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Cell. 2019 Jul 25;178(3):686-698.e14. doi: 10.1016/j.cell.2019.05.054. Epub 2019 Jun 27.

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

Author information

1
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
5
Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
6
Division of Surgery, Tel-Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
7
Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.
8
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
9
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
11
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
12
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: eran.elinav@weizmann.ac.il.
13
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: ido.amit@weizmann.ac.il.

Abstract

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.

KEYWORDS:

Alzheimer disease; Trem2 pathway; fatty liver diseases; immunology; macrophages; metabolic diseases; metabolism; obesity; single-cell genomics; systems biology

PMID:
31257031
DOI:
10.1016/j.cell.2019.05.054

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