“An Exercise-Inducible Metabolite That Suppresses Feeding and Obesity”, 2022-06-15 ():
[commentary] Exercise confers protection against obesity, type2 diabetes and other cardiometabolic diseases. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear.
Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signaling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs.
In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training.
Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species.
These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
…Acute Lac-Phe treatment suppressed food intake by ~50% compared with vehicle-treated mice over a period of 12h (Figure 3a). Of note, ambulatory activity was not different between groups (Figure 3b), which demonstrates that the suppression of feeding behaviors was not simply due to reduced movement. Acute Lac-Phe treatment also did not alter oxygen consumption, carbon dioxide production or respiratory exchange ratios (Extended Data Figure 3e-g). In a separate group of DIO mice, Lac-Phe administration did not alter kaolin or water intake, which demonstrates that a component of nausea is not involved in its hypophagic effects (Extended Data Figure 3h-j). Lac-Phe also did not alter circulating levels of other appetite-regulating hormones, including leptin and ghrelin (Extended Data Figure 3k, 3l). In chow-fed, lean mice, Lac-Phe did not suppress food intake, even at up to 3× higher doses (150mg/kg–1, i.p. injection; Extended Data Figure 4). These data demonstrate that pharmacological administration of Lac-Phe to obese but not lean mice specifically suppresses energy intake without altering energy expenditure pathways…Oral dosing of Lac-Phe in obese mice did not suppress food intake or body weight (Extended Data Figure 5), which is probably due to the chemical lability of Lac-Phe peptide bond in the digestive system.