A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer

Borniger, J. C., Walker Ii, W. H., Surbhi, , Emmer, K. M., Zhang, N., Zalenski, A. A., Muscarella, S. L., Fitzgerald, J. A., Smith, A. N., Braam, C. J., TinKai, T., Magalang, U. J., Lustberg, M. B., Nelson, R. J., DeVries, A. C. (July 2018) A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer. Cell Metab, 28 (1). 118-129 e5. ISSN 1932-7420 (Electronic)1550-4131 (Linking)

Abstract

We investigated relationships among immune, metabolic, and sleep abnormalities in mice with non-metastatic mammary cancer. Tumor-bearing mice displayed interleukin-6 (IL-6)-mediated peripheral inflammation, coincident with altered hepatic glucose processing and sleep. Tumor-bearing mice were hyperphagic, had reduced serum leptin concentrations, and enhanced sensitivity to exogenous ghrelin. We tested whether these phenotypes were driven by inflammation using neutralizing monoclonal antibodies against IL-6; despite the reduction in IL-6 signaling, metabolic and sleep abnormalities persisted. We next investigated neural populations coupling metabolism and sleep, and observed altered activity within lateral-hypothalamic hypocretin/orexin (HO) neurons. We used a dual HO-receptor antagonist to test whether increased HO signaling was causing metabolic abnormalities. This approach rescued metabolic abnormalities and enhanced sleep quality in tumor-bearing mice. Peripheral sympathetic denervation prevented tumor-induced increases in serum glucose. Our results link metabolic and sleep abnormalities via the HO system, and provide evidence that central neuromodulators contribute to tumor-induced changes in metabolism.

Item Type:	Paper
Subjects:	organism description > animal behavior > REM sleep diseases & disorders > cancer > cancer types > breast cancer organs, tissues, organelles, cell types and functions > tissues types and functions > suprachiasmatic nucleus > hypothalamus organs, tissues, organelles, cell types and functions > tissues types and functions > hypothalamus organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse
CSHL Authors:	Borniger, Jeremy
Communities:	CSHL labs > Borniger lab
Depositing User:	Adrian Gomez
Date:	3 July 2018
Date Deposited:	03 Jan 2020 20:03
Last Modified:	03 Jan 2020 20:03
PMCID:	PMC6031468
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38862

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