MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss
- 1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Perfor
Abstract
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.
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BibTeX
@misc{xiao2026mct6,
title = {{MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss}},
author = {S. Xiao and A. S.-H. Tung and J. Spaas and S. Fu and X. Chen and T. K. Trinh and M. D. Moya-Garzon and V. L. Li and H. T. Cessna and K. Ito and S. C. Reghupathy and C. Lin and X. Lyu and S. H. Raun and M. D. W. Tyner and A. Germakovski and J. Tondreau and M. Yeckley and W. Wei and M. R. Howitt and M. D. Parker and J. A. Sprowl and S. M. Hinshaw and J. Z. Long},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753556},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753556v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss
AU - S. Xiao
AU - A. S.-H. Tung
AU - J. Spaas
AU - S. Fu
AU - X. Chen
AU - T. K. Trinh
AU - M. D. Moya-Garzon
AU - V. L. Li
AU - H. T. Cessna
AU - K. Ito
AU - S. C. Reghupathy
AU - C. Lin
AU - X. Lyu
AU - S. H. Raun
AU - M. D. W. Tyner
AU - A. Germakovski
AU - J. Tondreau
AU - M. Yeckley
AU - W. Wei
AU - M. R. Howitt
AU - M. D. Parker
AU - J. A. Sprowl
AU - S. M. Hinshaw
AU - J. Z. Long
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753556
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753556v1
AB - 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.
ER -