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, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, 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. Display omitted •scRNA-seq reveals a dynamic adipose tissue immune cell atlas in mice and humans•Massive induction of a conserved LAM program during obesity•The lipid receptor Trem2 is essential for LAM protective functions•LAMs counteract inflammation, adipocyte hypertrophy, and metabolic disease A single-cell atlas of human and mouse adipose tissue uncovers protective lipid-associated macrophages (LAMs), which perform lipid uptake and metabolism to prevent adipocyte hypertrophy, inflammation, and systemic metabolic dysregulation in a Trem2 signaling-dependent manner.