Scientists identify rare gene variants which confer up to 6-fold increase in risk of obesity
The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood.
The study, published in Nature Genetics, was led by researchers at the Medical Research Council (MRC) Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.
The researchers used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals.
They found that genetic variants in the gene BSN, also known as Bassoon, can raise the risk of obesity as much as six times and was also associated with an increased risk of non-alcoholic fatty liver disease and of type 2 diabetes.
The Bassoon gene variants were found to affect 1 in 6,500 adults, so could affect about 10,000 people in the UK.
The brain’s role in obesityObesity is a major public health concern as it is a significant risk factor for other serious diseases, including cardiovascular disease and type 2 diabetes, yet the genetic reasons why some people are more prone to weight gain are incompletely understood.
Previous research has identified several obesity-associated gene variants conferring large effects from childhood, acting through the leptin-melanocortin pathway in the brain, which plays a key role in appetite regulation.
However, while both BSN and APBA1 encode proteins found in the brain, they are not currently known to be involved in the leptin-melanocortin pathway. In addition, unlike the obesity genes previously identified, variants in BSN and APBA1 are not associated with childhood obesity.
This has led the researchers to believe that they may have uncovered a new biological mechanism for obesity, different to those we already know for previously identified obesity gene variants.
Based on published research and laboratory studies they report in this paper, which indicate that BSN and APBA1 play a role in the transmission of signals between brain cells, the researchers suggest that age-related neurodegeneration could be affecting appetite control.
Professor John Perry, study author and an MRC Investigator at the University of Cambridge, said: “These findings represent another example of the power of large-scale human population genetic studies to enhance our understanding of the biological basis of disease. The genetic variants we identify in BSN confer some of the largest effects on obesity, type 2 diabetes and fatty liver disease observed to date and highlight a new biological mechanism regulating appetite control.”
The use of global dataThe accessibility of large-scale databases such as UK Biobank has enabled researchers to search for rare gene variants that may be responsible for conditions including obesity.
For this study, the researchers worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico. This is important as the researchers can now apply their findings beyond individuals of European ancestry.
If the researchers can better understand the neural biology of obesity, it could present more potential drug targets to treat obesity in the future.
Dr Slavé Petrovski, VP of the Centre for Genomics Research at AstraZeneca, said: “Rigorous large-scale studies such as this are accelerating the pace at which we uncover new insights into human disease biology. By collaborating across academia and industry, leveraging global datasets for validation, and embedding a genomic approach to medicine more widely, we will continue to improve our understanding of disease – for the benefit of patients.”
Next steps for researchProfessor Giles Yeo, study author based at the MRC Metabolic Diseases Unit, added: “We have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seen, but perhaps more importantly, that the variation in Bassoon is linked to adult-onset and not childhood obesity. Thus these findings give us a new appreciation of the relationship between genetics, neurodevelopment and obesity.”
Reference
Zhao, T et al. Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease. Nat Gen; 4 Apr 2024; DOI: 10.1038/s41588-024-01694-x
Adapted from a press release from the Medical Research Council
Cambridge researchers have identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date.
We have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seenGiles YeoWorld Obesity FederationWoman with obesity washing food
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AI predicts healthiness of food menus
Cambridge researchers have used artificial intelligence to predict the healthiness of café, takeaway and restaurant menus at outlets across Britain and used this information to map which of its local authorities have the most and least healthy food environments.
Genetic mutation in a quarter of all Labradors hard-wires them for obesity
This obesity-driving combination means that dog owners must be particularly strict with feeding and exercising their Labradors to keep them slim.
The mutation is in a gene called POMC, which plays a critical role in hunger and energy use.
Around 25% of Labradors and 66% of flatcoated retriever dogs have the POMC mutation, which researchers previously showed causes increased interest in food and risk of obesity.
The new study reveals how the mutation profoundly changes the way Labradors and flatcoated retrievers behave around food. It found that although they don’t need to eat more to feel full, they are hungrier in between meals.
In addition, dogs with the POMC mutation were found to use around 25% less energy at rest than dogs without it, meaning they don’t need to consume as many calories to maintain a healthy body weight.
“We found that a mutation in the POMC gene seems to make dogs hungrier. Affected dogs tend to overeat because they get hungry between meals more quickly than dogs without the mutation,” said Dr Eleanor Raffan, a researcher in the University of Cambridge’s Department of Physiology, Development and Neuroscience who led the study.
She added: “All owners of Labradors and flatcoated retrievers need to watch what they’re feeding these highly food-motivated dogs, to keep them a healthy weight. But dogs with this genetic mutation face a double whammy: they not only want to eat more, but also need fewer calories because they’re not burning them off as fast.”
The POMC mutation was found to alter a pathway in the dogs’ brains associated with body weight regulation. The mutation triggers a starvation signal that tells their body to increase food intake and conserve energy, despite this being unnecessary.
The results are published today in the journal Science Advances.
Raffan said: “People are often rude about the owners of fat dogs, blaming them for not properly managing their dogs’ diet and exercise. But we’ve shown that Labradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.”
The researchers say owners can keep their retrievers distracted from this constant hunger by spreading out each daily food ration, for example by using puzzle feeders or scattering the food around the garden so it takes longer to eat.
In the study, 87 adult pet Labrador dogs - all a healthy weight or moderately overweight - took part in several tests including the ‘sausage in a box’ test.
First, the dogs were given a can of dogfood every 20 minutes until they chose not to eat any more. All ate huge amounts of food, but the dogs with the POMC mutation didn’t eat more than those without it. This showed that they all feel full with a similar amount of food.
Next, on a different day, the dogs were fed a standard amount of breakfast. Exactly three hours later they were offered a sausage in a box and their behaviour was recorded. The box was made of clear plastic with a perforated lid, so the dogs could see and smell the sausage, but couldn’t eat it.
The researchers found that dogs with the POMC mutation tried significantly harder to get the sausage from the box than dogs without it, indicating greater hunger.
The dogs were then allowed to sleep in a special chamber that measured the gases they breathed out. This revealed that dogs with the POMC mutation burn around 25% fewer calories than dogs without it.
The POMC gene and the brain pathway it affects are similar in dogs and humans. The new findings are consistent with reports of extreme hunger in humans with POMC mutations, who tend to become obese at an early age and develop a host of clinical problems as a result.
Drugs currently in development for human obesity, underactive sexual desire and certain skin conditions target this brain pathway, so understanding it fully is important.
A mutation in the POMC gene in dogs prevents production of two chemical messengers in the dog brain, beta-melanocyte stimulating hormone (β-MSH) and beta-endorphin, but does not affect production of a third, alpha-melanocyte stimulating hormone (α-MSH).
Further laboratory studies by the team suggest that β-MSH and beta-endorphin are important in determining hunger and moderating energy use, and their role is independent of the presence of α-MSH. This challenges the previous belief, based on research in rats, that early onset human obesity due to POMC mutations is caused only by a lack of α-MSH. Rats don’t produce beta-melanocyte stimulating hormone, but humans and dogs produce both α- and β-MSH.
The research was funded by The Dogs Trust and Wellcome.
Reference: Dittmann, M.T. et al: ‘Low resting metabolic rate and increased hunger due to β-MSH and β-endorphin deletion in a canine model.’ Science Advances, March 2024. DOI: 10.1126/sciadv.adj3823
New research finds around a quarter of Labrador retriever dogs face a double-whammy of feeling hungry all the time and burning fewer calories due to a genetic mutation.
Labradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.Eleanor RaffanJane GoodallLabrador retriever dog
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Scientists identify how fasting may protect against inflammation
In research published in Cell Reports, the team describes how fasting raises levels of a chemical in the blood known as arachidonic acid, which inhibits inflammation. The researchers say it may also help explain some of the beneficial effects of drugs such as aspirin.
Scientists have known for some time that our diet – particular a high calorie Western diet – can increase our risk of diseases including obesity, type 2 diabetes and heart disease, which are linked to chronic inflammation in the body.
Inflammation is our body’s natural response to injury or infection, but this process can be triggered by other mechanisms, including by the so-called ‘inflammasome’, which acts like an alarm within our body’s cells, triggering inflammation to help protect our body when it senses damage. But the inflammasome can trigger inflammation in unintentional ways – one of its functions is to destroy unwanted cells, which can result in the release of the cell’s contents into the body, where they trigger inflammation.
Professor Clare Bryant from the Department of Medicine at the University of Cambridge said: “We’re very interested in trying to understand the causes of chronic inflammation in the context of many human diseases, and in particular the role of the inflammasome.
“What's become apparent over recent years is that one inflammasome in particular – the NLRP3 inflammasome – is very important in a number of major diseases such as obesity and atherosclerosis, but also in diseases like Alzheimer's and Parkinson's disease, many of the diseases of older age people, particularly in the Western world.”
Fasting can help reduce inflammation, but the reason why has not been clear. To help answer this question, a team led by Professor Bryant and colleagues at the University of Cambridge and National Institute for Health in the USA studied blood samples from a group of 21 volunteers, who ate a 500kcal meal then fasted for 24 hours before consuming a second 500kcal meal.
The team found that restricting calorie intake increased levels of a lipid known as arachidonic acid. Lipids are molecules that play important roles in our bodies, such as storing energy and transmitting information between cells. As soon as individuals ate a meal again, levels of arachidonic acid dropped.
When the researchers studied arachidonic acid’s effect in immune cells cultured in the lab, they found that it turns down the activity of the NLRP3 inflammasome. This surprised the team as arachidonic acid was previously thought to be linked with increased levels of inflammation, not decreased.
Professor Bryant, a Fellow of Queens’ College, Cambridge, added: “This provides a potential explanation for how changing our diet – in particular by fasting – protects us from inflammation, especially the damaging form that underpins many diseases related to a Western high calorie diet.
“It’s too early to say whether fasting protects against diseases like Alzheimer's and Parkinson's disease as the effects of arachidonic acid are only short-lived, but our work adds to a growing amount of scientific literature that points to the health benefits of calorie restriction. It suggests that regular fasting over a long period could help reduce the chronic inflammation we associate with these conditions. It's certainly an attractive idea.”
The findings also hint at one mechanism whereby a high calorie diet might increase the risk of these diseases. Studies have shown that some patients that have a high fat diet have increased levels of inflammasome activity.
“There could be a yin and yang effect going on here, whereby too much of the wrong thing is increasing your inflammasome activity and too little is decreasing it,” said Professor Bryant. “Arachidonic acid could be one way in which this is happening.”
The researchers say the discovery may also offer clues to an unexpected way in which so-called non-steroidal anti-inflammatory drugs such as aspirin work. Normally, arachidonic acid is rapidly broken down in the body, but aspirin stops this process, which can lead to an increase in levels of arachidonic acid, which in turn reduce inflammasome activity and hence inflammation.
Professor Bryant said: “It’s important to stress that aspirin should not be taken to reduce risk of long terms diseases without medical guidance as it can have side-effects such as stomach bleeds if taken over a long period.”
The research was funded by Wellcome, the Medical Research Council and the US National Heart, Lung, and Blood Institute Division of Intramural Research.
Reference
Pereira, M & Liang, J et al. Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting. Cell Reports; 23 Jan 2024; DOI: 10.1016/j.celrep.2024.113700
Cambridge scientists may have discovered a new way in which fasting helps reduce inflammation – a potentially damaging side-effect of the body’s immune system that underlies a number of chronic diseases.
Our work adds to a growing amount of scientific literature that points to the health benefits of calorie restrictionClare BryantCarol Yepes (Getty Images)Intermittent fasting conceptual image
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