Obesity Disrupts H3K4me3 ‐Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages

Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.