̽��ֱ�� of Cambridge - genetic

Genetic study points to oxytocin as possible treatment for obesity and postnatal depression

cjb250 — Tue, 02 Jul 2024 15:00:18 +0000

Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.

While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the ̽��ֱ�� of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. ̽��ֱ��mothers also had obesity, but in addition had experienced postnatal depression.

To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).

Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.

Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”

TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.

Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.

Professor Sadaf Farooqi from the Institute of Metabolic Science at the ̽��ֱ�� of Cambridge said: “There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.

̽��ֱ��researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”

There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. ̽��ֱ��team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.

Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Reference
Li, Y, Cacciottolo, TM & Yin, N. Loss of Transient Receptor Potential Channel 5 Causes Obesity and Postpartum Depression. Cell; 2 July 2024; DOI: 10.1016/j.cell.2024.06.001

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. ̽��ֱ��discovery, reported on 2 July in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.

This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology. We need to be more understanding and sympathetic towards people who suffer with these conditions

Sadaf Farooqi

Olli Turho (Getty Images)

Illustration of a tired African American mother crying

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Genetics study points to potential treatments for restless leg syndrome

cjb250 — Wed, 05 Jun 2024 09:00:25 +0000

Restless leg syndrome can cause an unpleasant crawling sensation in the legs and an overwhelming urge to move them. Some people experience the symptoms only occasionally, while others get symptoms every day. Symptoms are usually worse in the evening or at night-time and can severely impair sleep.

Despite the condition being relatively common – up to one in 10 older adults experience symptoms, while 2-3% are severely affected and seek medical help – little is known about its causes. People with restless leg syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension, and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci – that is, regions of our genome that contain changes associated with increased risk of developing the condition. But there are still no known ‘biomarkers’ – such as genetic signatures – that could be used to objectively diagnose the condition.

To explore the condition further, an international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, Institute of Human Genetics of the Technical ̽��ֱ�� of Munich (TUM) and the ̽��ֱ�� of Cambridge pooled and analysed data from three genome-wide association studies. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless leg syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

̽��ֱ��results of the study are published today in Nature Genetics.

Co-author Dr Steven Bell from the ̽��ֱ�� of Cambridge said: “This study is the largest of its kind into this common – but poorly understood – condition. By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide.”

̽��ֱ��team identified over 140 new genetic risk loci, increasing the number known eight-fold to 164, including three on the X chromosome. ̽��ֱ��researchers found no strong genetic differences between men and women, despite the condition being twice as common in women as it is men – this suggests that a complex interaction of genetics and the environment (including hormones) may explain the gender differences we observe in real life.

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4 respectively, which are important for nerve and brain function. These could potentially be targeted by existing drugs, such as anticonvulsants like perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless leg syndrome.

̽��ֱ��researchers say it would be possible to use basic information like age, sex, and genetic markers to accurately rank who is more likely to have severe restless leg syndrome in nine cases out of ten.

To understand how restless leg syndrome might affect overall health, the researchers used a technique called Mendelian randomisation. This uses genetic information to examine cause-and-effect relationships. It revealed that the syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless leg syndrome – because they can lead to a fall in the neurotransmitter dopamine – the researchers did not find strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Professor Juliane Winkelmann from TUM, one of senior authors of the study, said: “For the first time, we have achieved the ability to predict restless leg syndrome risk. It has been a long journey, but now we are empowered to not only treat but even prevent the onset of this condition in our patients.”

Professor Emanuele Di Angelantonio, a co-author of the study and Director of the NIHR and NHS Blood and Transplant-funded Research Unit in Blood Donor Health and Behaviour, added: "Given that low iron levels are thought to trigger restless leg syndrome, we were surprised to find no strong genetic links to iron metabolism in our study. It may be that the relationship is more complex than we initially thought, and further work is required."

̽��ֱ��dataset included the INTERVAL study of England’s blood donors in collaboration with NHS Blood and Transplant.

A full list of funders can be found in the study paper.

Reference
Schormair et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology, and risk prediction. Nature Genetics; 5 June 2024; DOI: 10.1038/s41588-024-01763-1

Scientists have discovered genetic clues to the cause of restless leg syndrome, a condition common among older adults. ̽��ֱ��discovery could help identify those individuals at greatest risk of the condition and point to potential ways to treat it.

By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide

Steven Bell

DANNY G

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Experts call for more mental health support for parents of children with genetic learning disabilities

cjb250 — Wed, 11 Mar 2020 00:02:58 +0000

As many as one in 20 families worldwide is thought to include a child with a learning disability, but little is known about how this affects the parents’ mental health and wellbeing. Although some parents experience depression and anxiety, it is not clear why some are at greater risk than others.

Professor Claire Hughes from the ̽��ֱ�� of Cambridge Centre for Family Research, said: “It’s important that we understand why some parents are at greater risk of mental health problems than others. If a parent experiences long-term mental health problems, this could have a knock-on effect on the whole family, affecting partner relationships, the wellbeing of their child with disability, and the experiences of siblings. That’s why interventions are often more successful when they are designed to help parents in order to help children.”

To address this question, Professor Hughes assembled an interdisciplinary team of researchers from the Universities of Cambridge and Birmingham to analyse information from 888 families taking part in the IMAGINE-ID study – a UK-wide project examining the links between genetic diagnoses, learning disabilities and mental health. Parents were asked to rate their everyday feelings and the nature and impact of their child’s difficulties, as well as to provide information about their family’s social circumstances.

One parent who participated in IMAGINE-ID said that professionals tended to focus on the child’s needs and did not consider the wider needs of families: “It’s very much about getting support for your child. At no point were we ever offered any mental health support, even though we have such a massive role to play in bringing up our children. We need support as well.”

̽��ֱ��study data shows that rates of negative symptoms such as worry, anxiety and stress were much higher in the IMAGINE-ID group of parents than in the general population of parents. Mothers in the IMAGINE-ID study – who were more likely to be the main caregiver – were particularly affected. Contrary to evidence from previous studies, social factors did not predict a parent’s risk of low mood and stress: more important were the type of genetic disorder that affected their child, their child’s physical and medical needs, and their child’s behaviour.

For the first time, the researchers were able to demonstrate that the cause of a child’s disabilities is one factor that predicts the emotional wellbeing of parents. A subgroup of genetic disorders is caused by short missing or duplicated sections of DNA (known as ‘copy number variants’). Parents within this subgroup reported that their child’s difficulties had a high level of impact on family life as well as restricting their child’s activities and friendships, and these impacts were the source of their own distress.

̽��ֱ��researchers say there could be a number of explanations for these findings, varying from the complex effects of chromosomal differences on children’s development through to the availability of support for these families. They have called for more multi-disciplinary, family-focused research to determine how genetic diagnoses are linked to parents’ mental health, so that support for families can be improved in future.

Dr Kate Baker, lead author of the research paper, based at the MRC Cognition and Brain Sciences Unit, ̽��ֱ�� of Cambridge, said: “These results suggest that we need to start looking at genetic diagnoses as useful not just for predicting a child’s needs and informing the support that they might receive, but also for predicting the broader impact that the diagnosis will have on their family.”

Francesca Wicks, former research coordinator for IMAGINE-ID and now Family Support and Information Officer for Unique, the rare chromosome and single gene disorder support charity, said: “It’s clear that not enough care and support is being offered to parents before, during and after their child’s diagnosis. ̽��ֱ��help and support offered by organisations such as Unique is incredibly valuable, but much more needs to be done within health and statutory services. Many of the families I have met have expressed feelings of anxiety and depression over the years, which is why we have produced our Carers Wellbeing guide.”

̽��ֱ��IMAGINE-ID study is funded by the UK Medical Research Council and Medical Research Foundation.

Reference
Baker, K et al. Childhood intellectual disability and parents’ mental health: integrating social, psychological and genetic influences. BJPsych; 11 March 2020; DOI: 10.1192/bjp.2020.38

Parents of children with genetic conditions that cause learning disabilities are at risk of mental health problems, suggests new research published today in the British Journal of Psychiatry. ̽��ֱ��teams behind the study have called for greater support for parents whose child receives a genetic diagnosis for their learning disability.

If a parent experiences long-term mental health problems, this could have a knock-on effect on the whole family, affecting partner relationships, the wellbeing of their child with disability, and the experiences of siblings

Claire Hughes

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Parent and child

Researcher profile: Dr Kate Baker

Image: Kate Baker (centre) with research assistant Elise Ng-Cordell (left) and post-doctoral research associate Diandra Brkic (right) on Rare Disease Day

Dr Kate Baker, a researcher at the MRC Cognition and Brain Sciences Unit, decided early on that she wanted to be a scientist as well as a doctor. At the time, she was a medical student and helping out in a brain research laboratory.

“There are just too many unanswered questions about genes, brains, and mental health, and patients deserve better answers and better treatments,” she says. “Initially I learned to study slices of post-mortem brain tissue – then I discovered that doing research with whole people is a lot more fun, even if they are more noisy and complicated.”

Kate says she has been extremely lucky to work with “fantastic” colleagues and research participants who share the same curiosities and motivations – “We want to understand brain development and improve care for children with neurodevelopmental disorders and their families. It’s a slow process but it is also very exciting and rewarding.”

Her research looks at the genetic differences that can affect children’s development by changing the way that their brain grows and functions. “ ̽��ֱ��most surprising aspect is how an extremely tiny change in one gene can have a devastating impact, whilst sometimes much larger genetic changes have only subtle effects which vary a lot from one person to another.”

Kate leads a small research team of psychologists and neuroscientists, but particularly enjoys joining forces with scientists from different research fields who use very different approaches to understand the same core problem, “working together to join the dots and build up a more complete answer”.

One such collaboration is with Professor Claire Hughes from the Centre for Family Research. Cambridge collaborations can begin in unlikely places. “Claire and I started discussing the research questions we have addressed in our new paper after a Sunday morning yoga class, not knowing we would be able to work together to actually find some answers!”

Kate hopes her research will make a difference for children and families affected by severe neurodevelopmental disorders, by changing the way we understand these conditions, and also by improving the treatments and support they can receive.

“Until now, treatments have been mainly ‘symptom-focused’, which don’t always work because the same problems, such as limited communication skills or impulsive behaviours, can come about because of many different underlying reasons. If we had a better understanding of each child’s disorder ‘under the surface’, I hope we can improve their quality of life, even for a small number of patients and families.”

As if this wasn’t enough, Kate and her family have embarked on a challenging project. “My husband, children and I have recently built our own home, on the outskirts of Cambridge. So you’re likely to find me nailing plasterboard, wheelbarrowing mud, making curtains, or (more likely) feeding all the friends and family who have come to help us with the project.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Genetics study adds further evidence that education reduces risk of Alzheimer’s disease

cjb250 — Thu, 07 Dec 2017 00:01:01 +0000

Alzheimer’s disease is the leading cause of dementia. Its chief hallmark is the build of ‘plaques’ and ‘tangles’ of misshapen proteins, which lead to the gradual death of brain cells. People affected by Alzheimer’s experience memory and communication problems, disorientation, changes in behaviour and progressive loss of independence.

̽��ֱ��causes of Alzheimer’s are largely unknown, and attempts to develop drug treatments to halt or reverse its effects have been disappointing. This has led to increasing interest in whether it is possible to reduce the number of cases of Alzheimer’s disease by tackling common risk factors that can be modified. In fact, research from the Cambridge Institute of Public Health has shown that the incidence of Alzheimer’s is falling in the UK, probably due to improvements in education, and smoking reduction and better diet and exercise.

“Many studies have shown that certain risk factors are more common in people with Alzheimer’s disease, but determining whether these factors actually cause Alzheimer’s is more difficult,” says Professor Hugh Markus from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge.

“For example, many studies have shown that the more years spent in full time education, the lower the risk of Alzheimer’s. But it is difficult to unravel whether this is an effect of education improving brain function, or whether it’s the case that people who are more educated tend to come from more wealthy backgrounds and therefore have a reduction in other risk factors that cause Alzheimer’s disease.”

Professor Markus led a study to unpick these factors using a technique known as ‘Mendelian randomisation’. This involves looking at an individual’s DNA and comparing genes associated with environmental risk factors – for example, genes linked to educational attainment or to smoking – and seeing which of these genes are also associated with Alzheimer’s disease. If a gene is associated with both, then it provides strong evidence that this risk factor really does cause the disease.

As part of a project known as CoSTREAM, researchers studied genetic variants that increase the risk of a variety of different environmental risk factors to see if these were more common in 17,000 patients with Alzheimer’s disease. They found the strongest association with genetic variants that predict higher educational attainment.

“This provides further strong evidence that education is associated with a reduced risk of Alzheimer’s disease,” says first author Dr Susanna Larsson, now based at the Karolinska Institute, Sweden. “It suggests that improving education could have a significant effect on reducing the number of people who suffer from this devastating disease.”

Exactly how education might reduce the risk of Alzheimer’s is uncertain. Previous studies have shown that the same amount of damage in the brain is associated with less severe and less frequent Alzheimer’s in people who have received more education. One possible explanation is the idea of ‘cognitive reserve’ – the ability to recruit alternative brain networks or to use brain structures or networks not normally used to compensate for brain ageing. Evidence suggests that education helps improve brain wiring and networks and hence could increase this reserve.

̽��ֱ��researchers also looked at other environmental risk factors, including smoking, vitamin D, and alcohol and coffee consumption. However, their results proved inconclusive. This may be because genes that predispose to smoking, for example, have only a very small effect on behaviour, they say.

̽��ֱ��study was supported by the European Union’s Horizon 2020 Research and Innovation Programme.

Reference
Larsson, SC et al. Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis. BMJ; 7 Dec 2017; DOI: 10.1136/bmj.j5375

̽��ֱ��theory that education protects against Alzheimer’s disease has been given further weight by new research from the ̽��ֱ�� of Cambridge, funded by the European Union. ̽��ֱ��study is published today in ̽��ֱ��BMJ.

Many studies have shown that certain risk factors are more common in people with Alzheimer’s disease, but determining whether these factors actually cause Alzheimer’s is more difficult

Hugh Markus

Cambridge ̽��ֱ��

Darwin Lecture Series

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Restless legs syndrome study identifies 13 new genetic risk variants

cjb250 — Thu, 12 Oct 2017 23:01:27 +0000

As many as one in ten people of European ancestry is affected by restless legs syndrome, in which sufferers feel an overwhelming urge to move, often in conjunction with unpleasant sensations, usually in the legs. Rest and inactivity provoke the symptoms, whereas movement can lead to temporary relief. ̽��ֱ��condition is chronic and can get progressively worse, with long-lasting effects on patients’ mental and physical health. People with restless legs syndrome have substantially impaired sleep, reduced overall quality of life, and increased risk of depression, anxiety disorders, hypertension, and, possibly, cardiovascular disease.

For around one in 50 people, the condition can be severe enough to require chronic medication, which may in turn have potentially serious side effects.

Studies of families and twins have shown that there is a strong genetic component to the disorder and led to the discovery of six genetic variants that increased the risk of developing the condition.

“We have studied the genetics of restless legs syndrome for more than 10 years and the current study is the largest conducted so far,” says Dr Barbara Schormair from the Institute of Neurogenomics at the Helmholtz Zentrum München, first author of the study. “We are convinced that the newly discovered risk loci will contribute substantially to our understanding of the causal biology of the disease.”

Now, an international team of researchers has compared the genetic data from over 15,000 patients with more than 95,000 controls, and identified a further 13 genetic risk variants. ̽��ֱ��findings were then replicated in a sample of 31,000 patients and 287,000 controls. ̽��ֱ��results are published today in Lancet Neurology.

“Restless legs syndrome is surprisingly common, but despite this, we know little about what causes it – and hence how to treat it,” says Dr Steven Bell from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, also one of the first authors on the study. “We already know that it has a strong genetic link, and this was something we wanted to explore in more detail.”

Several of the genetic variants have previously been linked to the growth and development of nerve cells – a process known as neurogenesis – and to changes in the formation of neuronal circuits. These findings strengthen the case for restless legs syndrome being a neurodevelopmental disorder whose origins may go back to development in the womb as well as impaired nerve cell growth in later life.

“ ̽��ֱ��genetic risk variants that we’ve discovered add more weight to the idea that this condition is related to the development of our nervous system,” says Dr Emanuele Di Angelantonio, also from the Department of Public Health and Primary Care. “It also gives us some clues to how we may treat patients affected by the condition.”

Prof Juliane Winkelmann, who heads the Institute of Neurogenomics at the Helmholtz Zentrum as well as a restless legs syndrome outpatient clinic at the Klinikum Rechts der Isar in Munich, adds: “Our genetic findings are an important step towards developing new and improved treatment options for our patients.”

One particular biological pathway implicated by the findings is known to be a target for the drug thalidomide. While the drug has a controversial reputation due to its previous use when treating pregnant women that led to serious birth defects in their offspring, it is now used to treat some cancers. ̽��ֱ��researchers suggest that thalidomide or similar drugs may offer potential treatment options for male patients with restless leg syndrome and female patients beyond reproductive age, but they stress the necessity of rigorous clinical testing for efficacy and side-effects before any such use.

̽��ֱ��study was largely funded by NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, UK Medical Research Council, Deutsche Forschungsgemeinschaft (DFG) and Helmholtz Zentrum München.

Reference
Schormair, B., Zhao, C., Bell, S. et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurology; 10th October 2017; DOI: 10.1016/S1474-4422(17)30327-7

A new study into the genetics underlying restless legs syndrome has identified 13 previously-unknown genetic risk variants, while helping inform potential new treatment options for the condition.

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Chicken korma, Eton mess and a genetic variant provide clues to our food choices

cjb250 — Tue, 04 Oct 2016 14:24:12 +0000

̽��ֱ��research has provided insights into why we make particular food choices, with potential implications for our understanding of obesity. This is one of the first studies to show a direct link between food preference and specific genetic variants in humans.

Most people find high fat, high sugar foods particularly appetising. This can lead to eating more calories than we need and can contribute to weight gain. But what influences food choice? ̽��ֱ��taste, appearance, smell and texture of food are all important, but biology may also play an important role.

Previous studies in mice have shown that disruption of a particular pathway in the brain involving the melanocortin-4 receptor (MC4R) can lead to mice eating a lot more fat. Unusually, these mice eat a lot less sugar. However, the relevance of these findings to eating behaviour in people has been unclear until now.

In a study published today in the journal Nature Communications, researchers at the ̽��ֱ�� of Cambridge gave participants an all-you-can-eat buffet of chicken korma – a popular type of curry – with three options manipulated to look and taste the same, but in which the fat content provided 20% (low), 40% (medium) and 60% (high) of the calories. They tested lean people, obese people, and people who were obese because they have a defect in a gene called MC4R.

After taking a small taster of each meal, people were allowed to eat freely from the three kormas. They could not tell the difference between the foods and were unaware that the fat content varied. ̽��ֱ��researchers found that, although there was no overall difference in the amount of food eaten between the groups, individuals with defective MC4R ate almost double the amount of high fat korma than lean individuals ate (95% more) and 65% more than obese individuals.

In a second arm of the study, people were given Eton mess, a dessert that includes a mixture of strawberries, whipped cream and broken meringue. Again, there were three options from which participants could freely choose, with sugar content providing 8% (low), 26% (medium) and 54% (high) of calorific content, but with the fat content fixed. Participants could choose freely which ones to eat.

Lean and obese individuals said they liked the high sugar Eton mess more than the other two desserts. However, paradoxically, individuals with defective MC4R liked the high sugar dessert less than their lean and obese counterparts and in fact, ate significantly less of all three desserts compared to the other two groups.

One in 100 obese people have a defect in the MC4R gene which makes them more likely to put on weight. ̽��ֱ��researchers think that for these individuals, the fact that the MC4R pathway is not working may lead to them preferring high fat food without realising it and therefore contribute to their weight problem. There are many other genes that increase the risk of gaining weight and the impact of these genes on eating behaviour needs to be studied in the future.

Professor Sadaf Farooqi from the Wellcome Trust–Medical Research Council Institute of Metabolic Science at the ̽��ֱ�� of Cambridge, who led the research team, says: “Our work shows that even if you tightly control the appearance and taste of food, our brains can detect the nutrient content. Most of the time we eat foods that are both high in fat and high in sugar. By carefully testing these nutrients separately in this study, and by testing a relatively rare group of people with the defective MC4R gene, we were able to show that specific brain pathways can modulate food preference.”

Professor Farooqi and colleagues think that humans and animals may have evolved pathways in the brain that modulate the preference for high fat food in order to cope with times of famine.

“When there is not much food around, we need energy that can be stored and accessed when needed: fat delivers twice as many calories per gram as carbohydrates or protein and can be readily stored in our bodies,” she explains. “As such, having a pathway that tells you to eat more fat at the expense of sugar, which we can only store to a limited extent in the body, would be a very useful way of defending against starvation.”

̽��ֱ��research was supported by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, the Bernard Wolfe Health Neuroscience Fund and the European Research Council, as well the European Union’s Seventh Framework Programme

Reference
van der Klaauw, AA et al. Divergent effects of central melanocortin signalling on fat and sucrose preference in humans. Nature Comms; 4 Oct 2016; DOI: 10.1038/NCOMMS13055

People who carry variants in a particular gene have an increased preference for high fat food, but a decreased preference for sugary foods, according to a new study led by the ̽��ֱ�� of Cambridge.

Our work shows that even if you tightly control the appearance and taste of food, our brains can detect the nutrient content

Sadaf Farooqi

Patrick Talbert

Chicken Korma with Nan Bread

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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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

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Genetic variant may help explain why Labradors are prone to obesity

cjb250 — Tue, 03 May 2016 15:57:14 +0000

In developed countries, between one and two in three dogs (34-59%) is overweight, a condition associated with reduced lifespan, mobility problems, diabetes, cancer and heart disease, as it is in humans. In fact, the increase in levels of obesity in dogs mirrors that in humans, implicating factors such as reduced exercise and ready access to high calorie food factors. However, despite the fact that dog owners control their pets’ diet and exercise, some breeds of dog are more susceptible to obesity than others, suggesting the influence of genetic factors. Labradors are the most common breed of dog in the UK, USA and many other countries worldwide and the breed is known as being particularly obesity-prone.

In a study published today in the journal Cell Metabolism, an international team led by researchers at the Wellcome Trust-Medical Research Council Institute of Metabolic Science, ̽��ֱ�� of Cambridge, report a study of 310 pet and assistance dog Labradors. Independent veterinary professionals weighed the dogs and assessed their body condition score, and the scientists searched for variants of three candidate obesity-related genes. ̽��ֱ��team also assessed ‘food motivation’ using a questionnaire in which owners reported their dog’s behavior related to food.

̽��ֱ��researchers found that a variant of one gene in particular, known as POMC, was strongly associated with weight, obesity and appetite in Labradors and flat coat retrievers. Around one in four (23%) Labradors is thought to carry at least one copy of the variant. In both breeds, for each copy of the gene carried, the dog was on average 1.9kg heavier, an effect size particularly notable given the extent to which owners, rather than the dogs themselves, control the amount of food and exercise their dogs receive.

“This is a common genetic variant in Labradors and has a significant effect on those dogs that carry it, so it is likely that this helps explain why Labradors are more prone to being overweight in comparison to other breeds,” explains first author Dr Eleanor Raffan from the ̽��ֱ�� of Cambridge. “However, it’s not a straightforward picture as the variant is even more common among flat coat retrievers, a breed not previously flagged as being prone to obesity.”

̽��ֱ��gene affected is known to be important in regulating how the brain recognises hunger and the feeling of being full after a meal. “People who live with Labradors often say they are obsessed by food, and that would fit with what we know about this genetic change,” says Dr Raffan.

Senior co-author Dr Giles Yeo adds: “Labradors make particularly successful working and pet dogs because they are loyal, intelligent and eager to please, but importantly, they are also relatively easy to train. Food is often used as a reward during training, and carrying this variant may make dogs more motivated to work for a titbit.

“But it’s a double-edged sword – carrying the variant may make them more trainable, but it also makes them susceptible to obesity. This is something owners will need to be aware of so they can actively manage their dog’s weight.”

̽��ֱ��researchers believe that a better understanding of the mechanisms behind the POMC gene, which is also found in humans, might have implications for the health of both Labradors and human.

Professor Stephen O’Rahilly, Co-Director of the Wellcome Trust-Medical Research Council Institute of Metabolic Science, says: “Common genetic variants affecting the POMC gene are associated with human body weight and there are even some rare obese people who lack a very similar part of the POMC gene to the one that is missing in the dogs. So further research in these obese Labradors may not only help the wellbeing of companion animals but also have important lessons for human health.”

̽��ֱ��research was funded by the Wellcome Trust, the Medical Research Council and the Dogs Trust.

Reference
Raffan, E et al. A deletion in the canine POMC gene is associated with weight and appetite in obesity prone Labrador retriever dogs. Cell Metabolism; 3 May 2016; DOI: 10.1016/j.cmet.2016.04.012

A genetic variation associated with obesity and appetite in Labrador retrievers – the UK and US’s favourite dog breed – has been identified by scientists at the ̽��ֱ�� of Cambridge. ̽��ֱ��finding may explain why Labrador retrievers are more likely to become obese than dogs of other breeds.

People who live with Labradors often say they are obsessed by food, and that would fit with what we know about this genetic change

Eleanor Raffan

Thomas Hawk

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