Circadian Clocks Impacted by Glucose and Obesity

Circadian clocks control cardiovascular disease risks; researchers are looking for new ways to “fix” the clocks.

The circadian clocks inside the body’s cells that help regulate timing of many body functions and control cardiovascular disease risks within a 24-hour day appear to be affected by high glucose in obesity. The Medical College of Georgia at Augusta University published an article about Dr. David Stepp, vascular biologist in the Vascular Biology Center, and Leon Henri Charbonnier, Endowed Chair in Physiology at the Medical College of Georgia at Augusta University, who demonstrated that glucose and cardiovascular problems are linked in obesity. “We know that high glucose impairs circadian clock functions, but now we want to know [if] by fixing the clock can we fix the cardiovascular problems,” says Stepp. Stepp and Dr. David Fulton, director of the Vascular Biology Center and Regents professor in the MCG Department of Pharmacology and Toxicology, are principal investigators for qualifying the use of intermittent fasting and developing a class of clock repair drugs to find the answer, funded by a $2.7 million grant from the National Institutes of Health.

Circadian rhythms are physical, mental, and behavioral changes in a 24-hour internal cycle. The body’s circadian clock controls the sleep-wake cycle. Circadian rhythms can also influence hormone release, eating habits, digestion, body temperature, etc. When the body’s circadian rhythm is irregular, there is a greater risk of developing various chronic health conditions such as obesity, sleep disorders, diabetes, or depression. Obesity is a major risk factor for cardiovascular disease, in association to high blood pressure and diabetes.

Fulton explained the importance of the body’s sleep-wake cycle and how the organs and cells function optimally at the right time during the cycles. “The clock in the cells of the body is used to predict daily needs.” says Fulton. The body’s metabolic needs differ during the times of day. “During sleep the body is at a period of rest, regeneration, and repair,” Stepp says. During daybreak, genes activate for daily activities and the body’s metabolism switches from restoration to active phase.

Due to the blood flow adjusting to metabolic needs, the body’s circadian clock is sort of “intermediaries” that coordinate the changes in metabolism and cardiovascular gene function. Past evidence has shown that obesity can affect metabolism and cardiovascular regulation. Fulton explained how excessive food consumption, especially high in sugar and carbohydrates leads to obesity and stunts the circadian clock function and impairs cardiovascular health.

Stepp and Fulton documented a study performed in mouse model of hyperphagia with both high glucose levels and circadian dysfunction. The obese mice were shown to have high blood glucose, high blood pressure, and dysfunction of the single layer of endothelial cells of blood vessels, which is an important factor in blood pressure increasing. Endothelial dysfunction is a major indicator of atherosclerosis which is associated to heart disease. Dysfunctional endothelial cells affect the passageway for blood in vessels and cells pile amongst the sticky walls, which contributes to coronary artery disease.

After disrupting the circadian clocks in the mice using genetic approaches and environmental modifications, the MCG scientists noticed an increased risk of endothelial dysfunction. This observation made Stepp and Fulton want to know how to best intervene, and how the clocks lose timing. To better track clock circadian activity of the mice, a clock reporter was attached to the mice where fluorescent protein lit up when the gear of the circadian clock was turned. A huge downturn in circadian rhythms was seen in high levels of glucose in the blood. Stepp questioned, why the clock rundown in obesity and what affects the circadian disruption on cardiovascular disease? “If we fix the disruption and get the amplitude back up, does that fix the cardiovascular problems?” Stepp asked.

The clock-fixer molecule, nobiletin, the scientists are using can enhance the amplitude and reverse reduction of clock function in obesity. Scientists are still wanting to learn more about if nobiletin can improve cardiovascular function or not. To assess the nobiletin associated with cardiovascular function, the scientists would have to check for an increased expression of galectin-3, a receptor associated with cardiovascular disease. Scientists explained that they may have seen this increase expression in their mouse model.

Stepp and Fulton are still uncertain which clocks are more associated with the problem. They are focusing their future studies on the clocks in the endothelial cells, where the increased expression of galectin-3 produces an expression of the gene NOX1, which converts oxygen to damaging super oxide, in the endothelial cells. Lastly, Fulton said he also thinks timing is a problem as well.

Practice Pearls:

• Glucose and cardiovascular problems are linked to obesity.
• Obesity is one of the leading causes of death.
• Circadian clocks set the rhythm of our bodies so that we eat, sleep, wake up at the right time.

 “Circadian Rhythms.” National Institute of General Medical Sciences, U.S. Department of Health and Human Services, https://www.nigms.nih.gov/education/pages/factsheet_circadianrhythms.aspx.

“Glucose Wears down Circadian Clocks in Obesity, May Drive Cardiovascular Risk.” ScienceDaily, ScienceDaily, 24 Oct. 2019, https://www.sciencedaily.com/releases/2019/10/191024093602.htm.

Taylor-Eugene Simmons, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, PharmD Candidate