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Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity

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Title: Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity
Authors: Rached, M-T
Millership, SJ
Pedroni, SMA
Choudhury, AI
Costa, ASH
Hardy, DG
Glegola, JA
Irvine, EE
Selman, C
Woodberry, MC
Yadav, VK
Khadayate, S
Vidal-Puig, A
Virtue, S
Frezza, C
Withers, D
Item Type: Journal Article
Abstract: Objective Sympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects. Methods To address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2LyzM−/− mice). Results These animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2LyzM−/− mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation. Conclusions Our studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.
Issue Date: 1-Feb-2019
Date of Acceptance: 25-Nov-2018
URI: http://hdl.handle.net/10044/1/66518
DOI: https://dx.doi.org/10.1016/j.molmet.2018.11.010
ISSN: 2212-8778
Publisher: Elsevier
Start Page: 38
End Page: 50
Journal / Book Title: Molecular Metabolism
Volume: 20
Copyright Statement: © 2018 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0)
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Medical Research Council
Funder's Grant Number: 093082/Z/10/Z
511377
MC-A654-5QB40
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Macrophage
Irs2
Obesity
Inflammation
BAT
Sympathetic neurons
ALTERNATIVELY ACTIVATED MACROPHAGES
INSULIN-RECEPTOR SUBSTRATE-2
BETA-CELL
GENE
HOMEOSTASIS
EXPRESSION
PROTEIN
SYSTEM
ROLES
CATECHOLAMINES
Publication Status: Published
Online Publication Date: 2018-11-28
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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