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

• Published in: Cell metabolism 2018-07, Vol.28 (1), p.118-129.e5
• Main Authors: Borniger, Jeremy C., Walker II, William H., Surbhi, Emmer, Kathryn M., Zhang, Ning, Zalenski, Abigail A., Muscarella, Stevie L., Fitzgerald, Julie A., Smith, Alexandra N., Braam, Cornelius J., TinKai, Tial, Magalang, Ulysses J., Lustberg, Maryam B., Nelson, Randy J., DeVries, A. Courtney
• Format: Article
• Language: English
• Subjects: Animals; breast cancer; Breast Neoplasms - complications; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line, Tumor; Female; ghrelin; Ghrelin - metabolism; glucose; Glucose - metabolism; Hyperphagia; hypocretin/orexin; IL-6; Interleukin-6 - immunology; leptin; Leptin - blood; Mammary Neoplasms, Experimental; Metabolic Diseases - etiology; Mice; Mice, Inbred BALB C; Neurons - metabolism; Orexin Receptor Antagonists - therapeutic use; Orexins - physiology; sleep; Sleep - drug effects; Sleep Wake Disorders - etiology
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.04.021

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. [Display omitted] •Tumors promote IL-6 driven inflammation and changes in metabolism and sleep•This is associated with aberrant activity of hypocretin/orexin (HO) neurons•Blocking HO signaling attenuated metabolic abnormalities and enhanced sleep quality•Reduced leptin and sensitivity to ghrelin may contribute to altered HO activity Cancer patients with metabolic and sleep dysfunction have worse prognoses. Using a mouse model of breast cancer, Borniger, Walker II, et al. provide evidence that tumors deregulate satiety hormones, which likely alters the activity of hypocretin/orexin neurons. Aberrant activity in these cells impairs sleep and alters glucose metabolism via the sympathetic nervous system.