Dataset Information

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

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.

SUBMITTER: Jaitin DA

PROVIDER: S-EPMC7068689 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Jaitin Diego Adhemar DA Adlung Lorenz L Thaiss Christoph A CA Weiner Assaf A Li Baoguo B Descamps Hélène H Lundgren Patrick P Bleriot Camille C Liu Zhaoyuan Z Deczkowska Aleksandra A Keren-Shaul Hadas H David Eyal E Zmora Niv N Eldar Shai Meron SM Lubezky Nir N Shibolet Oren O Hill David A DA Lazar Mitchell A MA Colonna Marco M Ginhoux Florent F Shapiro Hagit H Elinav Eran E Amit Ido I

Cell 20190627 3

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<sup>+</sup> lipid-associated macrophage (LAM ...[more]

PMID: 31257031

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Project description:Background & aimsMetabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions.MethodsLiver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches.ResultsDeletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001).ConclusionsHepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.

Dataset Information

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

Publications

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

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