Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream LAM molecular program during obesity, leading to adipocyte hypertrophy and both tissue-level and systemic hypercholesterolemia and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases. At age 8-9 weeks, for some mice the normal chow was replaced with a high fat diet. Founding Trem2-/- knockout (KO) breeder mice were crossed with wild-type (WT) mice to produce second-generation cohorts of WT and KO littermates. F1 offspring was bred to produce homozygous WT or KO, some of which were also set to feed on HFD. Mice were euthanized and nd perfused immediately through the left ventricle of the heart The epididymal (visceral) adipose tissue (EAT) was readily located and excised right above the epididymis. The subcutanous adipose tissue (SAT) was obtained from the inguinal fat depot. The 'metadata.txt' contains the details associating each single cell with its amplification batch and index sorting readouts To comply with the institutional review board, the raw files for human samples have been uploaded to the European Genome-phenome Archive (EGA) at the European Bioinformatics Institute (EBI).