Dr. Devanjan Sikder, Burnham Institute for Medical Research at Lake Nona.
Burnham Team Investigates How the Hormone Impacts Obesity, Diabetes and Cancer
ORLANDO—Devanjan Sikder was studying how metabolism impacts sleep and weight control when he stumbled across some very interesting research involving orexin.
Sikder began investigating how orexin—a hypothalamic neuropeptide—regulates metabolism, sleep patterns and feeding behavior, and the role that hunger plays in the regulation of fat metabolism and insulin secretion.
“Orexin agonists and antagonists have immense clinical implication for narcolepsy, insomnia, eating disorders—anorexia, bulimia and Prader-Willi syndrome—and even addiction,” said Sikder, DVM, PhD, an assistant professor at Burnham Institute for Medical Research at Lake Nona specializing in genetic engineering. “Orexin improves glucose sensitivity by stimulating glucose dependent insulin release from the pancreatic beta cells, and at the cellular level, augments the mitochondria’s ability to burn sugar and enhance basal energy expenditure. Using genetic, genomic and biochemical tools, we’re trying to understand biochemical attributes defining sleep, wakefulness and hunger.”
What’s known is this: sleep-wake cycles impinge on metabolic state, and vice versa. Blood glucose controls the availability of orexin. High blood glucose following meal consumption reduces orexin levels and induces inactivity and sleep.
“Plunging glucose levels following overnight fasting elevates orexin levels, which wakes us up to hunt up some food,” he said. “In other words, soaring orexin levels trigger wakefulness, vigilance and hunger; reduced levels induce inactivity and somnolence.”
Consistent with the theory that the regulation of hunger and consciousness appear to be intimately tied to an individual’s metabolic state, Sikder said 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, Sikder said, several epidemiological studies have reported correlation between lower orexin levels with higher incidence of obesity and type-2 diabetes.
“Disruption of orexin function in humans and mice results in narcolepsy, a sleep disorder that is associated with type-2 diabetes and obesity,” he said. “Our primary focus is to understand how flawed regulation and intentional abuse of the ‘sleep-wake switch’ contribute to the development of diabetes and obesity.”
Orexin agonists and antagonists are already in clinical trials for narcolepsy, insomnia, eating disorders and even addiction, Sikder noted.
“Given that the hormone is detectable in plasma and the receptors expressed in pancreas and adipose tissue, it’s of immense interest to address the impact of orexin signaling in peripheral tissues,” he said. “Using genomics and biochemical tools, we find that orexins improve glucose sensitivity by intensifying glucose-dependent insulin release from pancreatic beta cells. At the cellular level, orexins augment mitochondria’s ability to burn sugar. Disruption of orexin function in mice results in age-related insulin resistance and impaired glucose tolerance.”
The Burnham team is creating transgenic and conditional knock out models to elucidate how orexins (OX1 and OX2) communicate with the peripheral tissues expressing the cognate receptors (OX1R and OX2R), said Sikder.
“Our primary focus is to understand how deregulation and intentional abuse of the metabolism-sensitive feeding and sleep switch contributes to diabetes and obesity,” he said.
There is a growing realization, Sikder noted, that nutrient availability and nutrient and hormone signaling pathways are tightly linked to cell proliferation and survival.
“Orexin-stimulated pathway increases the metabolic capacity of cells, and in doing so it appears to increase tumorigenic potential,” he said. “For example, orexin down-regulates VHL expression and loss of VHL function is known to promote hemangioblastomas and clear cell renal carcinoma. Orexin stabilizes HIF1-alpha, a protein whose role in cancer is widely accepted. Also, orexin induces cell proliferation. The orexin metabolic boost by itself can provide selective survival advantage, allowing aggressive lineages to out-compete the rest. So the question we seek to address is: Could orexin signaling activate tumorigenesis? Preliminary investigations suggest that acquisition of orexin signaling may play critical roles in the dynamics of neoplastic evolution. Efforts are underway to dissect the impact of orexin signaling in cancer.”