Protein Key to Circadian Clocks, Sleep Cycles, and Metabolic Health

A key protein that has been linked to the body’s natural circadian clock may provide insights into how the body regulates vital metabolic functions, according to new research.

“Understanding the mechanisms that link circadian gene oscillations with metabolism are critical for the development of new treatment of metabolic diseases,” Katerina Akassoglou, PhD, Senior Investigator at the Gladstone Institutes and Professor of Neurology at the University of California, San Francisco, told ConsultantLive.

“Moreover, studies in humans have shown that the circadian clock is linked with metabolic dysfunction, cancer, and neurodegenerative and autoimmune diseases,” she said. “Understanding the mechanisms and discovering new genes that link the clock with peripheral functions could be critical for developing new therapies for various diseases in humans.”

Dr Akassoglou and colleagues have found that production of the p75 neurotrophin receptor (p75^NTR) protein oscillates in time with the body’s natural circadian clock.

“Our study identifies p75^NTRas a new gene under rhythmic oscillation,” she said. “In the absence of p75^NTR, we show that the expression of metabolic genes in the liver that regulate lipid and glucose homeostasis is disrupted.”

The study results may reveal p75^NTR as a therapeutic target for diseases with altered circadian oscillation, such as sleep disorders, neurological and behavioral disorders, and metabolic diseases, the authors noted.

Changes in expression of clock and metabolic liver genes could have important implications in the metabolic functions of the organism. “Indeed, our previous studies showed that p75^NTR plays a central role in the regulation of insulin resistance,” Dr Akassoglou said.

p75^NTR traditionally has been studied for its expression in the brain as a receptor for neurotrophins. However, similar to other proteins that link circadian clocks and metabolism, p75^NTR is expressed in many tissues throughout the body as well as in the brain. This suggests that it p75^NTR affects a variety of biological functions.

Last year, Dr Akassoglou’s group discovered that p75^NTR is present in the liver and in fat cells and that it regulates glucose levels in the blood.

“Our studies revealed an unanticipated function of p75^NTR as a clock gene and an important regulator of metabolic functions that modulates the communication between the brain and the rest of the organs in the body,” she said.

The studies in mice have shown that a drop in p75^NTR levels could have a major impact in metabolic diseases, such as type 2 diabetes mellitus.

“Disruption of the circadian clock has been identified as a risk factor for cardiovascular, neurodegenerative, and autoimmune diseases in humans. Therefore, it is possible that p75^NTR levels might regulate a wide spectrum of clock-regulated pathologies,” Dr Akassoglou said, adding that the role of p75^NTR in the circadian clock systems in humans is still unknown.

“Our finding that p75^NTR is a clock gene with metabolic functions is a novel and unexpected finding,” Dr Akassoglou stated. “We are currently working to determine the contribution of p75^NTR in regulating the relationship between the circadian clock, metabolism, and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption, including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer disease.”

A deeper understanding of the pleiotropic functions of p75^NTR would be required before considering human studies, Dr Akassoglou noted.

The researchers published their results in the June 19, 2013 Journal of Neuroscience.