biostudies-literatureHedaya LQatar National Research Fund1296https://www.ebi.ac.uk/biostudies/studies/S-EPMC12384308biostudies-literatureUnknown14(16)N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increaCellsN-Lactoyl Phenylalanine Disrupts Insulin Signaling, Induces Inflammation, and Impairs Mitochondrial Respiration in Cell Models.PMC12384308ARG01-0420-230007Elashi AADavey GPElrayess MAHedaya LAl-Asmakh MEspino-Guarch MNaja KAnwardeen NAldirbashi OYAlmuraikhy SZughaier SMfalseN-Lactoyl Phenylalanine Disrupts Insulin Signaling, Induces Inflammation, and Impairs Mitochondrial Respiration in Cell Models.N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increa2025-01-01T00:00:00Z2025 Aug2026-04-08T10:37:18.682Z2026-04-08T01:29:47.474ZS-EPMC123843084086277410.3390/cells14161296