MCT1‐mediated Lactate Shuttle to Mitochondria Governs Macrophage Polarization and Modulates Glucose Homeostasis by Affecting β Cells

Abstract As a major fuel source for the tricarboxylic acid cycle, lactate controls energy metabolism through cell‐to‐cell or tissue‐to‐tissue lactate shuttles via monocarboxylate transporters (MCTs). Although lactate is shown to influence macrophage functions via histone lactylation, the specific functions of MCTs in macrophages remain incompletely understood. This study discovers that MCT1 and MCT4 have contrasting effects on regulating macrophage polarization. M1 polarization is associated with increase of MCT4 while M2 polarization is accompanied with increase of MCT1. MCT1 is mainly localized in mitochondria while MCT4 is localized on the plasma membrane. M1 polarization elevates lactate efflux from the cytoplasm to extracellular space, while M2 polarization increases intracellular lactate flux to mitochondria. At cellular level, blocking MCT1 exacerbates LPS‐induced M1‐like polarization and impairs mitochondria function. At animal level, deletion of MCT1 in macrophages exacerbates glucose intolerance, suppresses insulin secretion and increases islet cell death in high‐fat diet fed mice. Mechanistically, lactate reduces insulin secretion through GPR81‐cAMP‐PKA signaling pathway. These findings not only disclose that the MCT1‐mediated intracellular lactate shuttle to the mitochondria plays a pivotal role in governing macrophage polarization but also uncovers a functional interplay between macrophages and β cells in maintaining glucose homeostasis.