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

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

  • Cell Metab. 2018 Jul 3;28(1):118-129.e5. doi: 10.1016/j.cmet.2018.04.021.
Jeremy C Borniger 1,  William H Walker Ii 2,  Surbhi 3,  Kathryn M Emmer 4,  Ning Zhang 3,  Abigail A Zalenski 3,  Stevie L Muscarella 3,  Julie A Fitzgerald 3,  Alexandra N Smith 3,  Cornelius J Braam 3,  Tial TinKai 3,  Ulysses J Magalang 5,  Maryam B Lustberg 6,  Randy J Nelson 3,  A Courtney DeVries 3
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
  • 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.
PMID: 29805100 DOI: 10.1016/j.cmet.2018.04.021
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.

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