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
Antioxidant compound from soybeans may prevent marijuana-induced blood vessel damage
July 30, 2019
Science Daily/American Heart Association
Marijuana exposure damages cells of the inner lining of blood vessels throughout the heart and vascular system. In studies with human cells and arteries from mice, a compound found in soybeans blocked the damage and may have potential in preventing cardiovascular side effects of marijuana use.
In laboratory tests, a compound found in soybeans blocked damage to the lining of blood vessels in the heart and circulatory system and may someday provide a way to prevent the cardiovascular side effects of recreational and medical marijuana use, according to preliminary research presented at the American Heart Association's Basic Cardiovascular Sciences 2019 Scientific Sessions.
Marijuana is the most widely used illicit drug worldwide and is increasingly being made legal for recreational and medicinal purposes. However, there have been studies that link marijuana smoking to an increased risk of heart attack and stroke.
There can also be cardiovascular side effects, including changes in heart rate and blood pressure, when people take FDA-approved medications containing a synthetic version of delta-9-tetrahydrocannabinol (THC) -- the main compound in marijuana that gives the sensation of being high.
"These medications are prescribed to reduce the nausea and vomiting induced by chemotherapy and to increase appetite in certain people with acquired immune deficiency syndrome," said Tzu-Tan "Thomas" Wei, Ph.D., the study's lead author and assistant professor of pharmacology in the College of Medicine at National Taiwan University in Taipei City. "The goal of our studies is to investigate the mechanisms of marijuana-induced damage and discover new drugs to prevent those side effects."
The effects of THC occur after it binds to one of two cannabinoid receptors (CB1 and CB2) that are found throughout the brain and body and are also acted on by naturally occurring cannabinoids.
In the current study, the researchers used endothelial cells (like those that line blood vessels) derived from the stem cells of five healthy people. Exposing the cells to THC, they found that:
THC exposure induced inflammation and oxidative stress, which are known to affect the inner linings of blood vessels and are associated with the development of heart disease.
Lab techniques that block access to the CB1 receptor by THC eliminated the effects of THC exposure on endothelial cells.
Treatment with JW-1, an antioxidant compound found in soybeans, eliminated the effects of THC exposure.
In addition, the researchers used a laboratory technique called wire myography to examine the response of mouse arteries to THC, finding that JW-1 blocked THC's negative effects on the function of the inner lining.
An earlier attempt to gain health benefits from blocking the CB1 receptor proved problematic.
"Previously, a drug that blocked CB1 was approved in Europe for the treatment of obesity, but it had to be withdrawn because of severe psychiatric side effects," Wei said. "In contrast, as an antioxidant, JW-1 may have neuroprotective effects. Discovering a new way to protect blood vessels without psychiatric side effects would be clinically important with the rapid growth of cannabis use worldwide."
The researchers are currently extending their research by testing cells derived from regular marijuana users and those who smoke both cigarettes and marijuana. In addition, they are looking at the impact of THC along with the other main component of marijuana, cannabidiol.
"Meanwhile, if you have heart disease, talk to your doctor before you use marijuana or one of the synthetic THC-containing medications," Wei said. "Marijuana may cause more severe effects on the cardiovascular system in those with pre-existing heart disease."
https://www.sciencedaily.com/releases/2019/07/190730182430.htm
New insight into how obesity, insulin resistance can impair cognition
Science Daily/April 22, 2019
Medical College of Georgia at Augusta University
Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, scientists report.
They knew that chronic activation of the receptor Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons.
Now Medical College of Georgia scientists have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.
"We know that obesity and insulin resistance break down the blood brain barrier in humans and animal models, but exactly how has remained a mystery," says Dr. Alexis M. Stranahan, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine at Augusta University. Stranahan is corresponding author of the study published in The Journal of Neuroscience that provides new insight.
In the brain, adenosine is a neurotransmitter that helps us sleep and helps regulate our blood pressure; in the body it's also a component of the cell fuel adenosine triphosphate, or ATP. Adenosine also activates receptors Adora1a and Adora2a on endothelial cells, which normally supports healthy relationships between brain activity and blood flow.
Problems arise with chronic activation, particularly in the brain, which is what happens with obesity, says Stranahan.
People who have obesity and diabetes have higher rates of cognitive impairment as they age and most of the related structural changes are in the hippocampus, a center of learning and memory and Stranahan's focus of study. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent obesity-related memory loss.
In a model that mimics what happens to some of us, young mice fed a high-fat diet got fat within two weeks, and by 16 weeks they had increases in fasting glucose and insulin concentrations, all signs that diabetes is in their future.
In the minute vasculature of the hippocampus, the investigators saw that obesity first increased permeability of the blood brain barrier to tiny molecules like fluorophore sodium fluorescein, or NaFl. Diet-induced insulin resistance heightened that permeability so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in blood, also could get through.
When they looked with electron microscopy, they saw a changed landscape. Resulting diabetes promoted shrinkage of the usually tight junctions between endothelial cells and actual holes in those cells. They also saw muscular cells called pericytes that wrap around the exterior of microscopic blood vessels in the brain to give them more strength and help move blood along, start to lose their grip, so blood vessels start to lose their tone and become dysfunctional and inflamed. Pericytes are known to express higher levels of Adora2a than endothelial cells, Stranahan notes. The high-fat diet also promoted swelling of protrusions on astrocytes called end-feet, which also are part of the blood brain barrier. Astrocytes are brain cells that normally nurture neurons, but the pathological state of obesity also altered their form and support.
Angiogenesis, the body's natural attempt to make more blood vessels -- albeit usually dysfunctional, leaky ones -- in response to impaired blood and oxygen flow was happening in the hippocampus by 12 weeks, and upon close inspection, blood vessels were inflamed.
When they gave a drug to temporarily block Adora2a, it also blocked problems with barrier permeability. Whether that could work in humans and long term as a way to avoid cognitive decline in obese humans, remains to be seen, Stranahan notes.
Next they developed a mouse in which they could selectively knock Adora2a out of endothelial cells.
In this transgenic mouse, they turned off Adora2a in the endothelial cells at 12 weeks, and at 16 weeks, when mice should have been exhibiting cognitive impairment and a leaky blood brain barrier, they instead had normal cognition and barrier function and no inflammation.
When they compared the transgenic mice that were on a high- or low-fat diet, they found evidence that the increased permeability of blood vessels in the brain initiates the cycle of inflammation and cognitive impairment.
While it's typically hard to jump from mice to men, the fact that this type of work actually started with human findings likely means that avoiding insulin resistance could potentially halt the increased permeability of the blood brain barrier and decrease in cognitive function, Stranahan says.
"If an individual has already progressed to insulin resistance, these studies underscore the importance of controlling blood sugar levels and avoiding progressing to insulin deficiency (diabetes), which opens the blood brain barrier even further."
The scientists report that the relative accessibility of blood vessels in the brain may also make them a good avenue for preventing obesity's effects on the brain.
It also points to the reality that a variety of drugs given to obese patients may impact their brains to a higher degree, which might be something for patients and their doctors to consider. Stranahan notes that for drugs intended to take action in the brain, such as those for Alzheimer's, that could be a good thing but still needs to be considered. Some commonly prescribed drugs like prednisone, on the other hand, already are really good at getting through and can potentially be bad for the brain, she says.
Next steps in her lab include figuring out where the signal arises that chronically activates Adora2 in fat mice. She suspects it's actually a cascade that includes endothelial cells getting stressed, which increases their metabolism, which means they use more ATP, which can activate Adora2a and set in motion a vicious cycle that eventually takes its toll on the blood brain barrier.
The concept that obesity could affect the blood brain barrier started with people a dozen years ago when Swedish researchers found obese individuals had higher levels of the major antibody immunoglobulin G in their cerebrospinal fluid, when it should have been in their blood. It was an important finding that suggested that obesity and diabetes could enable things to get from the blood to the brain that should not, Stranahan says. Animal studies confirmed it was happening but, again, few studies have looked at why, Stranahan says.
Blood vessels come up from the body and get exceedingly small and fragile as they dive into the brain. While blood vessels that supply areas like our arms and heart are meant to be more porous so they can share plenty of glucose, oxygen and immune cells and other things the body needs, the vasculature in the brain, is supposed to be much more restrictive, letting comparatively little through.
"It's more like a gate than a barrier," says Stranahan, and it's a dynamic barrier at that, based on what the brain is up to. "It's got transporters that can move things across and what is happening in the brain and in the blood can change the way it operates."
She notes that the brain is a huge consumer, sucking up 70 to 80 percent of our oxygen and glucose, but also more fragile than other tissues, super sensitive even to our own immune cells.
"It's like a kid who grows up playing outside in the dirt is going to have a more robust immune system than a kid who grows up staying inside and playing video games," Stranahan says.
Cognitive tests on mice in the study included object recognition and maneuvering a water maze. The scientists looked at other normal functions, like simple motor functions, to see if there were other effects and, at least at those early time points, did not identify others.
https://www.sciencedaily.com/releases/2019/04/190422082253.htm