Glucose wears down circadian clocks in obesity, may drive cardiovascular risk
October 24, 2019
Science Daily/Medical College of Georgia at Augusta University
High glucose in obesity appears to gum up the works of the circadian clocks inside our cells that help regulate the timing of many body functions across the 24-hour day and drive the risk of cardiovascular disease, scientists say.
"We have demonstrated that glucose and cardiovascular problems are intrinsically linked in obesity," says 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.
"We have also demonstrated that high glucose impairs circadian clock function. Now we want to know if we fix the clock, do we fix the cardiovascular problems," says Stepp.
He and Dr. David Fulton, director of the Vascular Biology Center and Regents professor in the MCG Department of Pharmacology and Toxicology, are principal investigators on a $2.7 million grant from the National Institutes of Health that is enabling the use of intermittent fasting and a developing category of clock repair drugs to find the answer.
Circadian clocks set the rhythm of our bodies so that we eat, sleep and wake at the right time. What is less well recognized is the important role of circadian clocks in anticipating these events and preparing our organs and cells so they function optimally at the right time as well as anticipating when to rest and rejuvenate, says Fulton.
"Every cell in your body has a clock in it that is used to anticipate daily needs," says Fulton, your blood pressure and heart rate drop at nighttime and surge in the morning when your feet hit the ground and blood must fight against gravity.
"Your metabolic needs at night are different than your metabolic needs when you are awake," says Stepp. "Some of them are more; some of them are just different."
Sleep is supposed to be a period of rest and recovery for each of our cells just like it is for us overall. "You are doing regeneration, you are doing restoration, you are doing repair," Stepp says. At daybreak, genes active at night should be turned off, and genes important for daily activities should be turned on and our metabolism should switch from a restorative to active phase.
Blood flow adjusts to match these dynamic metabolic needs, and our circadian clocks are sort of intermediaries between metabolism and our cardiovascular system that coordinate changes in metabolism with changes in cardiovascular gene function.
The MCG scientists have evidence that obesity can break these links between metabolism and cardiovascular regulation. Excessive food consumption, particularly foods that are high in sugar and carbohydrates, some of which our body also breaks down into glucose, dampens clock function and imperils cardiovascular health. "It's certainly an accelerant," Fulton says of high glucose.
They have documented both high glucose levels and significant circadian dysfunction in a mouse model of hyperphagia. These obese mice have tremendous appetites, high glucose and high blood pressure that does not dip at night when it should, and most importantly, dysfunction of the single layer of endothelial cells that line blood vessels. Normally endothelial cells provide a smooth surface for blood to pass over and play a key role in enabling blood vessels to dilate in response to greater blood volume so blood pressure doesn't increase too much.
Endothelial dysfunction, a focus of their cardiovascular studies, is a major initiator of atherosclerosis, and what many of us think of as heart disease. Dysfunctional endothelial cells become inflamed, sticky and produce more damaging reactive oxygen species and less nitric oxide, which impairs blood vessel dilation. The result can be a tortuous passageway for blood, sticky walls where cells pile up and coronary artery disease.
When the MCG scientists disrupt the gears of circadian clocks in mice using genetic approaches or environmental modifications, including jet lag light cycles, both approaches result in loss of clock function and increase the risk of endothelial dysfunction and disease. Now Fulton and Stepp want to know more about how the clocks lose timing and how best to intervene.
They have bred the obese mice with a clock reporter, a gear of the circadian clock linked to a fluorescent protein that lights up when the gear is turned, so they can better track clock activity.
Using these clock reporter mice, they saw huge downturns in circadian rhythms and clock-related genes in obese mice and high levels of glucose in the blood upstream of these events.
"The first thing we want to know is can we understand why the clock is rundown in obesity," says Stepp. "The second thing is what mediates the effects of circadian disruption on cardiovascular disease, and if we fix that disruption, get the amplitude back up, does it fix the cardiovascular problems."
If intermittent fasting, which should help restore the normal peaks and valleys of glucose levels, or the clock-fixer drugs they are using for these studies interfere with progression to cardiovascular problems, they should have some answers.
They and others already have evidence that the small, clock-fixer molecule they are using, nobiletin, enhances the amplitude of and reverses the reduction of clock function in obesity. Whether or not that improves cardiovascular function, is one of the things they want to learn more about now.
That includes checking whether high glucose and resulting clock dysfunction work through the increased expression of galectin-3, a receptor associated with cardiovascular disease that they have seen in their mouse model, to produce expression of the gene NOX1, which converts oxygen to damaging super oxide, in endothelial cells.
They still are not certain which clock(s) are most central to this problem. Everywhere they have looked -- heart, kidney, liver, blood vessels and endothelial cells -- they have seen these rundown clocks. For now they are focusing on clocks in the endothelial cells, where they think a lot of the problems start. They don't expect to identify a specific clock(s) in these studies, but if their findings continue to hold they will start knocking out clocks in other cells in future studies.
They think the problem quite literally is about timing, says Fulton. Proper signaling requires a peak and trough and constant overstimulation by too much glucose has the body instead trying to turn clocks off.
The scientists note that if you have a healthy musculature despite obesity, it mitigates, at least for a time, the impact of high glucose on the vasculature. Muscle is a first and fast user of glucose, quickly pulling it out of the circulation. "If it goes into the muscle, it never comes out again," says Stepp. "It gets used or stored for later." Obese mice, like humans, lose muscle mass. In some of their initial studies, they preserved muscle mass in obese mice, which also prevented cardiovascular damage.
They note that both aging, when muscle naturally loses volume even in individuals who remain active, and spinal cord injuries or other conditions that leave us immobile, have some of the same cardiovascular risks as obesity.
While circadian-related cardiovascular risk also is heightened by lifelike scenarios like shiftwork or chronic jet lag in even a lean mouse, it is way worse for an obese one, Stepp says.
Adult obesity results from factors that include consuming more calories than are expended, medications and other exposures as well as genetics, including gene variants that increase hunger and food intake, according to the Centers for Disease Control and Prevention. It is associated with poorer mental health, reduced quality of life and contributes to the leading causes of death in the United States including diabetes, heart disease, stroke and some types of cancer. Obesity itself is considered a major risk factor for cardiovascular disease, and a major risk as well for diabetes and high blood pressure, which are other top cardiovascular risks.
https://www.sciencedaily.com/releases/2019/10/191024093602.htm
Why lack of sleep is bad for your heart
Study finds short-sleepers have lower levels of gene-regulating microRNA
May 21, 2019
Science Daily/University of Colorado at Boulder
People who sleep fewer than 7 hours per night have lower levels of gene-regulating molecules, or microRNAs, which help dampen down inflammation in cells and support vascular health.
In recent years, numerous studies have shown that people who don't get enough sleep are at greater risk of stroke and heart attack.
A new University of Colorado Boulder study, published in the journal Experimental Physiology, helps explain why.
It found that people who sleep fewer than 7 hours per night have lower blood levels of three physiological regulators, or microRNAs, which influence gene expression and play a key role in maintaining vascular health.
The findings could potentially lead to new, non-invasive tests for sleep deprived patients concerned about their health, the authors said.
"This study proposes a new potential mechanism through which sleep influences heart health and overall physiology," said senior author Christopher DeSouza, a professor of Integrative Physiology.
Despite recommendations by the American Heart Association that people get 7 to 9 hours of sleep each night, about 40 percent of adults in the United States fall short. Overall, the average American's sleep duration has plummeted from 9 hours nightly to 6.8 hours nightly over the past century.
In another recent study, DeSouza's group found that adult men who sleep 6 hours per night have dysfunctional endothelial cells -- the cells that line blood vessels -- and their arteries don't dilate and constrict as well as those who get sufficient sleep.
But the underlying factors leading to this dysfunction aren't well known.
MicroRNAs are small molecules that suppress gene expression of certain proteins in cells. The exact function of circulating microRNAs in the cardiovascular system, and their impact on cardiovascular health is receiving a lot of scientific attention, and drugs are currently in development for a variety of diseases, including cancer, to correct impaired microRNA signatures.
"They are like cellular brakes, so if beneficial microRNAs are lacking that can have a big impact on the health of the cell," said DeSouza.
For the new study, which is the first to explore the impact of insufficient sleep on circulating microRNA signatures, DeSouza and his team took blood samples from 24 healthy men and women, age 44 to 62, who had filled out questionnaires about their sleep habits. Half slept 7 to 8.5 hours nightly; Half slept 5 to 6.8 hours nightly.
They measured expression of nine microRNAs previously associated with inflammation, immune function or vascular health.
They found that people with insufficient sleep had 40 to 60 percent lower circulating levels of miR-125A, miR-126, and miR-146a, (previously shown to suppress inflammatory proteins) than those who slept enough.
"Why 7 or 8 hours seems to be the magic number is unclear," said DeSouza. "However, it is plausible that people need at least 7 hours of sleep per night to maintain levels of important physiological regulators, such as microRNAs."
Research is now underway in DeSouza's lab to determine whether restoring healthy sleep habits can restore healthy levels of microRNAs.
Ultimately, he said, it's possible that microRNAs in blood could be used as a marker of cardiovascular disease in people with insufficient sleep, enabling doctors to glean important information via a blood test rather than current, more invasive tests.
For now, DeSouza says, the takeaway message for those burning the midnight oil is this:
"Don't underestimate the importance of a good night's sleep."
https://www.sciencedaily.com/releases/2019/05/190521101502.htm