N-Lactoyl Phenylalanine Disrupts Insulin Signaling, Induces Inflammation, and Impairs Mitochondrial Respiration in Cell Models

  • Cells. 2025 Aug 20;14(16):1296. doi: 10.3390/cells14161296.
Laila Hedaya  1 ,  Khaled Naja  1 ,  Shamma Almuraikhy  1 ,  Najeha Anwardeen  1 ,  Asma A Elashi  1 ,  Maha Al-Asmakh  2 ,  Susu M Zughaier  3 ,  Meritxell Espino-Guarch  4 ,  Osama Y Aldirbashi  5  6  7 ,  Gavin P Davey  8 ,  Mohamed A Elrayess  1  3
Affiliations
  • 1. Biomedical Research Center, QU Health, Qatar University, Doha P.O. Box 2713, Qatar.
  • 2. Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar.
  • 3. College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar.
  • 4. Laboratory of Immunoregulation, Translational Medicine, Sidra Medicine, Doha P.O. Box 26999, Qatar.
  • 5. Department of Lab Medicine & Pathology, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.
  • 6. College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar.
  • 7. College of Health & Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 17666, Qatar.
  • 8. School of Biochemistry and Immunology, Trinity College Dublin, D02 PN40 Dublin, Ireland.
PMID: 40862774 DOI: 10.3390/cells14161296
Abstract

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 increases the secretion of pro-inflammatory cytokines in C2C12 skeletal muscle cells and markedly impairs mitochondrial respiration in HepG2 liver cells and rat brain-derived synaptosomes, but not in isolated mitochondria. These findings highlight potential adverse metabolic effects of Lac-Phe, especially when administered at high concentrations, and underscore the necessity of conducting a comprehensive risk assessment and dose optimization before considering Lac-Phe or related Lac-AAs as therapeutic agents. Our work provides important insights into the molecular liabilities associated with Lac-Phe and calls for further studies to balance its therapeutic promise against possible metabolic risks.

Keywords
N-lactoyl phenylalanine; cytokines; insulin signaling; mitochondrial respiration.
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