Free Fatty Acids (FFAs, NEFA)

Free fatty acids (FFAs, also called non-esterified fatty acids or NEFA) are a primary vector of stress-induced tissue damage, and their chronic elevation is inseparable from the pathology of diabetes, heart failure, neurodegeneration, and aging. 3 Peat argued that when the body lacks sufficient glucose, FFAs are released from adipose stores, and their oxidation actively blocks the oxidation of glucose even when it becomes available, creating a self-perpetuating energy deficit. 1 He identified this Randle cycle interference as the core mechanism by which stress causes harm, noting that "just about everything that goes wrong involves free fatty acid increase." 3 Even saturated FFAs, while less harmful than polyunsaturated ones, still tend to shift mitochondrial metabolism away from glucose and fructose oxidation, lowering carbon dioxide production and turning on stress-related pathways. 3

The toxicity of circulating FFAs is overwhelmingly determined by their degree of unsaturation. Peat explained that when fat stores contain predominantly polyunsaturated fatty acids (PUFAs) from dietary sources like corn or safflower oil, the FFAs liberated during stress will be mostly linoleic acid and arachidonic acid. 2 These unsaturated FFAs are more water-soluble and are preferentially released into the bloodstream, where they stimulate the stress hormones ACTH, cortisol, adrenaline, glucagon, and prolactin, which in turn drive further lipolysis in a vicious, self-amplifying circle. 5 In contrast, the stress reaction is self-limiting in the relative absence of PUFA, because saturated FFAs provide negative feedback that inhibits the production of adrenaline and adrenal steroids. 5 This distinction explains why Peat considered the chronic, spontaneous release of small amounts of arachidonic acid from tissue phospholipids to be a major driver of the mild chronic inflammation underlying obesity and metabolic syndrome. 4

At the cellular level, elevated NEFA causes mitochondrial respiratory damage, cell swelling, and a generalized increase in membrane permeability that admits calcium and water, depleting blood volume and leading to a systemic inflammatory state that can culminate in shock. 2 Dinkov has written that one of the main roles of adipose tissue is to sequester dangerous PUFAs in an inert triglyceride form, keeping them away from vital organs, and that rapid weight loss through fasting or exhaustive exercise is harmful precisely because it floods the bloodstream with these stored PUFAs. 9 In nerves, the energy failure caused by FFA-driven suppression of glucose oxidation prevents the production of protective neurosteroids from cholesterol and instead upregulates the enzyme aromatase, increasing local estrogen synthesis and contributing to diabetic neuropathy and brain degeneration. 2 Dinkov and Roddy have further noted that the lipid peroxidation of released PUFAs is necessary for the formation of lipofuscin, a primary structural change of aging that accumulates inside mitochondria and progressively slows metabolism. 10

Therapeutically, Peat pointed to niacinamide and aspirin as very good regulators of FFA expression, capable of restoring energy production in failing hearts and protecting nerves by suppressing the lipolytic release of fatty acids. 2 He also emphasized that dietary sugar and protein quickly end the stress-driven liberation of FFAs, whereas high-meat, low-carbohydrate diets chronically elevate both free fatty acids and free amino acids, accelerating degenerative processes. 2 Roddy has summarized this perspective by noting that the liberation of FFAs into the blood interrupts glucose oxidation in both the short and long term, and that the use of fat as fuel supplies less carbon dioxide than the complete oxidation of glucose, undermining the anti-stress, pro-respiratory state governed by active thyroid hormone. 8