Lac-Phe

N-lactoyl-phenylalanine (Lac-Phe) is a novel, exercise-inducible metabolite and signaling moiety, discovered through untargeted metabolomics, that is synthesized from the condensation of lactate and phenylalanine PMID 39136551PMID 39456173PMID 36633863.

• Appetite and Feeding Suppression: Lac-Phe functions as a blood-borne messenger that acts on the central nervous system (specifically appetite control centers like the hypothalamus) to suppress food intake and appetite PMID 39456173PMID 38917635PMID 37247469.
• Enzymatic Synthesis: Its production is catalyzed by the enzyme carnosine dipeptidase 2 (CNDP2), also known as cytosolic non-specific dipeptidase, which is primarily expressed in epithelial cells (such as those in the gut and kidney), macrophages, and monocytes PMID 39456173PMID 38917635PMID 36633863.
• Lactate-Driven Mechanism: The synthesis of Lac-Phe is substrate-concentration driven, meaning it increases as blood lactate levels rise during physical activity PMID 36633863.
• Metabolic Consequences: Genetic deletion of the CNDP2 enzyme in animal models leads to increased adiposity, obesity, and reduced insulin sensitivity PMID 38917635.

Lac-Phe is classified as an exerkine based on multi-tissue metabolomic mapping that shows it is a highly dynamic molecular transducer of physical activity:

• Strongest Exercise Response: In exercise-induced metabolomics assessments of blood plasma in mice, Lac-Phe was identified as the most strongly and significantly induced metabolite PMID 39136551PMID 39456173PMID 37247469.
• Cross-Species Induction: Its elevation in response to exercise is conserved across multiple species, including mice, racehorses, and humans PMID 39136551PMID 39456173.
• Systemic Signaling: It fulfills the criteria of an exerkine by being released into the circulation in response to exercise stimuli to facilitate inter-organ communication between peripheral tissues and the brain PMID 39456173PMID 37247469.

• Obesity and Weight Management: Lac-Phe is highlighted as a promising therapeutic target for treating obesity and metabolic syndrome because exogenous administration significantly reduces feeding and total body weight without altering physical activity levels PMID 39456173PMID 38917635PMID 37247469.
• Metabolic Disease Treatment: It is identified as a potential lead for treating Non-alcoholic Fatty Liver Disease (NAFLD) and fatty liver, as it helps protect against high-fat diet-induced liver lipid accumulation PMID 38917635.
• Pharmacological Interaction: Evidence suggests that metformin, a widely used drug for diabetes and weight loss, may exert its appetite-suppressing effects through the induction of Lac-Phe PMID 39456173.
• Exercise Mimetics: Because it captures specific benefits of physical activity (appetite suppression), it is viewed as a candidate for the development of exercise-mimicking pharmaceuticals for patients with limited mobility PMID 39456173PMID 35304603.

From PMID 39456173: Li et al. [235] began their search for exerkines by performing an exercise-induced metabolomics assessment of blood plasma in mice. One of the most significantly induced non-targeted metabolites was shown to be N-lactoyl-phenylalanine (Lac-Phe) [235]. They then reported that the enzyme responsible for the synthesis of Lac-Phe, CNDP2 (cytosolic non-specific dipeptidase, also known as carnosine dipeptidase 2), was found predominantly in epithelial cells and macrophages [235]. CNDP2 is found in the gut and kidney [236]. Although the mechanism is still being determined, Lac-Phe suppresses appetite and food intake [235,236]. Ultimately, the result of exercise generates Lac-Phe, which leads to a reduction in body weight. Interestingly, metformin (a drug widely used in diabetes and off-label in PD) mediates weight loss through Lac-Phe [237].

The most extensively studied therapeutic application is in obesity and metabolic disease. The most extensively studied therapeutic application is in obesity and metabolic disease. Lac-Phe suppresses appetite and reduces body weight in diet-induced obese mice, with chronic administration improving glucose homeostasis and decreasing adiposity. PMID 35705806 These effects appear mediated through central mechanisms, including inhibition of orexigenic agouti-related peptide neurons. PMID 41547294 The first human clinical trial in individuals with obesity began dosing in 2025, evaluating appetite suppression and glucose-lowering effects. PMID 41547294

Anti-inflammatory and neuroprotective effects represent another therapeutic avenue. Lac-Phe promotes anti-inflammatory macrophage polarization, conferring protection in murine models of colitis and spinal cord injury. PMID 41547294 In spinal cord injury specifically, Lac-Phe modulates lipid metabolism in microglia/macrophages via the AMPK-PGC1α-PPARγ pathway, shifts polarization toward the anti-inflammatory M2 phenotype, and significantly improves motor function recovery. PMID 40579710

Cardiovascular applications are emerging, with Lac-Phe demonstrating blood pressure-lowering effects in angiotensin II-induced hypertensive mice, alleviating increases in both systolic and diastolic blood pressure. PMID 41478213

However, important caveats exist. High-concentration Lac-Phe exposure in cell models impairs insulin signaling, increases pro-inflammatory cytokine secretion, and disrupts mitochondrial respiration. PMID 40862774 These findings underscore the necessity of comprehensive risk assessment and dose optimization before clinical translation. PMID 40862774 The therapeutic window and optimal dosing strategies remain to be fully defined as this field advances from preclinical models to human trials. PMID 41547294