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

Diego Adhemar Jaitin, Lorenz Adlung, Christoph A. Thaiss, Assaf Weiner, Baoguo Li, Hélène Descamps, Patrick Lundgren, Camille Bleriot, Zhaoyuan Liu, Aleksandra Deczkowska, Hadas Keren-Shaul, Eyal David, Niv Zmora, Shai Meron Eldar, Nir Lubezky, Oren Shibolet, David A. Hill, Mitchell A. Lazar, Marco Colonna, Florent GinhouxHagit Shapiro, Eran Elinav*, Ido Amit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)686-698.e14
JournalCell
Volume178
Issue number3
DOIs
StatePublished - 25 Jul 2019

Funding

FundersFunder number
Global Probiotics Council
Helen and Martin Kimmel
NeuroMac DFG/TransregionalMS Alliance/NMSS PA-1604-08459
Penn Center for Molecular Studies in Digestive and Liver DiseasesP30-DK-050306
Penn Institute for Immunology
National Institutes of HealthDK49780
Howard Hughes Medical Institute
National Institute of Diabetes and Digestive and Kidney DiseasesK08DK116668
Bill and Melinda Gates Foundation
National Multiple Sclerosis SocietyPA-1604-08459
Achelis Foundation
Melanoma Research Alliance509044
Gilead Sciences
Children's Hospital of Philadelphia
Leona M. and Harry B. Helmsley Charitable Trust
Canadian Institute for Advanced Research
Diabetes Research CenterP30-DK-019525
Thompson Family Foundation
International Progressive MS Alliance
Penn Skin Biology and Diseases Resource-based Center, University of PennsylvaniaP30-AR-069589
European Research CouncilERC-COG) 724471-HemTree2.0
Wolfson Foundation
Israel Science Foundation703/15
Ludwig-Maximilians-Universität München
Helmholtz Association

    Keywords

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

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