Dietary Saturated Fatty Acids as Evolutionarily Conserved Signals of Immune Activation

Dietary fat is comprised largely of fatty acids (FAs), which function not only as metabolic substrates but also as key intracellular signaling molecules. Saturated fatty acids (SFAs) have long been linked to metabolic and inflammatory disease, yet the mechanisms by which they regulate immune function remain incompletely defined. In this review, we synthesize evidence that dietary SFAs directly modulate innate and adaptive immune responses through conserved inflammatory pathways. We highlight mechanisms of myeloid cell activation, including endoplasmic reticulum stress, inflammasome engagement, and NF-κB-dependent cytokine production, and discuss findings implicating SFAs in T cell activation and differentiation. We integrate recent work from our group demonstrating that dietary SFAs promote lung innate immune activation, linking lipid exposure to neutrophilic inflammation and impaired pulmonary function. Finally, we propose an evolutionary framework in which SFA-induced immune activation was adaptive during intermittent exposure but becomes maladaptive with chronic consumption, such as in modern diets.