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

Rached, M.-T. et al. (2019) Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Molecular Metabolism, 20, pp. 38-50. (doi: 10.1016/j.molmet.2018.11.010) (PMID:30553769) (PMCID:PMC6358539)

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.

• Item Type: Articles
• Additional Information: MTR was supported by a 3 year Wellcome Trust Studentship via the Sanger Centre. VKY was supported by the Wellcome Trust (098051). Work in the CF laboratory was supported by the Medical Research Council (MRC_MC_UU_12022/6). DJW received grants from the Wellcome Trust: Project Grant (093082/Z/10/Z), a Wellcome Trust Strategic Award (098565/Z/12/Z) and funding from the Medical Research Council (MC-A654-5QB40). SV and AVP were funded by the BHF (RG/18/7/ 33636).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Selman, Professor Colin
• Authors: Rached, M.-T., Millership, S. J., Pedroni, S. M.A., Choudhury, A. I., Costa, A. S.H., Hardy, D. G., Glegola, J. A., Irvine, E. E., Selman, C., Woodberry, M. C., Yadav, V. K., Khadayate, S., Vidal-Puig, A., Virtue, S., Frezza, C., and Withers, D. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Molecular Metabolism
• Publisher: Elsevier
• ISSN: 2212-8778
• ISSN (Online): 2212-8778
• Published Online: 28 November 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Molecular Metabolism 20: 38-50
• Publisher Policy: Reproduced under a Creative Commons License