Sympathetic signaling directs macrophage efferocytosis in thermogenic adipose tissue

Brown adipose tissue (BAT) undergoes significant remodeling upon thermogenic activation. During this process, brown adipocytes and immune cells, such as macrophages, contribute to thermogenesis and energy expenditure. Among the various functions exerted by macrophages, the clearance of dying cells, known as efferocytosis, is a key regulator of tissue remodeling across multiple organs in both physiological and pathological contexts. However, whether macrophages contribute to BAT remodeling and thermogenic adaptation through efferocytosis, and what drives efferocytosis in BAT, remain unknown. Here, we identify norepinephrine (NE), which is highly released in BAT upon cold challenge, as a tissue-specific trigger of macrophage efferocytosis. Transcriptomic and lipidomic analyses of BAT after cold exposure revealed a population of lipid-handling macrophages enriched in efferocytosis-related transcripts. Consistently, cold exposure enhanced the efferocytic capacity of BAT macrophages. These effects were recapitulated by stimulation of macrophages with NE and were dependent on {beta}2-adrenergic signaling and the efferocytic receptors AXL and MERTK. Mice lacking Axl and Mertk in macrophages exhibited impaired lipolysis, reduced thermogenic gene expression, and increased adipose tissue inflammation. Together, our findings identify a so far neglected role for NE in adipose tissue, linking sympathetic activation to macrophage efferocytosis and thereby promoting tissue remodeling and metabolic adaptation. Uncovering the role of NE in one of the core functions of macrophages, efferocytosis, not only expands our understanding of the multifaceted effects of NE on the immune system but also highlights therapeutic potential for targeting impaired efferocytosis in metabolic disorders. One sentence summaryNorepinephrine is a novel trigger of macrophage efferocytosis in brown adipose tissue, linking sympathetic signaling to metabolic adaptation and macrophage tissue remodeling responses through {beta}2-adrenergic and Axl/Mertk pathways.