> Moderation (in cure). You could get the same effect on Cox and Lox with wild willow bark extract (no impact on Cox-1, with is fine for stomach integrity) but well on platelet (low). Fine too by combining with one type of curcumin + EO as eucalyptus citriodora and lavendula x hybryd / burnatii.
3 types of curcumin: THC (theracurmin / brain), C3 Reduct, Phytosome (Meriva / arthrosis and prostatis).
Tableau comparatif 2 – curcumine en gélule (softgel) – critères de sélection
https://mirzoune-ciboulette.forumactif.org/t921p100-biodisponibilite-de-la-curcumine-ou-trouver-la-plus-assimilable#30845

Weigh the pros and cons
The risk lies in justifying a high dose based on one mechanism (anti-inflammatory action) when the initially stated objective is different (membrane fluidity). These are two distinct targets requiring two different dosages; conflating them amounts to answering a question that was not originally being asked.

In the event of higher omega-3 intake (2 to 3 g)
IA says (Claude):
"An excess of unused PUFAs does more than just excessively fluidize the membrane: their oxidation products (MDA, 4-HNE) are electrophiles that damage proteins and DNA, deplete antioxidants, and can even reverse the intended effect—instead of anti-inflammatory resolvins, pro-inflammatory derivatives are produced. The body does not store an additional benefit; it manages an oxidative liability."
Studies demonstrating the pro-inflammatory paradox (a shift from resolvins to oxidized derivatives that activate NF-κB) and a net increase in markers such as 4-HNE typically employ EPA doses of 2–4 g/day—levels comparable to those in pharmacological trials like REDUCE-IT (icosapent ethyl, 4 g/day) or research protocols investigating oxidative stress. However, at an intake of 0.6–1 g of EPA+DHA per day (equivalent to one gram of 60% oil), the dosage falls within a range comparable to consuming fatty fish two or three times a week—an intake level that cohort studies associate with cardiovascular benefits rather than harm. Consequently, the "major oxidative cascade" narrative is not applicable in this context.

TexugoDoMel

What I have to say about the studies on “essential fatty acid deficiency (EFAD)” is that they are all incomplete, and it is necessary to piece the studies together like a puzzle, in addition to seeking out others that may not specifically address EFAD.

1. The overwhelming number of symptoms attributed to EFAD actually stems from the high metabolic rate caused by TEWL, which activates thermogenesis.

If you neutralize TEWL in an EFAD-affected animal by increasing the humidity in the laboratory, it grows and develops normally without any symptoms. In many studies on EFAD, researchers mention “spontaneous recovery”—usually in the summer, lasting for long periods—followed by a worsening of symptoms, which they attribute to the seasons and their fluctuations in humidity.

2- The body is a dissipative system; if you remove n-3/n-6, the body changes the way it handles various processes that previously relied on them. It is a mistake in these studies to remove n-6 while keeping the diet essentially the same.

I’ll give an example using zinc, a deficiency of which causes similar skin symptoms:

This table shows an EFAD (HCO) diet and a non-EFAD (corn oil) diet, and both have versions supplemented with zinc (C-2 and D-2); the key point here is that the protein source is casein (this detail will be important later):

Now, in this table, it's the same thing, but supplemented with egg albumin instead of casein:

It can be seen from these two tables that EFAD causes skin problems if:

There is a zinc deficiency
The proteins are casein-based, rather than egg albumin.

I was curious as to why the type of protein would influence the symptoms, so I remembered this:

Egg albumin is rich in sulfur-containing amino acids.

I considered the possibility of contamination with PUFA, but they also use soy protein, which I think theoretically poses a greater risk:

Is it possible that, with enough zinc, they could live indefinitely on an EFAD diet? Who knows... Well, if the problem is humidity, people who live by the beach can easily follow a diet like this and reap the benefits of the EFAD (resistance to endotoxins, inflammation, autoimmune diseases, snake venom, etc.).

And btw, it is possible for a human to live well in EFAD, without skin problems, in a city as well.

(not mine)

Thanks to learnmyhelpless at X for reminding me of zinc and EFAD relationship haha

AlphaZance

Potential Role of the Skin in Hypertension Risk Through Water Conservation

Abstract
Previous basic and clinical investigations have identified various pathogenic factors and determinants of risk that contribute to hypertension. Nevertheless, the pathogenesis of hypertension has not been fully elucidated. Moreover, despite the availability of antihypertensive medications for the management of blood pressure, treatments that address the full spectrum of the pathophysiological defects underpinning hypertension remain to be identified. To further investigate the mechanisms of primary hypertension, it is imperative to consider novel potential aspects, such as fluid management by the skin, in addition to the conventional risk factors. There is a close association between body fluid regulation and blood pressure, and the kidney, which, as the principal organ responsible for body fluid homeostasis, is the primary target for research in the field of hypertension. In addition, the skin functions as a biological barrier, potentially contributing to body fluid regulation. In this review, we propose the hypothesis that changes in skin water conservation are associated with hypertension risk based on recent findings. Further studies are required to clarify whether this novel hypothesis is limited to specific hypertension or applies to physiological blood pressure regulation.
hypertensionaha.123.20700.fig01.jpg
Figure. Fluid loss, skin water conservation, and high blood pressure. Fluid loss activates the systemic water conservation system, leading to high blood pressure, because it is coupled with vasoconstriction. Reduction in skin blood flow contributes to water conservation by suppressing transepidermal water loss.
https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.20700

Transepidermal water loss and dermal water content for quantitative assessment of cardiac congestion

Congestion assessment is essential for managing congestive heart failure (CHF). Perfusion and tissue water-related skin biophysical properties, namely transepidermal water loss (TEWL) and tissue dielectric constant (TDC), could reflect helpful information regarding circulatory change and oedema severity in these patients. This study compared these biophysical properties between 51 adult participants with CHF and 49 age- and sex-match controls without CHF and assessed their correlations with clinical indicators of congestion. TEWL, epidermal and dermal TDC were measured from the medial and lateral sides of the shin and peri-malleolar areas in a sitting position. Covariate-adjusted multiple linear regressions were used to determine the associations between the biophysical parameters and outcomes. Compared to controls, higher dermal TDC at the shin and medial malleolus, higher epidermal TDC and lower TEWL of the medial shin were observed among CHF individuals and associated with the CHF status regardless of oedema severity, age, sex, and metabolic comorbidities. Medial shin TDC estimates demonstrated the strongest association with CHF status (coefficient [95%CI]: 4.87 [2.06, 7.68]), and positional correlations with other CHF-associated biophysical parameters except for the medial shin TEWL. Subgroup analyses among CHF patients showed positive correlations between the medial shin TDC estimates and the clinical severity of pitting oedema (coefficient [95%CI]: 3.89 [1.11, 6.67]), and the medial shin TEWL estimates and symptomatic CHF status (coefficient [95%CI]: 2.12 [0.13, 4.11]). Given these findings, medial shin TEWL and dermal TDC could be utilised as objective assessments of congestion severity in CHF patients.
https://www.jidonline.org/article/S0022-202X(24)00666-3/fulltext

Assessing Vascular Tone and Fluid Balance in Septic and Cardiogenic Shock: A Feasibility Study on Skin Water Loss as a Diagnostic Tool

Background/Objectives: Fluid management in shock remains a clinical challenge, with ongoing debate about optimal guidance. Despite advanced technologies, fluid balance assessment is often inadequate. The SkInShock study investigated whether transepidermal water loss (TEWL) measurements could improve fluid balance estimation and serve as a non-invasive marker of vascular tone in patients with septic or cardiogenic shock. Methods: In this prospective single-center feasibility study (DRKS00027981), TEWL was measured daily in eight mechanically ventilated patients using a Tewameter (Courage+Khazaka, Cologne, Germany), which quantifies transcutaneous water evaporation. Total daily skin water loss was calculated either via direct TEWL measurements or an estimation formula (6 mL/kg/day + 20%/°C deviation from 37 °C). Systemic vascular resistance index (SVRI) was measured simultaneously using PiCCO technology (Pulsion Medical Systems, Munich, Germany) to evaluate the relationship between TEWL and vascular tone. Results: TEWL values were consistent across most body sites, except the forehead. TEWL-based estimates of skin water loss were significantly lower than formula-based estimates (p < 0.01). Formula-based values overestimated water loss at low TEWL levels and underestimated it at higher levels, with deviations reaching ±100%. While absolute TEWL values did not correlate with SVRI, intra-individually normalized values showed a significant negative correlation, indicating that higher skin water loss corresponded to lower vascular tone. Conclusions: TEWL measurement is feasible in ICU patients and may enhance fluid balance assessment and vascular tone monitoring. Our preliminary findings indicate that this non-invasive method could complement current diagnostics but warrants further investigation in larger cohorts.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12650400/

Transepidermal water loss (TEWL): Environment and pollution—A systematic review

Abstract
Introduction
Transepidermal water loss (TEWL) is an objective measurement of skin integrity measured as the amount of water lost across the stratum corneum. TEWL varies greatly across variables such as age and anatomic location, and disruptions in the skin barrier have been linked to inflammatory dermatoses such as psoriasis and atopic dermatitis. Impact of environmental conditions and pollution on TEWL has yet to be determined. Accordingly, this review summarizes effects of environmental conditions and pollution on TEWL.

Conclusion
Exposure to pollution is reported to cause increases in TEWL, likely through free radical damage. Significant discrepancies exist among current literature as to the effects of season and climate on TEWL. There is a need to continue examining environmental variables other than temperature and relative humidity, such as atmospheric and steam pressure, that may impact TEWL.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9168018/

Dietary fish-oil supplementation in humans reduces UVB-erythemal sensitivity but increases epidermal lipid peroxidation

Abstract
Ultraviolet radiation (UVR)-induced erythema may be mediated in part by free radical-generated tissue damage, including lipid peroxidation. We have examined the effect of dietary fish oil rich in omega-3 fatty acids upon susceptibility to UVB-induced erythema and epidermal lipid peroxidation. Fifteen volunteers took 10 g fish oil, containing 18% eicosapentaenoic acid and 12% docosahexaenoic acid, daily for 3 or 6 months. Sensitivity to UVB was assessed at intervals on fish oil, and 2.5 months after stopping treatment. Paired skin shave biopsies were taken from six subjects, at baseline and 3 months, from both irradiated and control skin. Fatty acid composition was analyzed and thiobarbituric acid-reactive substances measured as an index of lipid peroxidation. With increasing time on fish oil the minimal erythema dose rose progressively, from 18.9 +/- 13.9 mJ/cm2 (mean +/- SD) at baseline to 41.1 +/- 16.6 mJ/cm2 at 6 months, p < 0.01. Ten weeks after stopping fish oil the minimal erythema dose fell to 23.1 +/- 4.9 mJ/cm2, p < 0.05. Epidermal total omega-3 fatty acids rose from 1.8 +/- 0.4% total fatty acids (mean +/- SEM) to 24.2 +/- 3.9% at 3 months, p < 0.01. This was accompanied by a rise in thiobarbituric acid-reactive substances in irradiated skin from 6 +/- 0.3 (mean +/- SEM) to 18.5 +/- 2.6 A532/g skin, p < 0.01. Hence dietary omega-3 fatty acids produce a pronounced reduction in UVB-erythemal sensitivity, although susceptibility of skin to lipid peroxidation is increased. Thus, omega-3 fatty acids may act as an oxidizable buffer, protecting more vital structures from free radical damage.
https://pubmed.ncbi.nlm.nih.gov/8040603/

Clinical effects of undershirts coated with borage oil on children with atopic dermatitis: a double-blind, placebo-controlled clinical trial

Abstract
It has been reported that gamma-linolenic acid contained in borage oil is effective against atopic dermatitis. The clinical effects of undershirts coated with borage oil rich in gamma-linolenic acid on atopic dermatitis were evaluated. Thirty-two children, aged 1-10 years, were involved in the clinical control study. Sixteen had worn undershirts coated with borage oil everyday for 2 weeks, and 16 had worn non-coated undershirts as a placebo. Their symptoms were assessed on a 4-point scale. Those children who had worn undershirts coated with borage oil for 2 weeks showed improvements in their erythema and itch, which were statistically significant. Transepidermal water loss from the back was decreased. In the placebo group, there were no statistically significant differences. The undershirts coated with borage oil were found to be statistically effective, and had no side-effects on children with mild atopic dermatitis.
https://pubmed.ncbi.nlm.nih.gov/18078406/

The protective effects of Gamma-linolenic acid against indomethacin-induced gastric ulcer in rats

Abstract
The primary goal of the investigation was to analyse the anti-inflammatory and antioxidant properties of Gamma-linolenic acid (GLA) on rats with indomethacin (IND)-induced gastric ulcers. Thirty rats were divided into five groups: Control, IND (50 mg/kg, p.o.), IND pretreated with GLA 100 mg/kg (p.o. for 14 d), IND pretreated with GLA 150 mg/kg (p.o. for 14 d) and IND pretreated with omeprazole (20 mg/kg, p.o. for 14 d). The stomach tissues were examined to calculate the ulcer index and pH and analyse biochemical markers (prostaglandin E2 (PGE2), cyclooxygenase 1 (COX1), TNF-1, IL-6 and intercellular adhesion molecule-1 (ICAM1)) and oxidative stress parameters (malondialdehyde: (MDA), superoxide dismutase (SOD), glutathione (GSH) and CAT (catalase)) as well as undergo histopathological assessment. GLA 100 and 150 mg/kg showed a protective effect against IND-induced gastric damage. It reduced levels of COX1, TNF-1, IL-6 and ICAM and increased PGE2 levels. GLA also normalised antioxidant function by modulating MDA, SOD, GSH and CAT. GLA intervention protects against IND-induced gastric ulcers by restoring oxidant/antioxidant balance and reducing inflammation.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/protective-effects-of-gammalinolenic-acid-against-indomethacininduced-gastric-ulcer-in-rats/F942CF859FFD1BB838D27FE3AC2A566C

Linoleic acid ameliorates intestinal mucosal barrier injury in early weaned pigeon squabs (Columba livia)

Abstract
The study aimed to investigate whether linoleic acid could improve the intestinal barrier function of squabs under weaning stress conditions. Totally 320 7-d-old weaned squabs were randomly divided into four treatment groups, including control group (CON), 0.7% linoleic acid addition group (LA007), 1.4% linoleic acid addition group (LA014) and 2.1% linoleic acid addition group (LA021). At 21 d, eight squabs were randomly selected from each treatment group for sampling and determination. The results showed that adding linoleic acid could improve (P < 0.05) the body weight of weaned squabs, and LA014 had the best effect. With the increase of linoleic acid dosage, villi height and villi area increased linearly or quadratically (P < 0.05), and reached the maximum in LA021 or LA014, respectively. The linoleic acid supplementation could improve the intestinal tight junction of weaned squabs, and the LA014 was the most significant (P < 0.05). With the linoleic acid increasing, the levels of intestinal IL-6 and TNF-α decreased linearly (P < 0.05), while intestinal IL-10 increased quadratically (P < 0.05) and reached the maximum in LA014. Serum endotoxin and diamine oxidase levels decreased linearly (P < 0.05) and reached the lowest level in LA014. The ultrastructure of villi revealed that the length of ileal microvilli in LA014 was significantly increased (P < 0.05) and the microvilli became dense, and the mitochondria in epithelial cells returned to normal state. Further exploring the mechanism of linoleic acid alleviating intestinal injury caused by weaning stress in squabs, it was found that linoleic acid down-regulated (P < 0.05) the relative protein expression of TLR4, MyD88, phosphorylated JNK, and phosphorylated p38, reducing secretion of pro-inflammatory factors IL-6 and TNF-α. This study indicated that linoleic acid could alleviate intestinal barrier injury of early weaned squabs by down-regulating TLR4-MyD88-JNK/p38-IL6/TNF-α pathway.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10195202/

thebiooracle

@AlphaZance on the EFAD side of this, Ray Peat went back to the Burr rats in his fats and degeneration article. He said later papers showed Burr's diet was short on B vitamins, and "The disease that appeared in Burr's animals could be cured by fat free B-vitamin preparations, or by purified vitamin B6 when it became available." He also mentioned Burr measured the deficient rats metabolizing 50% faster than rats getting linoleic and linolenic acid. That fits what TexugoDoMel said about skin water loss pushing metabolism up. Has anyone seen the humidity experiments done with the B6 fixed?

AlphaZance

@thebiooracle
Modern Multivitamins and B-complex put too much pyridoxine, modern foods fortified with it, with many personal reports on the internet stating they have high B6 in blood and symptoms of neuropathy from it, they don't even supplement. Yet lots of acne and other skin problems still on the internet, I've almost never seen B6 reported as solution to skin problems, we already have too much? Ray Peat himself stated he took 100,000 I.U. of Vitamin A and not B vitamins to prevent acne.

Rats vs. Humans: Surface Area, Fur, and TEWL Dynamics

The physical difference between a 200g rodent and a 70kg human dramatically alters how Trans-Epidermal Water Loss (TEWL) affects metabolic rate and heat regulation.

The Physics of Scale (Surface-Area-to-Volume Ratio)
Rats: A small animal has a massive surface-area-to-volume ratio. Because heat is produced by body volume (mass) but lost through surface area, a rat loses heat to its environment at a rate almost 10 times higher per gram of tissue than a human.

Fur Factor: Fur traps a boundary layer of warm, humid air next to the skin, which naturally dampens TEWL. When EFA deficiency/B-vitamin issues cause hair loss (alopecia) and skin scaling in rats, it strips away that protective microclimate.

The Metabolic Impact on Rats: Unprotected skin + massive surface area = extreme evaporative cooling. A rat must crank its metabolic rate by 30–50% just to avoid dying of hypothermia.

The Human Reality
Humans: Humans are large, relatively hairless, and have a very low surface-area-to-volume ratio.

The Metabolic Impact on Humans: If a human experience elevated TEWL (e.g., from dry winter air or skin barrier breakdown), they do experience increased water loss and mild thermogenic stress, but it will not force a 50% spike in basal metabolic rate. The heat capacity of human body mass buffers against rapid cooling.

The Takeaway: The extreme 50% metabolic surge seen in Burr's EFA-deficient rats was an artifact of rodent physics. In humans, barrier impairment leads to dry skin, eczema, or local inflammation, rather than an explosive rise in global metabolism.

B6 Needs Cofactors: For B6 to work in skin metabolism, it requires adequate riboflavin (B2), magnesium, and zinc. Isolated high B6 intake without these cofactors is metabolically useless.
Human cells lack Δ12 and Δ15 desaturase enzymes, which means they cannot insert double bonds past carbon 9 on a fatty acid chain.
You cannot omit linoleic acid entirely because human biology lacks the desaturase enzymes required to manufacture it from scratch. However, if your goal is to minimize PUFA in line with Ray Peat's principles, the body's actual requirement for linoleic acid is extremely small—easily satisfied by trace amounts found naturally in fruit, dairy, and ruminant meats—without ever needing seed oils or high-PUFA fats.

Much like the argument with sterile gut improving lifespan of rats that is almost impossible for normal people, how good of a "laboratory environment" can you make for yourself? Could you omit a bioavailable nutrient in favor of another "perfect nutrient" biosynthesized through lots of cofactors and metabolic stages/steps, that may work for rats and not humans?

That is a profound analogy. Just like the germ-free (gnotobiotic) lab rat that lives 30% longer because its immune system isn't fighting a constant barrage of bacterial endotoxin—a feat virtually impossible for a human living in the real world—attempting to bypass essential nutrients or metabolic pathways through sheer cofactor optimization is a classic trap of reductionist biology.

When you ask if you can omit a conditionally required or bioavailable nutrient by throwing an army of cofactors at a downstream pathway to force your body to build it from scratch, the answer touches on the fundamental difference between in vitro biochemistry and in vivo human reality.

1. The Bottleneck of Multistep Biosynthesis

In a laboratory setting, if you give an isolated cell or a genetically modified rodent all the cofactors (B6, B2, magnesium, zinc, ATP, NADPH), biochemical pathways can theoretically crank out whatever molecule is missing. But human physiology has harsh operational limits:

Enzymatic Capacity vs. Demand: Even with optimal cofactors, human enzymes have maximum turnover rates (V_max). Trying to force your liver to synthesize structural components from scratch that are normally absorbed directly from the diet creates a massive metabolic bottleneck.
The Energy Tax (ATP & Reducing Equivalents): Running long biosynthetic cascades isn't free. Every time your body has to elongate and desaturate a carbon chain instead of using a pre-formed molecule, it burns precious ATP and NADPH (electrons). In a bioenergetic sense, forcing your body to act as a chemical factory to bypass a missing nutrient steals energy away from basal metabolic rate, body temperature, and tissue repair.
The "Junction" Vulnerability: Complex metabolic pathways have multiple chokepoints. If a pathway requires 6 sequential enzymatic steps, and step #4 is sluggish due to a transient stressor, inflammation, or genetic variance, the whole assembly line backs up, leading to the accumulation of toxic intermediates.

2. Pre-formed vs. Biosynthesized: The Vitamin A / Carotene Analogy

A perfect human example of this "rat lab vs. real life" mismatch is the conversion of plant carotenoids (beta-carotene) into active Retinol (Vitamin A):

The Theory: Mainstream nutrition tells us humans don't "need" pre-formed animal Vitamin A because our bodies can take beta-carotene from carrots and convert it into retinol using various enzymatic cofactors.
The Reality: The conversion rate in humans is notoriously inefficient (often requiring massive amounts of carotene to yield tiny amounts of active retinol), and the conversion drops off a cliff in people with hypothyroidism, diabetes, or genetic polymorphisms in the BCO1 enzyme.
The Peat Connection: Ray Peat heavily emphasized pre-formed Vitamin A (from liver, butter, and eggs) precisely because relying on your body to biosynthesize crucial fat-soluble molecules through multiple metabolic stages is a high-failure strategy for a stressed human.

3. Where the "Perfect Nutrient" Strategy Breaks Down

If a biohacker tries to curate a "perfect laboratory environment" inside their own body—relying on extreme cofactor saturation to make up for missing foundational inputs—they usually hit three walls:

Allostatic Load: Maintaining that level of biochemical perfection requires a stressful, hyper-vigilant lifestyle. The psychological and physiological cost of micro-managing every cofactor often outweighs the theoretical biological benefit.
The Imperfect Environment: Unlike a lab rat in a climate-controlled, pathogen-free box eating a purified chow, humans face sleep deprivation, work stress, environmental toxins, and gut permeability. Under real-world stress, your body downregulates complex biosynthetic pathways to conserve energy for survival.
The Law of Diminishing Returns: Flooding your system with cofactors doesn't turn your cells into an infinite-yield chemical plant; it often just overloads specific transport proteins or creates mineral imbalances (e.g., massive zinc intake crashing copper status).

The Bioenergetic Takeaway

Ray Peat’s philosophy, despite its heavy reliance on biochemical mechanisms, was remarkably practical at its core: Feed the organism what it can use with the least amount of metabolic friction.

Trying to bypass missing or restricted inputs by forcing your cellular machinery through grueling, multi-step biosynthetic gymnastics is a "rat lab" fantasy. Just as you cannot easily replicate a sterile, germ-free gut in downtown Manhattan, you cannot treat your metabolism like an industrial bioreactor. Real-world human health relies on consuming clean, bioavailable, pre-formed building blocks—like those found in traditional, nutrient-dense foods—so your cells can spend their energy on living, rather than manufacturing spare parts.

user1

@AlphaZance hi, any picture available of a human hand skin from a person that was label as essential fatty acid deficient in one of these experiments?

AlphaZance

@user1

Human essential fatty acid deficiency: treatment by topical application of linoleic acid

Abstract
An essential fatty acid (EFA) deficiency developed in a 19-year-old man who was being maintained on a long-term regimen of fat-free, intravenous hyperalimentation fluids. The EFA deficiency was reversed after 21 days by daily, topical application of linoleic acid to the patient's skin. The ratio of eicosatrienoic acid (20:3, n-9) to eicosatetraenoic acid (20:4, n-6) decreased to normal levels in the skin and serum with clinical improvement of the EFA deficiency syndrome. The cutaneous manifestations (scalp dermatitis, alopecia, and depigmentation of hair) were reversed with continued, topical application of safflower oil, which contains 60% to 70% linoleic acid.
https://pubmed.ncbi.nlm.nih.gov/406855/

Essential fatty acid deficiency while a patient receiving fat regimen total parenteral nutrition

Abstract
A 32-year-old man was diagnosed with lymphoma and underwent Billroth’s II operation because of upper gastrointestinal haemorrhage. Although the patient received fat regimen total parenteral nutrition (TPN), the patient developed typical skin rash of essential fatty acid deficiency after 2 weeks of starting TPN. The diagnosis was confirmed by biochemical and histological analyses. After increasing the lipid infusion, the rash was gradually improved with complete resolution after 19 days.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3387468/

user1

@AlphaZance i can not open the full text links, could you share the picture of the first link on the thread?

ThinPicking

@user1 said:

i can not open the full text links, could you share the picture of the first link on the thread?

DOI's 10.5021/ad.2012.24.2.168 for that other site.