Exercise in pregnancy improves health of obese mothers by restoring their tissues

August 29, 2019

Science Daily/University of Cambridge

Exercise immediately prior to and during pregnancy restores key tissues in the body, making them better able to manage blood sugar levels and lowering the risk of long term health problems, suggests new research carried out in mice.

Researchers at the University of Cambridge, who led the study published today in the journal Physiological Reports, say the findings reinforce the importance of an active lifestyle when planning pregnancy.

In the UK, more than a half of all women of reproductive age and almost a third of pregnant women are overweight or obese. This is particularly concerning, as being overweight or obese during pregnancy increases the risk of complications in the mother, such as gestational diabetes, and predisposes both her and her infant to develop metabolic diseases such as type 2 diabetes in the years after pregnancy.

Exercise is known to improve how the body manages blood sugar levels and thereby reduce the risk of type-2 diabetes and metabolic syndrome in non-pregnant women. It also has positive effects prior to and during pregnancy, with beneficial outcomes for both mother and her child, preventing excessive gestational weight gain and the development of gestational diabetes, and the need for insulin use in women who have already developed gestational diabetes. However, little is known about the changes that exercise causes to the tissues of obese pregnant mother.

To answer this questions, researchers at the University of Cambridge fed mice a sugary, high fat diet such that they become obese and then the obese mice were exercised. The mice exercised on a treadmill for 20 minutes a day for at least a week before their pregnancy and then for 12.5 minutes a day until day 17 of the pregnancy (pregnancy lasts for around 20 days in mice).

Mice are a useful model for studying human disease as their biology and physiology have a number of important characteristics in common with those of humans, including showing metabolic changes with obesity/obesity-causing diets and in the female body during pregnancy.

The researchers found that the beneficial effects on metabolic health in obese mothers related to changes in how molecules and cells communicate in maternal tissues during pregnancy.

"A moderate level of exercise immediately before and then during pregnancy leads to important changes in different tissues of the obese mother, effectively making the tissues more like those seen in non-obese mothers," says Dr Amanda Sferruzzi-Perri, a Royal Society Dorothy Hodgkin Research Fellow from the Centre for Trophoblast Research in the Department of Physiology, Development and Neuroscience at the University of Cambridge, who co-led the study.

"We believe these changes may explain how exercise improves the metabolism of the obese mother during pregnancy and, in turn, may prevent her babies from developing early signs of type 2 diabetes after birth."

The key organs of the mother that were affected by exercise were:

·      white adipose tissue -- the fatty tissue that stores lipids and can be found in different parts around the body, including beneath the skin and around internal organs;

·      skeletal muscle -- muscle tissue that uses glucose and fats for contraction and movement;

·      the liver -- the organ that stores, as well as syntheses lipids and glucose.

Exercise affected key signalling pathways -- the ways that molecules and cells within tissue communicate -- involved in responding to insulin (the hormone that stimulates glucose uptake by white adipose tissue and skeletal muscle), in storage and breakdown of lipids (fats found in the blood and tissue) and in growth and the synthesis of proteins.

White adipose tissue showed the greatest number of changes in response to exercise in the obese pregnant mouse, being restored to a state similar to that seen in the tissue of non-obese mothers. This suggests that insulin resistance of the mother's white adipose tissue may be the cause of poor glucose-insulin handling in obese pregnancies. The findings are different to that seen in non-pregnant animals, whereby exercise typically affects insulin signalling in the skeletal muscle.

In addition, the team's previous work showed that exercise improves sensitivity to insulin and glucose handling throughout the whole body in the obese mother. It also prevents the development of insulin resistance in the offspring of obese mothers after birth. Low insulin sensitivity/insulin resistance requires larger amounts of insulin to control blood glucose levels.

"Our findings reinforce the importance of having an active lifestyle and eating a healthy balanced diet when planning pregnancy and throughout for both the mother and her developing child," says co-lead Professor Susan Ozanne from the Wellcome Trust-Medical Research Council Institute of Metabolic Science at the University of Cambridge.

"This is can be important in helping to reduce the risk of adverse health problems in the mother and of later health problems for her child."

https://www.sciencedaily.com/releases/2019/08/190829214754.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

Effects of a high-fat diet may be passed on for three generations

October 12, 2018

Science Daily/BioMed Central

A high-fat diet in female mice affects their offspring's obesity, insulin resistance and addictive-like behaviors for three generations, according to a new study.

Researchers at ETH Zurich, Switzerland showed that second generation offspring -- grandchildren of mice that had consumed a high-fat diet before, during and after pregnancy showed addictive-like behaviors such as increased sensitivity and preference for drugs, as well as characteristics of obesity, including changes in their metabolism. In third generation offspring (the great grandchildren), the authors observed differences between males and females, with only females showing addictive-like behaviors and only males showing obesity characteristics.

This was the case although the original female mice themselves never became obese and although none of the following generations consumed a high-fat diet.

Dr Daria Peleg-Raibstein, the corresponding author said: "Most studies so far have only looked at the second generation or followed the long-term effects of obesity and diabetes on the immediate offspring. This study is the first to look at the effects of maternal overeating up until the third generation in the context of addiction as well as obesity."

The authors investigated these effects specifically for transmission via male offspring up until, and including, the third generation. To do so, they fed female mice either high-fat diet or a standard laboratory diet for nine weeks -- pre-mating, during pregnancy and during lactation. Their male offspring were then mated with females that had been fed a standard laboratory diet to generate the second-generation offspring. The male offspring of these mice was again mated with females that had been fed a standard laboratory diet to generate the third-generation offspring.

The authors measured body weight, insulin sensitivity, metabolic rates, and blood plasma parameters such as insulin and cholesterol in second and third-generation offspring. In behavioral experiments they investigated if the mice chose a high-fat over a standard laboratory diet or an alcohol solution over water, as well as their activity levels after exposure to amphetamines. They did this to better understand if a maternal high-fat diet had an effect on obesity, overeating and drug sensitivity in subsequent generations.

Dr Peleg-Raibstein said: "To combat the current obesity epidemic, it is important to identify the underlying mechanisms and to find ways for early prevention. The research could help improve health advice and education for pregnant and breastfeeding couples and give their children, grandchildren and great-grandchildren a better chance of a healthy lifestyle. It may also provide a way of identifying risk factors for how people develop obesity and addiction and suggest early interventions for at-risk groups."

Dr Peleg-Raibstein added: "It is quite a leap to apply conclusions from mouse studies to humans, but studying effects of maternal over-eating is almost impossible to do in people because there are so many confounding factors, such as socio-economic background, the parents' food preferences or their existing health conditions. The mouse model allowed us to study the effects of a high-fat diet on subsequent generations without these factors."

Further studies are needed to determine the molecular mechanism by which the effects of a female high-fat diet may be passed on to following generations.

https://www.sciencedaily.com/releases/2018/10/181012082710.htm

Study links irregular sleep schedules to adverse metabolic health in women

Study is first to examine individual differences in habitual sleep timing in relation to indices of metabolic health

February 1, 2016

Science Daily/American Academy of Sleep Medicine

Frequent shifts in sleep timing may be related to adverse metabolic health among non-shift working, midlife women, new research shows. Results show that greater variability in bedtime and greater bedtime delay were associated with higher insulin resistance, and greater bedtime advance was associated with higher body mass index (BMI).

Results show that greater variability in bedtime and greater bedtime delay were associated with higher insulin resistance, and greater bedtime advance was associated with higher body mass index (BMI). In prospective analyses, greater bedtime delay -- for example, staying up 2 hours later than usual -- also predicted an increase in insulin resistance 5 years later. The cross-sectional and prospective associations between these measures were significant only when both weekdays and weekends were included in the analysis, suggesting that large deviations in bedtime between work days and free days contributed to impaired glucose regulation.

"Irregular sleep schedules, including highly variable bedtimes and staying up much later than usual, are associated in midlife women with insulin resistance, which is an important indicator of metabolic health, including diabetes risk," said senior author Martica Hall, PhD, professor of psychiatry at the University of Pittsburgh. "We found that weekday-weekend differences in bedtime were especially important."

Study results are published in the February issue of the journal Sleep.

"This study emphasizes the important health benefits of keeping a regular sleep schedule," said American Academy of Sleep Medicine President Dr. Nathaniel Watson, who was not involved in the study. "In addition to sleeping 7 or more hours per night on a regular basis, adults should strive to maintain a consistent schedule by going to bed and waking up at the same times on weekdays and weekends."

Led by Hall and lead author Briana J. Taylor, the research team analyzed data from the SWAN Sleep Study, an ancillary project to the Study of Women's Health Across the Nation (SWAN). The community-based sample comprised 370 Caucasian, African American and Chinese non-shift working women between the ages of 48 and 58 years. Daily diary-reported bedtimes were used to calculate four measures of sleep timing: mean bedtime, bedtime variability, bedtime delay and bedtime advance. BMI and insulin resistance were measured at baseline and again an average of 5 years later.

"The results are important because diabetes risk increases in midlife women," said Hall. "Our study suggests that irregular sleep schedules may be an important piece of this puzzle. The good news is that sleep timing is a modifiable behavior. Metabolic health was better in women who had more regular sleep schedules, including regular bedtimes across weekdays and weekends."

According to the authors, irregular bedtime schedules expose the body to varying levels of light, which is the most important timing cue for the body's circadian clock. By disrupting circadian timing, bedtime variability may impair glucose metabolism and energy homeostasis.

The authors suggest that future studies of sleep timing and metabolic health should examine potential mechanisms including melatonin as well as other hormones that are relevant to metabolic health and sensitive to circadian misalignment, including leptin, ghrelin and cortisol.

http://www.sciencedaily.com/releases/2016/02/160201125510.htm

Lack of Sleep Leads to Insulin Resistance in Teens

September 29, 2012

Science Daily/American Academy of Sleep Medicine

A new study suggests that increasing the amount of sleep that teenagers get could improve their insulin resistance and prevent the future onset of diabetes.

"High levels of insulin resistance can lead to the development of diabetes," said lead author Karen Matthews, PhD, of the University of Pittsburgh Department of Psychiatry. "We found that if teens that normally get six hours of sleep per night get one extra hour of sleep, they would improve insulin resistance by 9 percent."

http://www.sciencedaily.com/releases/2012/09/120929140234.htm