Lac-Phe (N-lactoyl-phenylalanine)

Lac-Phe (N-lactoyl-phenylalanine) is a conjugate of lactate and phenylalanine and the most abundant member of the N-lactoyl-amino acids. Lac-Phe is formed by CNDP2-mediated condensation of lactate and phenylalanine. Plasma Lac-Phe levels are elevated by diverse stimuli that increase circulating lactate or phenylalanine levels, or increase glycolytic flux, in both mice and humans. These stimuli include sprint exercise, metformin treatment, feeding, phenylketonuria, and mitochondrial disease. Lac-Phe is an anorexigenic signaling metabolite that suppresses food intake. Pharmacological Lac-Phe injection reduces food intake and adiposity. Genetic ablation of CNDP2 abolishes Lac-Phe biosynthesis and renders the animals resistant to the anti-obesity effects of both exercise and metformin treatment. As a common signaling metabolite stimulated by diverse physiologic stimuli, the role of Lac-Phe beyond energy balance warrants further studies. Lac-Phe is a lactate-derived signaling metabolite tightly linked to lactate metabolism and glycolytic flux, as well as to phenylalanine levels. CNDP2 is the primary biosynthetic enzyme for Lac-Phe and is required for basal and exercise- and metformin-inducible Lac-Phe synthesis. CNDP2 is a ubiquitous cytosolic enzyme and shows highest expression levels in myeloid cells and in epithelial cells of the gut and kidney. Exercise-inducible Lac-Phe synthesis is driven by increased circulating levels of muscle-derived lactate. Metformin increases Lac-Phe synthesis through increased intracellular lactate and increased glycolytic flux. The transporters and molecular targets of Lac-Phe remain unknown. Lac-Phe administration suppresses food intake and body weight without affecting locomotor behavior and energy expenditure in diet-induced obese mice. Chronic administration of Lac-Phe reduces adiposity and improves glucose homeostasis. Exercise- and metformin-inducible Lac-Phe mediates weight loss in diet-induced obese mice. Exercise-inducible Lac-Phe levels are associated with adipose tissue loss during endurance training in humans with obesity. Lac-Phe is a mediator of metformin-associated weight loss in humans. Lac-Phe is a biomarker for mitochondrial dysfunction and predicts mortality in septic shock. Other metabolic roles of Lac-Phe beyond feeding regulation remain largely unknown. S.X. is supported by the Stanford School of Medicine Dean's Fellowship and a Postdoctoral Fellowship from the American Heart Association (24POST1200064). V.L.L. is supported by the National Institutes of Health (NIH) (GM113854) and a Bio-X SIGF Graduate Student Fellowship. This work was supported by the NIH (DK124265 and DK136526 to J.Z.L.), the Wu Tsai Human Performance Alliance (research grant to J.Z.L.), the Stanford Diabetes Research Center (P30DK116074), the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute (research grant to J.Z.L.), and the Ono Pharma Foundation (research grant to J.Z.L.). Figures were created with BioRender. The authors have no interests to declare