Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity

• DOI: 10.20900/immunometab20190010
• Publication Date: 2019-08-07T11:44:25Z
• Authors: Monika Sharma; Martin Schlegel; Emily J. Brown; Brian E. Sansbury; Ada Weinstock; Milessa S. Afonso; Emma M. Corr; Coen van Solingen; Lianne C. Shanley; Daniel Peled; Ravichandran Rama...; Ann Marie Schmidt; Matthew Spite; Edward A. Fisher; Kathryn J.Moore
• Keywords: Adipose tissue macrophages; PRDM16

Macrophages accumulate prominently in the visceral adipose tissue (VAT) of obese humans and high fat diet (HFD) fed mice, this is linked to insulin resistance type II diabetes. While mechanisms regulating macrophage recruitment obesity have been delineated, signals directing persistence VAT are poorly understood. We previously showed that neuroimmune guidance cue netrin-1 expressed mice humans, where it promotes accumulation. To better understand source its effects on (ATM) fate function obesity, we generated with myeloid-specific deletion (Ntn1fl/flLysMCre+/-; Ntn1Δmac). Interestingly, Ntn1Δmac a modest decrease HFD-induced adiposity adipocyte size, absence changes food intake or leptin, was accompanied by an increase markers beiging (Prdm16, UCP-1). Using single cell RNA-seq, combined conventional histological flow cytometry techniques, show caused 50% attrition ATMs HFD-fed particularly resident subset, altered phenotype residual enhance lipid handling. Pseudotime analysis transcriptomes netrin-1, macrophages underwent phenotypic switch majority activating program genes specialized handling, including fatty acid uptake intracellular transport, droplet formation lipolysis, regulation localization. Furthermore, had reduced expression involved arachidonic metabolism, targeted LCMS/MS metabololipidomics revealed decreases proinflammatory eicosanoids (5-HETE, 6-trans LTB4, TXB2, PGD2) VAT. Collectively, our data reprograms ATM leading inflammation, improved handling metabolic function.