Lac-Phe: An Emerging Appetite-Regulating Exerkine with Health and Therapeutic Benefits.

PURPOSE OF REVIEW: This review provides an up-to-date overview of molecular mechanisms and translational potential of N-lactoyl-phenylalanine (Lac-Phe), highlighting recent advances and suggesting future research directions. RECENT FINDINGS: Recent studies have revealed the neurobiological mechanism of Lac-Phe, demonstrating its ability to suppress appetite through KATP channel-mediated inhibition of hypothalamic AgRP neurons. Furthermore, emerging research has highlighted its therapeutic potential in type 2 diabetes, inflammatory bowel disease, and spinal cord injury through metabolic and anti-inflammatory pathways. Current evidence establishes Lac-Phe as an exercise-responsive metabolite that suppresses appetite and correlates with exercise intensity, metformin use, and multiple disease states. Its biosynthesis via intestinal CNDP2 and appetite suppression through hypothalamic AgRP neuron inhibition are elucidated. However, clarifying its brain transporters, pharmacokinetics, and the discrepancy between its strong correlation with insulin resistance in healthy individuals and its role as a mediator of metformin’s weight loss effect will be essential to evaluate the diagnostic and therapeutic potential of Lac-Phe.