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Cell Metab. 2018 May 1;27(5):1138-1155.e6. doi: 10.1016/j.cmet.2018.03.015.

A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism.

Author information

1
Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
2
Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
3
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
4
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
5
Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
6
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland.
7
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
8
Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA.
9
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
10
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
11
Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA. Electronic address: jlusis@mednet.ucla.edu.

Abstract

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.

KEYWORDS:

Lipocalin-5; Notum; SPARC-related modular calcium binding 1; adipocyte beiging; cross-tissue communication; endocrine; inter-alpha-trypsin inhibitor heavy chain H5; mitochondria; pro-platelet basic protein; secreted peptides; skeletal muscle respiration

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