S. Xiao, A. S.-H. Tung, J. Spaas, S. Fu, X. Chen, T. K. Trinh, M. D. Moya-Garzon, V. L. Li, H. T. Cessna, K. Ito, S. C. Reghupathy, C. Lin, X. Lyu, S. H. Raun, M. D. W. Tyner, A. Germakovski, J. Tondreau, M. Yeckley, W. Wei, M. R. Howitt, M. D. Parker, J. A. Sprowl, S. M. Hinshaw, J. Z. Long
Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable 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, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.