Patients with cancer often suffer from sleep and metabolic problems, but the mechanistic basis for these issues is unclear. Now, new research has directly linked cancer to both sleep disruption and metabolic dysregulation.
In a mouse model of non-metastatic breast cancer, Jeremy Borniger, William Walker II and colleagues show that cancer alters satiety hormone signalling. This change disrupts central hypocretin-producing neurons, which results in sleep and metabolic dysregulation via the sympathetic nervous system.
“Prior research has shown that cancer can promote an inflammatory state that may promote sleep and metabolic problems; however, although we found evidence of inflammation in tandem with sleep and metabolic disruption in our model of non-metastatic breast cancer, blocking inflammation did not rescue these problems,” explains Borniger. “We therefore investigated neural populations that couple sleep and metabolism, and as hypocretin-producing neurons have been widely studied, we started there.”
The authors began by measuring changes to sleep during the course of tumour development in their mouse model using electroencephalogram and electromyogram telemetry. Borniger explains that in their experiments they used non-metastatic breast cancer cells (67NR) to prevent cancer cells metastasizing to the brain or elsewhere and promoting sleep and/or metabolic problems. They then examined inflammation in the periphery and brain; glucose, lactate and pyruvate tolerance; and the activity of hypocretin-producing neurons and melanin-concentrating hormone-producing neurons.
“The primary finding was that non-metastatic tumours alone can alter sleep and metabolism by first altering leptin and ghrelin signalling, which sets off a cascade of events that promote sleep and metabolic dysregulation,” adds Borniger. “Our data provide a holistic view of tumour–brain–liver communication that mediates multiple aspects of cancer co-morbidities.”
The authors hope that with further research they will be able to learn more about how hypocretin-producing neurons are linked to abnormalities in sleep and metabolism in cancer and define whether this pathway is conserved in humans.
Borniger, J. C. et al. A role for hypocretin/orexin in metabolic and sleep abnormalities in a mouse model of non-metastatic breast cancer. Cell Metab. https://doi.org/10.1016/j.cmet.2018.04.021 (2018)
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Morris, A. Cancer linked to sleep and metabolic disruption. Nat Rev Endocrinol 14, 440 (2018). https://doi.org/10.1038/s41574-018-0043-z