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Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity.
Rached, Marie-Therese; Millership, Steven J; Pedroni, Silvia M A; Choudhury, Agharul I; Costa, Ana S H; Hardy, Darran G; Glegola, Justyna A; Irvine, Elaine E; Selman, Colin; Woodberry, Megan C; Yadav, Vijay K; Khadayate, Sanjay; Vidal-Puig, Antonio; Virtue, Samuel; Frezza, Christian; Withers, Dominic J.
Afiliación
  • Rached MT; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
  • Millership SJ; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
  • Pedroni SMA; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
  • Choudhury AI; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
  • Costa ASH; MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
  • Hardy DG; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
  • Glegola JA; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
  • Irvine EE; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
  • Selman C; Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
  • Woodberry MC; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
  • Yadav VK; Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK; Department of Genetics and Development, Columbia University, New York, 10032, USA.
  • Khadayate S; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
  • Vidal-Puig A; Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK.
  • Virtue S; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK.
  • Frezza C; MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
  • Withers DJ; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK. Electronic address: d.withers@imperial.ac.uk.
Mol Metab ; 20: 38-50, 2019 02.
Article en En | MEDLINE | ID: mdl-30553769
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Simpático / Tejido Adiposo Pardo / Células Precursoras de Monocitos y Macrófagos / Proteínas Sustrato del Receptor de Insulina / Obesidad Límite: Animals Idioma: En Revista: Mol Metab Año: 2019 Tipo del documento: Article Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Simpático / Tejido Adiposo Pardo / Células Precursoras de Monocitos y Macrófagos / Proteínas Sustrato del Receptor de Insulina / Obesidad Límite: Animals Idioma: En Revista: Mol Metab Año: 2019 Tipo del documento: Article Pais de publicación: Alemania