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Nat Immunol. 2017 Jun;18(6):654-664. doi: 10.1038/ni.3728. Epub 2017 Apr 17.

A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

Author information

1
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
2
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
3
German Center for Diabetes Research, Neuherberg, Germany.
4
Department of Ophthalmology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
5
Department of Neurology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
6
ELAN Pharmaceuticals, San Francisco, California, USA.
7
Developmental Biology Section, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
8
Division of Hematology, University of Washington, Seattle, Washington, USA.
9
Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
10
Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.

Abstract

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

PMID:
28414311
PMCID:
PMC5436941
DOI:
10.1038/ni.3728
[Indexed for MEDLINE]
Free PMC Article

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