Ever wonder why you feel sleepy after a heavy meal and why it is difficult to catch some Zs when you’re hungry? It’s because our blood glucose levels directly control the amount of a hormone called orexin, which influences hunger and sleep/wake cycles. High glucose after a meal reduces orexin levels and the activity of orexin-producing neurons, making us feel sluggish. Plunging glucose levels following overnight fasting elevates orexin levels, which wakes us up to seek food. In other words, soaring orexin levels trigger wakefulness, vigilance and hunger; reduced levels induce inactivity and somnolence.“Regulation of hunger and consciousness appear to be intimately tied to our metabolic state,” says Dr. Dev Sikder, an assistant professor in the Metabolic Signaling and Disease program at Sanford-Burnham’s Lake Nona campus . “Consistent with this theory, the cyclic waxing and waning of orexin levels appears to be perturbed in metabolic disorders such as type 2 diabetes, obesity and even cancer. These disorders are also a consequence of physical inactivity and sleep/wake disturbances, which are directly influenced by orexin. Indeed, several epidemiological studies have reported a correlation between lower orexin levels and a higher incidence of obesity and type 2 diabetes.”
Orexin agonists and antagonists are already in clinical trials for narcolepsy, insomnia, eating disorders and even addiction. Given that the hormone is detectable in plasma and the receptors are expressed in pancreatic and fat tissue, it is of immense interest to address the impact of orexin signaling in peripheral tissues.
At the cellular level, orexins augment the mitochondria’s ability to burn sugar. Disruption of orexin function in mice results in age-related insulin resistance and impaired glucose tolerance. Dr. Sikder is currently studying how deregulation and intentional abuse of the metabolism-sensitive feeding and sleep switch contribute to diabetes and obesity.
Orexin and Cancer
There is a growing realization that nutrient availability, nutrient signaling pathways and hormone signaling pathways are tightly linked to cell proliferation and survival. The orexin-stimulated pathway increases the metabolic capacity of cells and in doing so appears to increase cancer potential. For example, orexin mutes VHL expression and loss of VHL function is known to promote hemangioblastoma and clear cell renal carcinoma. Orexin stabilizes HIF1-alpha, a protein known to promote cancer. The orexin metabolic boost by itself gives aggressive cells the ability to “out-compete” their less aggressive cousins. So the question is: Could orexin signaling activate tumorigenesis? Preliminary investigations suggest that orexin signaling may play a critical role in the process that turns normal cells into cancerous cells. Efforts are underway to analyze the impact of orexin signaling in cancer.