MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple local intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) as a model system, we identify the orphan transporter MCT6/SLC16A5 as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe in vitro, mediates Lac-Phe efflux in cells, and is required for maintaining normal circulating Lac-Phe levels in vivo, particularly following metformin treatment or high-intensity exercise. High-fat-diet-fed mice with global or intestinal epithelial-specific deletion of MCT6 exhibit resistance to metformin-associated weight loss. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-knockout (KO) mice. These data connect MCT6 to Lac-Phe and gut glycolytic flux and underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.