IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure

Prashant Rajbhandari; Brandon J Thomas; An-Chieh Feng; Cynthia Hong; Jiexin Wang; Laurent Vergnes; Tamer Sallam; Bo Wang; Jaspreet Sandhu; Marcus M Seldin; Aldons J Lusis; Loren G Fong; Melanie Katz; Richard Lee; Stephen G Young; Karen Reue; Stephen T Smale; Peter Tontonoz

doi:10.1016/j.cell.2017.11.019

IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure

Cell. 2018 Jan 11;172(1-2):218-233.e17. doi: 10.1016/j.cell.2017.11.019. Epub 2017 Dec 14.

Authors

Prashant Rajbhandari¹, Brandon J Thomas², An-Chieh Feng², Cynthia Hong¹, Jiexin Wang¹, Laurent Vergnes³, Tamer Sallam⁴, Bo Wang¹, Jaspreet Sandhu¹, Marcus M Seldin⁵, Aldons J Lusis⁵, Loren G Fong⁴, Melanie Katz⁶, Richard Lee⁶, Stephen G Young⁴, Karen Reue⁷, Stephen T Smale⁸, Peter Tontonoz⁹

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Ionis Pharmaceuticals, Carlsbad, CA 92008, USA.
⁷ Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ptontonoz@mednet.ucla.edu.

Abstract

Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPβ recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.

Keywords: IL-10; adipogenesis; immunometabolism; thermogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factors / metabolism
Adipocytes / metabolism*
Animals
CCAAT-Enhancer-Binding Protein-beta / metabolism
Cell Line
Cells, Cultured
Chromatin Assembly and Disassembly*
Energy Metabolism*
Interleukin-10 / genetics
Interleukin-10 / metabolism*
Male
Mice
Mice, Inbred C57BL
Signal Transduction
Thermogenesis*

Substances

Activating Transcription Factors
CCAAT-Enhancer-Binding Protein-beta
Interleukin-10

Abstract

Publication types

MeSH terms

Substances

Grants and funding