Abstract # 3107 A role for hypocretin/orexin in metabolic and sleep abnormalities in a mouse model of non-metastatic breast cancer

Abstract

Among cancer patients, metabolic and sleep abnormalities are significant problems that are associated with decreased quality of life and increased mortality. In spite of the abundance of metabolic and sleep abnormalities in cancer patients, the mechanisms by which tumors alter metabolism and sleep remain unknown. Utilizing a non-metastatic murine breast cancer model, we investigated the relationships among immune, metabolic, and sleep abnormalities. Tumor bearing mice displayed increased serum interleukin-6 concentrations, concurrent with hyperglycemia, altered gluconeogenesis/glycolysis gene expression, and sleep abnormalities. To test whether tumor induced elevations in IL-6 were responsible for the metabolic and sleep abnormalities observed in our study, we reduced IL-6 signaling by administering a monoclonal antibody against IL-6. Despite successfully suppressing IL-6 signaling, metabolic and sleep abnormalities remained. Next, we investigated hypocretin/orexin (HO) signaling in the lateral hypothalamus as this population of neurons is known to regulate both metabolism and sleep, and observed increased HO activity. We administered a dual HO receptor antagonist (almorexant) to test whether the increased HO signaling was driving the altered hepatic glucose production and hyperglycemia. Administration of almorexant rescued the tumor-induced deficits in hyperglycemia, hepatic glucose production, and improved sleep quality, independent of IL-6. Together, our data demonstrate a novel mechanism by which non-metastatic tumors can promote energy availability, and suggest that targeting HO system may represent a potential intervention for breast cancer patients with metabolic dysfunctions.