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 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…
MCT6, a transporter protein, plays a crucial role in the production and distribution of metformin, a widely used diabetes medication that leads to weight loss. Metabolites, molecules that transmit physiological signals, have gained attention for their impact on overall health, but the link between intracellular production and their systemic action has been elusive.
In a study using Lac-Phe, an anorexigenic metabolite, researchers discovered that MCT6 serves as an intestinal exporter, controlling how much of the synthesized Lac-Phe enters the bloodstream. This transporter not only allows Lac-Phe to be transported within cells but also facilitates its efflux, maintaining its blood levels in mice.
Deleting MCT6, either globally or specifically in the intestinal epithelium, results in resistance to weight loss caused by metformin on a high-fat diet. Restoring the transport defect by administering exogenous Lac-Phe can normalize the weight of MCT6-deficient mice. These findings establish a connection between MCT6 and metformin's pharmacology, as well as intestinal lactate metabolism, highlighting the significance of transporter-mediated release in transforming intracellular metabolic states into circulating effectors.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
