̽��ֱ�� of Cambridge - Susan Ozanne

Exercising during pregnancy normalises eating behaviours in offspring from obese mice

Anonymous — Tue, 04 Jun 2024 18:00:43 +0000

Previous studies in both humans and animal models have shown that the offspring of mothers living with obesity have a higher risk of developing obesity and type 2 diabetes themselves when they grow up. While this relationship is likely to be the result of a complex relationship between genetics and environment, emerging evidence has implicated that maternal obesity in pregnancy can disrupt the baby’s hypothalamus—the region of the brain responsible for controlling food intake and energy regulation.

In animal models, offspring exposed to overnutrition during key periods of development eat more when they grow up, but little is known about the molecular mechanisms that lead to these changes in eating behaviour.

In a study published today in PLOS Biology, researchers from the Institute of Metabolic Science and the MRC Metabolic Diseases Unit at the ̽��ֱ�� of Cambridge found that mice born from obese mothers had higher levels of the microRNA miR-505-5p in their hypothalamus—from as early as the fetal stage into adulthood. ̽��ֱ��offspring of obese mothers chose to eat more specifically of foods that were high in fat, which is consistent with fat sensing being disrupted in the hypothalamus.

Dr Laura Dearden from the Institute of Metabolic Science, the study’s first author, said: “Our results show that obesity during pregnancy causes changes to the baby's brain that makes them eat more high fat food in adulthood and more likely to develop obesity.”

Senior author Professor Susan Ozanne from the MRC Metabolic Diseases Unit and Institute of Metabolic Science said: “Importantly, we showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brain.”

Cell culture experiments showed that miR-505-5p levels can be influenced by exposing hypothalamic neurons to long-chain fatty acids and insulin, which are both high in pregnancies complicated by obesity. ̽��ֱ��researchers identified miR-505-5p as a regulator of pathways involved in fatty acid uptake and metabolism – high levels of the miRNA make the offspring brain unable to sense when they are eating high fat foods. Several of the genes that miR-505-5p regulates are associated with high body mass index in human genetic studies, showing these same changes in humans can cause obesity.

̽��ֱ��study is one of the first to demonstrate the molecular mechanisms linking nutritional exposure in utero to eating behaviour.

Dr Dearden added: “While our work was only carried out in mice, it may help us understand why the children of mothers living with obesity are more likely to become obese themselves, with early life exposures, genetics and current environment all being contributing factors.”

Reference
Dearden, L et al. Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food. PLOS Biology; 4 Jun 2024; DOI: 10.1371/journal.pbio.3002641

Adapted from a press release by PLOS Biology

Maternal obesity in pregnancy changes the eating behaviours of offspring by increasing long-term levels of particular molecules known as microRNAs in the part of the brain that controls appetite – but this can be changed by exercise during pregnancy, a study in obese mice has suggested.

We showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brain

Susan Ozanne

Engin_Akyurt (Pixabay)

Fast food meal of burger and fries

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Exercise in pregnancy improves health of obese mothers by restoring their tissues, mouse study finds

cjb250 — Thu, 29 Aug 2019 23:17:07 +0000

Researchers at the ̽��ֱ�� 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 mothers.

To answer this question, researchers at the ̽��ֱ�� of Cambridge fed mice a sugary, high fat diet such that they become obese and then the obese mice were exercised. ̽��ֱ��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.

̽��ֱ��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 ̽��ֱ�� 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.”

̽��ֱ��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. ̽��ֱ��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 ̽��ֱ�� of Cambridge.

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

This work received funding from the European Union, Medical Research Council, Biotechnology and Biological Sciences Research Council, British Heart Foundation, São Paulo Research Foundation, Centre for Trophoblast Research, and the Royal Society.

Reference
Musial, B et al. Exercise alters the molecular pathways of insulin signalling and lipid handling in maternal tissues of obese pregnant mice. Physiological Reports; 28 August 2019; DOI: 10.14814/phy2.14202

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.

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

Amanda Sferruzzi-Perri

ArtCoreStudios (Pixabay)

Workout

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Why we just can't stop eating: the complex truth behind obesity

cjb250 — Mon, 23 Jul 2018 08:27:40 +0000

Britain has seen a dramatic transformation in recent years in its attitude towards food. We have gone from being a country ridiculed for its bland, carb-heavy cuisine, for whom the chicken tikka masala was the height of exoticness, to becoming a nation obsessed with food.

But alongside this obsession with food has come a growing understanding of the impact that our diet has on our bodies – not only on our waistlines, but also on conditions such as diabetes, heart disease, cancer, and even dementia.

This relationship between our diet and our weight is simple: you eat too much, you get fat. Hence, some would argue, the solution should be equally simple: you eat less, you lose weight.

If only it were this easy. Anyone who has tried to shed a few pounds – and, crucially, to keep them off – knows that the answer is rarely so straightforward. In fact, even the food – and volume – that we ‘choose’ to eat is influenced by a surprising number of factors.

Obesity is often characterised as nothing more than greed and lack of willpower. ̽��ֱ��truth is far more complex.

Cedric Bousquet

Chattering teeth

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Missing link in epigenetics could explain conundrum of disease inheritance

cjb250 — Thu, 07 Jul 2016 18:00:30 +0000

̽��ֱ��study, published in Science by researchers at ̽��ֱ�� of Cambridge, Queen Mary ̽��ֱ�� of London (QMUL) and King’s College London, shows that the genetic variation of ribosomal DNA (rDNA) could be driving how the environment within the womb determines an offspring’s attributes. rDNA is the genetic material that forms ribosomes - the protein building machines within the cell.

Lead researcher Professor Vardhman Rakyan from QMUL said: “ ̽��ֱ��fact that genetic variation of ribosomal DNA seems to play such a major role suggests that many human genetics studies in humans could be missing a key part of the puzzle. These studies only looked at a single copy part of individuals’ genomes and never at ribosomal DNA.

“This could be the reason why we’ve only so far been able to explain a small fraction of the heritability of many health conditions, which makes a lot of sense in the context of metabolic diseases, such as type 2 diabetes.”

̽��ֱ��environmental factors that play a role alongside genetic factors in determining a person’s attributes are also present in the in-utero environment. When offspring are in the womb, the environment experienced by their mothers (for example, diet, stress, smoking), influences the attributes of their offspring when they are adults. This ‘developmental programming’ is thought to contribute to the obesity and type 2 diabetes epidemic seen today.

A major contributor to this process is ‘epigenetics’. This describes naturally-occurring modifications to genes that control how they are expressed. One such modification involves tagging DNA with chemical compounds called methyl groups. These epigenetic markers determine which genes are expressed or not expressed. Liver cells and kidney cells are genetically identical in terms of their DNA sequence but differ in their epigenetic marks. It has been proposed that in response to a poor in-utero environment, an offspring’s epigenetic profile will change.

̽��ֱ��team compared the offspring of pregnant mice when given a low protein diet (8 per cent protein) and a normal diet (20 per cent protein). After they were weaned, all offspring were given a normal diet, and the team then looked at the difference in the offspring’s DNA methylation, from mothers exposed to a low protein diet and those that were not.

Professor Rakyan said: “When cells are stressed, for example when nutrient levels are low, they alter protein production as a survival strategy. In our low protein mice mothers, we saw that their offspring had methylated rDNA. This slowed the expression of their rDNA, which could be influencing the function of ribosomes, and resulted in smaller offspring – as much as 25 per cent lighter.”

These epigenetic effects occur during a critical developmental window while the offspring is in-utero but is a permanent effect that remains into adulthood. A mother’s diet while pregnant is therefore likely to have more severe consequence on the offspring’s epigenetic state than an offspring’s own diet after it has been weaned.

Professor Susan Ozanne from the ̽��ֱ�� of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit added: “Perhaps our most surprising finding was that, despite all of our mice being bred to be genetically identical, their rDNA was different. In fact, even within an individual mouse, different copies of rDNA were genetically distinct."

In any given genome, there are many copies of rDNA, and the researchers found that not all copies of the rDNA were responding in the same way epigenetically. In offspring from mothers who were fed a low protein diet, it was only one form of rDNA – the ‘A-variant’ - that appeared to undergo methylation and affect weight. Professor Ozanne added: “This variation in rDNA appears to be playing a large role in determining the response of the fetus to the in utero environment and therefore its phenotype later in life.”

This means that the epigenetic response of a given mouse is determined by the genetic variation of the rDNA - those who have more A-variant rDNA end up being smaller.

Heritability (how much the risk of a disease is explained by genetic factors) of type 2 diabetes has been estimated to be between 25 and 80 per cent in different studies. However, less than 20 per cent of the heritability of type 2 diabetes has been explained by genome studies of people with the disease. ̽��ֱ��major role played by genetic variation of rDNA, together with the fact that rDNA analysis would not have been included in these studies, could explain some of this missing heritability.

̽��ֱ��findings also complement other studies that have found that mice that are put on high fat diets have offspring who show increased rDNA methylation. This suggests that methylation is a general stress response and may also explain the rise in obesity that is happening across the world.

̽��ֱ��study was funded by the Biotechnology and Biological Sciences Research Council, Research Councils UK, the European Union, British Heart Foundation and Medical Research Council.

Reference
Holland, ML et al. Early life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science; 7 July 2016; DOI: 10.1126/science.aaf7040

Adapted from a press release from Queen Mary ̽��ֱ�� of London

̽��ֱ��process by which a mother’s diet during pregnancy can permanently affect her offspring’s attributes, such as weight, could be strongly influenced by genetic variation in an unexpected part of the genome, according to research published today. ̽��ֱ��discovery could shed light on why many human genetic studies have previously not been able to fully explain how certain diseases, such as type 2 diabetes and obesity, are inherited.

Christian Guthier

Molecule display

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Supplement could reduce heart disease risk in people of low birth weight

cjb250 — Wed, 10 Dec 2014 13:02:49 +0000

Researchers at the Institute of Metabolic Science fed low birth weight rats a supplement of the molecule co-enzyme Q (CoQ) and found that in those rats that grew quickly after birth, the supplement prevented cells in the aorta from ageing prematurely, which can lead to heart disease. Scientists have known for some years that babies with a low birth weight who grow quickly are more likely to develop heart disease than those with a normal birth weight. This new study, published in ̽��ֱ��FASEB Journal, has identified a novel mechanism underlying this phenomenon and suggests a possible treatment.

Researchers funded by the British Heart Foundation and the Medical Research Council (MRC) fed pregnant rats either a control diet or a low protein, high carbohydrate diet. ̽��ֱ��mothers fed the low protein diet had pups with a low birth weight, but which grew quickly when suckled by a control-fed mother. When the researchers examined the aorta from these rats, they found that their cells had aged more quickly than those from the normal birth weight offspring and that this was associated with a deficit in CoQ in the aorta.

When the researchers gave the low birth weight rats extra CoQ in their diet after weaning, they found that this prevented the accelerated aging of and damage to their aortas. CoQ is produced naturally in the body and is required to ensure that the mitochondria – the cells’ ‘batteries’ – work properly and to protect cells from oxidative stress caused by highly reactive molecules known as free radicals, which can cause damage to proteins, membranes and genes.

̽��ֱ��team also found that CoQ is reduced in white blood cells from low birth weight offspring and hence that levels of CoQ in the blood cells can be used to see how much damage there is in the aorta.

“Our study has answered a question that has puzzled doctors for some time now – why children of low birth weight who grow quickly are prone to heart disease in later life,” explains Professor Susan Ozanne from the MRC Metabolic Diseases Unit, who led the study. “We believe it’s because they are deficient in co-enzyme Q. As this molecule is also then deficient in the individual’s blood cells, it may be possible to develop a simple blood test capable of diagnosing the amount of damage to their aorta and therefore likely to develop heart disease.”

Dr Jane Tarry-Adkins, first author on the study, adds: “Although our study is only in rodents, it may one day have major implications for both the prevention and early treatment of heart disease. It suggests that it may be possible to treat at-risk individuals with a safe and cost-effective supplement that has the potential to prevent heart disease before they display any symptoms of the disease.”

Globally, cardiovascular disease is responsible for more deaths than any other disease, claiming an estimated 17.3 million lives in 2008, a number which is predicted to grow to over 23.3 million by 2030. Reliable, early diagnostic tests for cardiovascular disease risk could help reduce this burden. ̽��ֱ��researchers plan to establish whether their findings can be confirmed in humans and therefore make their prognostic potential a realistic possibility.

Reference
Tarry-Adkins, JL et al. Nutritional programming of Coenzyme Q – potential for prevention and intervention? FASEB; 29 Aug 2014

A simple supplement could be a safe and cost-effective way of reducing heart disease in individuals born with a low birth weight, suggests research from the ̽��ֱ�� of Cambridge. ̽��ֱ��study, carried out in rats, also raises the possibility of developing a blood test to indicate how much damage there is in the aortas of these individuals.

Our study has answered a question that has puzzled doctors for some time now – why children of low birth weight who grow quickly are prone to heart disease in later life

Susan Ozanne

Gabriela Pinto

Heart pulse

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You are what your mother ate

ns480 — Mon, 21 Mar 2011 10:03:37 +0000

Poor diet during pregnancy increases offspring's vulnerability to the effects of aging, new research has shown for the first time. ̽��ֱ��research, by scientists from the ̽��ֱ�� of Cambridge, provides important insight into why children born to mothers who consumed an unhealthy diet during pregnancy have an increased risk of type 2 diabetes (a significant contributing factor to heart disease and cancer) later in life.

"What is most exciting about these findings is that we are now starting to really understand how nutrition during the first nine months of life spent in the womb shape our long term health by influencing how the cells in our body age," said Dr Susan Ozanne, the senior author on the paper and British Heart Foundation Senior Fellow from the Institute of Metabolic Science at the ̽��ֱ�� of Cambridge.

It is well established that environmental factors interact with genes throughout life, affecting the expression of those genes and, consequently, tissue function and disease risk. Diet during critical periods of development, such as during the nine months in the womb, has been cited as one such environmental factor. Epigenetics, which refers to modifications to the DNA that regulate how much of a gene is produced, has been suggested to underlie these effects.

However, until now, very little was understood about the underlying mechanisms that control the interaction between diet during gestation and gene expression in offspring throughout their adult life. Research, funded by the BBSRC and the British Heart Foundation, has now shown that the gene Hnf4a, which has been linked to type 2 diabetes, is regulated by maternal diet through epigenetic modifications to our DNA. Additionally, they found that poor diet exacerbates the rate at which these key epigenetic modifications accumulate during the aging process.

Previous research has shown that the gene Hnf4a plays an important role both during development of the pancreas and later in the production of insulin. ̽��ֱ��researchers hypothesised that diet during pregnancy influences the expression of this gene later in life, thereby influencing the risk of diabetes.

To test their theory, the researchers used a well-established rat model where, by altering the protein content of the mother's diet during pregnancy, the offspring develop type 2 diabetes in old age.

First, they studied the RNA from insulin secreting cells in the pancreas from offspring of normally fed as well as malnourished mothers in young adult life and in old age. When they compared the two, they found that there was a significant decrease in the expression of the Hnf4a gene in the offspring prone to type 2 diabetes. ̽��ֱ��expression of Hnf4a also decreased with age in both groups.

Second, they studied the DNA and found that the decrease of Hnf4a was caused by epigenetic changes. ̽��ֱ��age associated epigenetic silencing was more pronounced in rats exposed to poor maternal diet. They concluded that the epigenetic changes resulting from maternal diet and aging lead to the reduced expression of the Hnf4a gene, decreasing the function of the pancreas and therefore its ability to make insulin (and thereby increasing the risk of diabetes).

̽��ֱ��scientists then studied the DNA from insulin secreting cells from human pancreases to show that expression of this important gene was controlled in the same way in humans.

"It is remarkable that maternal diet can mark our genes so they remember events in very early life," said Dr Miguel Constancia, the senior co-author on the paper from the Department of Obstetrics and Gynaecology and Metabolic Research Laboratories at the ̽��ֱ�� of Cambridge. "Our findings reveal a novel mechanism by which maternal diet and aging interact through epigenetic processes to determine our risk of age-associated diseases."

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "We already know that a healthy pregnancy is important in shaping a child's health, and their risk of heart disease as they grow up. ̽��ֱ��reasons why are not well understood, but this study in rats adds to the evidence that a mother's diet may sometimes alter the control of certain genes in her unborn child. It's no reason for expectant mothers to be unduly worried. This research doesn't change our advice that pregnant women should try to eat a healthy, balanced diet."

Professor Douglas Kell, Chief Executive, BBSRC said: "Epigenetics is a relatively young field of research with tremendous potential to underpin our understanding of many biological processes in all organisms. ̽��ֱ��fact that there is a relationship between the biology of a pregnant mother and the long term health of her child has been known for some time but our understanding of the biological processes behind some of the more subtle effects is still at a nascent stage. This study uncovers - through epigenetics and molecular biology research - an important piece of this puzzle and shows us how apparently minor changes within cells at the very earliest stages of development can have a major influence on our health into old age."

Research provides new insight into why poor diet during pregnancy negatively affects offspring’s long term health.

What is most exciting about these findings is that we are now starting to really understand how nutrition during the first nine months of life spent in the womb shape our long term health by influencing how the cells in our body age.

Dr Susan Ozanne

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baby in the womb

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