A subset of Kupffer cells regulates metabolism through the expression of CD36

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM– population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions. [Display omitted] •Unbiased high-throughput approaches reveal two subsets of murine Kupffer cells (KCs)•CD206hiESAM+ KC2 exhibit a distinct metabolic signature•Depletion of metabolically wired KC2 subset prevents diet-induced obesity•CD36hi KC2 regulate liver oxidative stress associated with obesity via CD36 expression Macrophage heterogeneity is well appreciated across tissues, but the diversity within the same tissue is often overlooked. Blériot et al. reveal the coexistence of two Kupffer cell subpopulations in murine liver with a minor CD206hiCD36hi one (KC2) endowed with metabolic functions, involved in regulating liver oxidative stress associated with obesity.