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Cell Metab. 2018 Jul 3;28(1):118-129.e5. doi: 10.1016/j.cmet.2018.04.021. Epub 2018 May 24.

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

Author information

1
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address: jcbornig@stanford.edu.
2
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address: william.walker2@hsc.wvu.edu.
3
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
4
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Veterinary Preventative Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
5
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
6
Comprehensive Cancer Center, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

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.

KEYWORDS:

IL-6; breast cancer; ghrelin; glucose; hypocretin/orexin; leptin; sleep

PMID:
29805100
PMCID:
PMC6031468
[Available on 2019-07-03]
DOI:
10.1016/j.cmet.2018.04.021

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