Cell biology

White adipose tissue

Biology

Endocrinology

Receptor

Biochemistry

Insulin

Myeloid cells

Immunology

Genetics

Homeostasis

Adipocyte

Immune system

In vitro

Insulin resistance

TREM2

Macrophage

Lipid metabolism

Obesity

Adipose tissue

Glucose homeostasis

Metabolic control analysis

Cell

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.

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner