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

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.

The role of PHOX2B‐derived astrocytes in chemosensory control of breathing and sleep homeostasis

“…Mice were deeply anaesthetized under isoflurane (3% induction, 1.5% maintenance) and implanted with PhysioTel F20-EET (Data Sciences International [DSI], St Paul, MN, USA) biotelemetry units to allow acquisition of electroencephalogram (EEG) and electromyogram (EMG) potentials as described previously (Borniger et al 2018). Following immobilization in a stereotaxic apparatus, a midline incision was made between the posterior margin of the eyes and the midpoint of the scapulae.…”

“…architecture and spectral analyses. Raw biopotentials were band-passed (0.3-25 Hz for EEG and 25-50 Hz for EMG) and analysed in 10 s epochs via the automated rodent sleep scoring module in Neuroscore (DSI) as previously described (Borniger et al 2018). Delta and theta ratio criteria, as well as EMG threshold values (for scoring of NREM, REM and wake, respectively), were adjusted on a per-animal basis to ensure accurate scoring across the experimental set.…”

Central regulation of breast cancer growth and metastasis

“…These problems are prevalent across a variety of cancer types, with lung and breast cancer patients making up the majority of the population experiencing these symptoms [2,[20][21][22] . A "chicken-or-the-egg" phenomenon has emerged: poor sleep associates with elevated cancer incidence and progression, and cancer and/or cancer treatments further promote sleep disturbance [2,3,6,23] . Due to the heterogeneity among cancer types, patient populations, treatment regimens, and lifestyle factors, it has been challenging to pin down cause and effect.…”

“…Indeed, brain-tumor-metabolic interactions were recently tested in a mouse model of non-metastatic breast cancer [6] . Borniger, Walker and colleagues examined sleep and whole-body metabolic changes during the course of tumor progression.…”

“…Tumors are capable of altering local macronutrient contents that modulate infiltrating immune cell function resulting in aberrant inflammation. Additionally, they secrete metabolic "waste", which can promote inflammation and alter the function of distal organs and tissues such as the liver and brain [6][7][8][9][10] . As evidence accumulates, we are learning that many of these cancer-associated co-morbidities are (at least in part) due to deregulation of normal brain function by the cancer itself, cancer treatment(s), or other factors.…”