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. Epub 2018 May 24.


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.

MeSH terms

  • Animals
  • Breast Neoplasms / complications*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Female
  • Ghrelin / metabolism
  • Glucose / metabolism
  • Hyperphagia
  • Interleukin-6 / immunology*
  • Leptin / blood
  • Mammary Neoplasms, Experimental
  • Metabolic Diseases / etiology*
  • Mice
  • Mice, Inbred BALB C
  • Neurons / metabolism*
  • Orexin Receptor Antagonists / therapeutic use
  • Orexins / physiology*
  • Sleep / drug effects
  • Sleep Wake Disorders / etiology*


  • Ghrelin
  • Hcrt protein, mouse
  • Interleukin-6
  • Leptin
  • Orexin Receptor Antagonists
  • Orexins
  • interleukin-6, mouse
  • Glucose