̽��ֱ�� of Cambridge - Sadaf Farooqi

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

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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 – 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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Obesity accelerates loss of COVID-19 vaccination immunity, study finds

ta385 — Thu, 11 May 2023 14:59:00 +0000

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. ̽��ֱ��reasons for this have, however, remained unclear.

This study, published in the journal Nature Medicine, shows that the ability of antibodies to neutralise the virus declines faster in vaccinated people who have obesity. ̽��ֱ��findings have important implications for vaccine prioritisation policies around the world.

During the pandemic, people with obesity were more likely to be hospitalised, require ventilators and to die from COVID-19. In this study, supported by the NIHR Bioresource and funded by UKRI, the researchers set out to investigate how far two of the most extensively used vaccines protect people with obesity compared to those with a normal weight, over time.

A team from the ̽��ֱ�� of Edinburgh, led by Prof Sir Aziz Sheikh, looked at real-time data tracking the health of 3.5 million people in the Scottish population as part of the EAVE II study. They looked at hospitalisation and mortality from COVID-19 in adults who received two doses of COVID-19 vaccine (either Pfizer-BioNTech BNT162b2 mRNA or AstraZeneca ChAdOx1).

They found that people with severe obesity (a BMI greater than 40 kg/m2) had a 76% higher risk of severe COVID-19 outcomes, compared to those with a normal BMI. A modest increase in risk was also seen in people with obesity (30-39.9kg/m2), which affects a quarter of the UK population, and those who were underweight. ‘Break-through infections’ after the second vaccine dose also led to hospitalisation and death sooner (from 10 weeks) among people with severe obesity, and among people with obesity (after 15 weeks), than among individuals with normal weight (after 20 weeks).

Prof Sir Aziz Sheikh said: “Our findings demonstrate that protection gained through COVID-19 vaccination drops off faster for people with severe obesity than those with a normal body mass index. Using large-scale data assets such as the EAVE II Platform in Scotland have enabled us to generate important and timely insights that enable improvements to the delivery of COVID-19 vaccine schedules in a post-pandemic UK.”

̽��ֱ�� ̽��ֱ�� of Cambridge team – jointly led by Dr James Thaventhiran, from the MRC Toxicology Unit and Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science – studied people with severe obesity attending the Obesity clinic at Addenbrooke’s Hospital in Cambridge, and compared the number and function of immune cells in their blood to those of people of normal weight.

They studied people six months after their second vaccine dose and then looked at the response to a third 'booster' vaccine dose over time. ̽��ֱ��Cambridge researchers found that six months after a second vaccine dose, people with severe obesity had similar levels of antibodies to the COVID-19 virus as those with a normal weight.

But the ability of those antibodies to work efficiently to fight against the virus (known as ‘neutralisation capacity’) was reduced in people with obesity. 55% of individuals with severe obesity were found to have unquantifiable or undetectable ‘neutralising capacity’ compared to 12% of people with normal BMI.

“This study further emphasises that obesity alters the vaccine response and also impacts on the risk of infection,” said Dr Agatha van der Klaauw from the Wellcome-MRC Institute of Metabolic Science and first author of the paper. “We urgently need to understand how to restore immune function and minimise these health risks.”

̽��ֱ��researchers found that antibodies produced by people with severe obesity were less effective at neutralising the SARS-CoV-2 virus, potentially because the antibodies were not able to bind to the virus with the same strength.

When given a third (booster) dose of a COVID-19 vaccine, the ability of the antibodies to neutralise the virus was restored in both the normal weight and severely obese groups. But the researchers found that immunity again declined more rapidly in people with severe obesity, putting them at greater risk of infection with time.

Dr James Thaventhiran, a Group Leader from the MRC Toxicology Unit in Cambridge and co-lead author of the SCORPIO study said: “It is promising to see that booster vaccines restore the effectiveness of antibodies for people with severe obesity, but it is concerning that their levels decrease more quickly, after just 15 weeks. This shows that the vaccines work as well in people with obesity, but the protection doesn’t last as long.”

Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science and co-lead author of the SCORPIO study said: “More frequent booster doses are likely to be needed to maintain protection against COVID-19 in people with obesity. Because of the high prevalence of obesity across the globe, this poses a major challenge for health services”.

Reference

A A van der Klaauw et al., ‘Accelerated waning of the humoral response to COVID-19 vaccines in obesity’, Nature Medicine (2023). DOI: 10.1038/s41591-023-02343-2

̽��ֱ��protection offered by COVID-19 vaccination declines more rapidly in people with severe obesity than in those with normal weight, scientists at the Universities of Cambridge and Edinburgh have found. ̽��ֱ��study suggests that people with obesity are likely to need more frequent booster doses to maintain their immunity.

This poses a major challenge for health services

Sadaf Farooqi

Steven Cornfield

Patient receiving a COVID-19 vaccination in their arm

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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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Female scientists lead Cambridge success in Royal Society awards 2021

ta385 — Tue, 24 Aug 2021 12:00:00 +0000

Bell Burnell is one of twelve former and current Cambridge researchers, including six women, to be recognised in 2021 for their exceptional research and outstanding contributions to science.

Dame Jocelyn has been honoured for her work on the discovery of pulsars in the 1960s while she was a postgraduate student at New Hall (now Murray Edwards College) carrying out research at Cambridge's Cavendish Laboratory.

Past winners of the Copley Medal have included Charles Darwin, Albert Einstein and Dorothy Crowfoot Hodgkin. Dame Jocelyn said: “I am delighted to be the recipient of this year’s Copley Medal, a prize which has been awarded to so many incredible scientists.

“With many more women having successful careers in science, and gaining recognition for their transformational work, I hope there will be many more female Copley winners in the near future.

“My career has not fitted a conventional – male – pattern. Being the first person to identify pulsars would be the highlight of any career; but I have also swung sledgehammers and built radio telescopes; set up a successful group of my own studying binary stars; and was the first female president of the Institute of Physics and of the Royal Society of Edinburgh.

“I hope that my work and presence as a senior woman in science continues to encourage more women to pursue scientific careers”.

̽��ֱ��Copley Medal award includes a £25,000 gift which Dame Jocelyn will add to the Institute of Physics' Bell Burnell Graduate Scholarship Fund, which provides grants to graduate students from under-represented groups in physics.

Three female scientists currently working at Cambridge have been recognised in 2021. Professor Sadaf Farooqi from the MRC Metabolic Diseases Unit receives the Croonian Medal and Lecture, together with Sir Stephen O'Rahilly, for their seminal discoveries regarding the control of human body weight, resulting in novel diagnostics and therapies, which improve human health.

Dr Serena Nik-Zainal from the MRC Cancer Unit has been awarded the Francis Crick Medal and Lecture, for her contributions to understanding the aetiology of cancers by her analyses of mutation signatures in cancer genomes, which is now being applied to cancer therapy.

Professor Anne Ferguson-Smith from the Department of Genetics and currently the ̽��ֱ��’s Pro-Vice-Chancellor for Research receives the Buchanan Medal, for her pioneering work in epigenetics, her interdisciplinary work on genomic imprinting, the interplay between the genome and epigenome, and how genetic and environmental influences affect development and human diseases.

Former Cavendish Laboratory Research Fellow, Professor Michelle Simmons, has won the Bakerian Medal and Lecture, for her seminal contributions to our understanding of nature at the atomic-scale by creating a sequence of world-first quantum electronic devices in which individual atoms control device behaviour.

Professor Frances Kirwan, alumna and Honorary Fellow of Clare College, received the Sylvester Medal, for her research on quotients in algebraic geometry, including links with symplectic geometry and topology, which has had many applications.

Other current Cambridge researchers honoured include Dr Sjors Scheres from the MRC Laboratory of Molecular Biology. Scheres has been awarded the Leeuwenhoek Medal and Lecture for his ground-breaking contributions and innovations in image analysis and reconstruction methods in electron cryo-microscopy, enabling the structure determination of complex macromolecules of fundamental biological and medical importance to atomic resolution.

Emeritus Professor Michael Green from the Department of Applied Mathematics and Theoretical Physics has been awarded Royal Medal A for crucial and influential contributions to the development of string theory over a long period, including the discovery of anomaly cancellation.

̽��ֱ��Royal Society’s President, Sir Adrian Smith, said: “Through its medals and awards the Royal Society recognises those researchers and science communicators who have played a critical part in expanding our understanding of the world around us.”

“From advancing vaccine development to catching the first glimpses of distant pulsars, these discoveries shape our societies, answer fundamental questions and open new avenues for exploration.”

Find the full list of 2021 Royal Society medal, award and prize winners here.

Professor Dame Jocelyn Bell Burnell has become only the second woman to be awarded the Royal Society’s prestigious Copley Medal, the world’s oldest scientific prize.

I hope there will be many more female Copley winners in the near future

Jocelyn Bell Burnell

https://www.youtube.com/watch?v=z_3zNw91MSY

Professor Dame Jocelyn Bell Burnell

̽��ֱ��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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̽��ֱ��Royal Society announces election of new Fellows 2021

cg605 — Thu, 06 May 2021 10:48:11 +0000

Over 60 outstanding scientists from all over the globe have joined the Royal Society as Fellows and Foreign Members. ̽��ֱ��distinguished group of scientists consists of 52 Fellows, 10 Foreign Members and one Honorary Fellow and were all selected for their exceptional contributions to science.

̽��ֱ��Royal Society is a self-governing Fellowship made up of the most eminent scientists, engineers and technologists from the UK and the Commonwealth. Its Foreign Members are drawn from the rest of the world.

̽��ֱ��Society’s fundamental purpose is to recognise, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity.

“ ̽��ֱ��global pandemic has demonstrated the continuing importance of scientific thinking and collaboration across borders,” said President of the Royal Society, Sir Adrian Smith.

“Each Fellow and Foreign Member bring their area of scientific expertise to the Royal Society and when combined, this expertise supports the use of science for the benefit of humanity.

“Our new Fellows and Foreign Members are all at the forefronts of their fields from molecular genetics and cancer research to tropical open ecosystems and radar technology. It is an absolute pleasure and honour to have them join us.”

̽��ֱ�� of Cambridge:

Professor Julie Ahringer FMedSci FRS

Director and a Senior Group Leader of the Gurdon Institute

Professor Ahringer has made wide-ranging contributions to molecular genetics through her work on the nematode C. elegans. She carried out the first systematic inactivation of all the genes in any animal, which pioneered genome-wide reverse genetic screening.

Her research has illuminated our understanding of the processes underlying cell polarity and gene expression. This includes showing that spindle positioning is controlled by heterotrimeric G protein signalling, discovering a connection between chromatin marking and mRNA splicing, and most recently revealing mechanisms and principles of genome organisation and gene expression regulation.

“I am honoured to be elected as a Fellow of the Royal Society,” said Ahringer. “Much of science today is done in teams, and this reflects the tremendous contributions of my past and present lab members.”

Professor Sadaf Farooqi FRCP FMedSci FRS

Wellcome Principal Research Fellow and Professor of Metabolism and Medicine, Wellcome-MRC Institute of Metabolic Science

Professor Farooqi is distinguished for her discoveries of fundamental mechanisms that control human energy homeostasis and their disruption in obesity. Farooqi discovered that the leptin-melanocortin system regulates appetite and weight in people and that genetic mutations affecting this pathway cause severe obesity. Findings by her team have directly led to diagnostic testing for genetic obesity syndromes world-wide and enabled life-saving treatment for some people with severe obesity.

Farooqi said: “As a clinician scientist, I am absolutely delighted to be elected to the Fellowship of the Royal Society. This prestigious honour recognises the work of many team members past and present, our network of collaborators across the world and the patients and their families who have contributed to our research.”

Professor Usha Goswami CBE FBA FRS

Professor of Cognitive Developmental Neuroscience, Department of Psychology, and Director of the Centre for Neuroscience in Education

Professor Goswami has pioneered the application of neuroscience to education. Her research investigates the sensory and neural basis of childhood disorders of language and literacy, which are heritable and found across languages. Goswami's research shows a shared sensory and neural basis in auditory rhythmic processing. ̽��ֱ��acoustic ‘landmarks’ for speech rhythm provide automatic triggers for aligning speech rhythms and brain rhythms, and Goswami has shown that this automatic process can be disrupted, thereby disrupting speech encoding for these children.

“It is a huge honour to be elected to the Royal Society and a wonderful acknowledgement of our research in the Centre for Neuroscience in Education,” said Goswami. “I have been interested in children's reading and language development since training as a primary school teacher, and we have used neuroscientific insights to understand the mechanisms underpinning developmental language disorders. It is fantastically rewarding for our work to be recognised in this way.”

Professor Rebecca Kilner FRS

Professor of Evolutionary Biology and Director of the ̽��ֱ�� Museum of Zoology

Professor Kilner researches the evolution of animal behaviour, and how this behaviour then affects the pace and scope of subsequent evolutionary change. Using experimental evolution, her current work investigates how quickly populations can adapt when environmental conditions change.

Kilner discovered novel ways in which social behaviour drives evolutionary change. She used elegant cross-fostering experiments in birds and insects to expose how family members exert selection on each other, and discovered hidden evolutionary conflicts between parents and their offspring, and among adults caring together for offspring.

Kilner said: “I’m astonished, honoured and delighted to be elected to the Fellowship of the Royal Society. This honour is shared with everyone I have ever worked with. Science is a team effort and I’ve been incredibly lucky to collaborate with brilliant colleagues throughout my career.”

Professor David Rowitch FMedSci FRS

Professor and Head of the Department of Paediatrics, Wellcome Trust Senior Investigator

Professor Rowitch’s basic and translational research on glial cells, comprising 90% of cells in the human brain, has been transformative. Rowitch’s established how embryonic central nervous patterning specifies myelinating oligodendrocytes through essential functions of Olig2, a study that helped initiate genetic methodologies in glial biology, and how astrocyte functional diversification is critical for support of neural circuits in the spinal cord. He has applied a developmental neuroscience perspective to better understand human neonatal brain development and white matter injury in premature infants, multiple sclerosis and leukodystrophy.

Rowitch said: “It is a great honour to be elected to the Fellowship of the Royal Society, joining many of my esteemed Cambridge, and other scientific, colleagues.”

Professor Richard Samworth FRS

Professor of Statistical Science and Director of the Statistical Laboratory

Professor Samworth has made fundamental contributions to the development of modern statistical methodology and theory. His research concerns the development of statistical methods and theory to address contemporary data challenges, often posed by the large volumes of data that are routinely collected in today's Big Data era.

“I was incredibly honoured when I found out I'd been elected a Fellow of the Royal Society,” said Samworth. “It's a real thrill to become a small part of such a respected institution.”

Professor Benjamin Simons FRS

Royal Society EP Abraham Professor, Department of Applied Mathematics and Theoretical Physics and Senior Group Leader of the Gurdon Institute

As a theorist, Professor Simons has contributed to a diverse range of fields, from quantum condensed matter physics to developmental and cancer biology. His research translates concepts and approaches from statistical physics to gain predictive insights in the collective dynamics of complex systems. In biology, his studies have revealed common mechanisms of stem cell regulation, and how these programmes become subverted during the early phase of tumour growth.

Simons said: “I am delighted to be elected to the Fellowship. I hope that my election may serve to emphasise the value of multidisciplinary research that stands at the interface between physics and the life sciences.”

Wellcome Sanger Institute:

Dr Peter Campbell FMedSci FRS, Head, Cancer, Ageing, and Somatic Mutations Programme, Wellcome Sanger Institute (and Wellcome-MRC Stem Cell Institute, ̽��ֱ�� of Cambridge).

MRC Laboratory of Molecular Biology:

Dr Christopher Tate FRS, MRC Investigator, MRC Laboratory of Molecular Biology

Dr Sjors Scheres FRS, Group Leader, Structural Studies Division, MRC Laboratory of Molecular Biology

British Antarctic Survey:

Professor Dame Jane Francis DCMG FRS, Director, British Antarctic Survey

Professor Richard Horne FRS, Head, Space Weather and Atmosphere, British Antarctic Survey

Cambridge scientists are among the new Fellows announced today by the Royal Society.

Our new Fellows and Foreign Members are all at the forefronts of their fields from molecular genetics and cancer research to tropical open ecosystems and radar technology.

Sir Adrian Smith, President of the Royal Society

Yes

Cambridge scientists recognised by major European research organisation

cjb250 — Tue, 18 Jun 2019 11:42:19 +0000

Cambridge ̽��ֱ�� has the highest number of new members of any institution within Europe. Five ̽��ֱ�� of Cambridge researchers are among the 48 scientists from 17 countries elected:

Professor Sadaf Farooqi – Wellcome-Medical Research Council (MRC) Institute of Metabolic Science
Dr Fanni Gergely – Cancer Research UK Cambridge Institute
Professor Paul Lehner – Department of Medicine and the Cambridge Institute for Medical Research
Professor Lalita Ramakrishnan – Department of Medicine and the MRC Laboratory of Molecular Biology
Professor Nicole Soranzo – Department of Haematology and Wellcome Sanger Institute

In addition, Dr Garib Murshudov from the MRC Laboratory of Molecular Biology has also been elected.

EMBO is an organisation of more than 1800 leading researchers in Europe and around the world, whose mission is to promote excellence in the life sciences in Europe and beyond. ̽��ֱ��major goals of the organisation are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information and help build a research environment where scientists can achieve their best work.

“EMBO Members are excellent scientists who conduct research at the forefront of all life science disciplines, ranging from computational models or analyses of single molecules and cellular mechanics to the study of higher-order systems in development, cognitive neuroscience and evolution,” says EMBO Director Maria Leptin.

“We’re very honoured to have been elected as members of EMBO,” says Professor Farooqi. “This is great recognition for the excellent science taking place across our city, particularly on the Cambridge Biomedical Campus. We are proud of the role we play in European science and look forward to continuing to work in partnership with colleagues across the continent.”

Researchers from the Cambridge Biomedical Campus have featured prominently in this year’s election to the prestigious European Molecular Biology Organisation (EMBO).

We are proud of the role we play in European science and look forward to continuing to work in partnership with colleagues across the continent

Sadaf Farooqi

CDC/ Melissa Brower

This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of rod-shaped drug-resistant Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB).

Yes

Discovery of genetic variants that protect against obesity and type 2 diabetes could lead to new weight loss medicines

cjb250 — Thu, 18 Apr 2019 15:00:18 +0000

Scientists have known for several years that genes can influence a person’s weight. One of the genes that is known to play a key role in regulating weight is MC4R, which codes for the melanocortin 4 receptor. This receptor acts like a switch in the brain to suppress appetite. People who have genetic variants that disrupt this receptor gain weight easily.

Now, in a study published today in the journal Cell, researchers have shown that other genetic variants in the MC4R gene that increase the activity of this brain receptor can protect people from becoming overweight, a finding that could lead to the development of new medicines that ‘copy’ the protective effect of these genetic variants to achieve or maintain weight-loss.

A team led by Professors Sadaf Farooqi and Nick Wareham and Dr Claudia Langenberg at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge looked at the MC4R gene in half a million volunteers from the UK population who have taken part in the UK Biobank study, finding 61 distinct naturally-occurring genetic variants. While some of these genetic variants predisposed people to become obese, other variants provided protection against obesity and some of its major complications, such as type 2 diabetes and heart disease.

To investigate the reasons for this mystery, Professor Farooqi’s team, who previously showed that MC4R works in the brain as a ‘switch’ to tell us to stop eating after a meal, studied the function of these genetic variants in a number of laboratory experiments. They found that MC4R gene variants linked to higher obesity risk stopped the gene from working, whereas variants that offered protection against obesity kept the gene ‘switched on’.

Around six per cent of study participants carried genetic variants that caused the receptor to remain ‘switched on’. People with these variants would eat less, which could explain their lower weight. People with two copies of these particular variants (1 in over 1,000 people) were on average 2.5 kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.

“This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity,” says Professor Farooqi of the ̽��ֱ�� of Cambridge Metabolic Research Laboratories.

̽��ֱ��discovery adds to recent work by the team which showed that some slim people have a genetic advantage when it comes to maintaining their weight.

“It doesn’t mean that we can’t influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favour of others,” added Professor Farooqi.

When the researchers looked in detail at the genetic variants in laboratory experiments, they found that MC4R can send signals through a pathway – known as the beta-arrestin pathway – that had not previously been linked to weight regulation. Genetic variants that sent signals preferentially through this pathway were the ones driving the association with protection against obesity and its complications and, importantly, were also associated with lower blood pressure. Designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies.

“A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer,” said Dr Luca Lotta, Senior Clinical Investigator at the Medical Research Council Epidemiology Unit and joint lead author of the study. “Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”

“Our work would not have been possible without the unique blend of expertise in large-scale genetic epidemiology analysis and laboratory experiments at the Institute of Metabolic Science,” says Professor Wareham, Director of the MRC Epidemiology Unit and Co-Director of the Institute.

“Genetic studies of thousands of people and a functional understanding of the mechanisms behind protective genetic variants can really help us inform the development of a new generation of medicines for common diseases like obesity and diabetes that affect millions of people globally.”

̽��ֱ��work was funded by the MRC and Wellcome, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Lotta, LA, Mokrosiński, J et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell; 18 April 2019; DOI: 10.1016/j.cell.2019.03.044

Around four million people in the UK carry genetic variants that protect them from obesity, type 2 diabetes and heart disease, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��team say the discovery could lead to the development of new drugs that help people lose weight.

This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity

Sadaf Farooqi

Siora Photography

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Slim people have a genetic advantage when it comes to maintaining their weight

ehs33 — Thu, 24 Jan 2019 19:00:00 +0000

More than six in ten adults in the UK are overweight, and one in four adults is obese. By age five, almost one in four children is either overweight or obese. Excess weight increases the risk of related health problems including type 2 diabetes and heart disease.

While it is well known that changes in our environment, such as easy access to high calorie foods and sedentary lifestyles, have driven the rise in obesity in recent years, there is considerable individual variation in weight within a population that shares the same environment. Some people seem able to eat what they like and remain thin. This has led some people to characterise overweight people as lazy or lacking willpower.

With support from Wellcome and the European Research Council, a team led by Professor Sadaf Farooqi at the Wellcome-MRC Institute of Metabolic Science, ̽��ֱ�� of Cambridge, established the Study Into Lean and Thin Subjects – STILTS – to examine why and how some people find it easier to stay thin than others. Studies of twins have shown that variation in body weight is largely influenced by our genes. To date studies have overwhelmingly focused on people who are overweight. Hundreds of genes have been found that increase the chance of a person being overweight and in some people faulty genes can cause severe obesity from a young age.

Professor Sadaf Farooqi’s team were able to recruit 2,000 people who were thin (defined as a body mass index (BMI) of less than 18 kg/m2) but healthy, with no medical conditions or eating disorders. They worked with general practices across the UK, taking saliva samples to enable DNA analysis and asking participants to answer questions about their general health and lifestyles. It is thought to be the only cohort of its kind in the world and the researchers say that the UK’s National Institute for Health Research – the National Health Service’s research infrastructure – strongly enabled and supported their research.

In a study published today in the journal PLOS Genetics, Professor Farooqi’s team collaborated with Dr Inês Barroso’s team at the Wellcome Sanger Institute to compare the DNA of some 14,000 people –1,622 thin volunteers from the STILTS cohort, 1,985 severely obese people and a further 10,433 normal weight controls.

Our DNA comprises of a sequence of molecules known as base pairs, represented by the letters A, C, G and T. Strings of these base pairs form genetic regions (which include or make up our genes). Our genes provide the code for how our body functions and changes in the spelling – for example, a C in place of an A – can have subtle or sometimes dramatic changes on features such as hair colour and eye colour but also on a person’s weight.

̽��ֱ��team found several common genetic variants already identified as playing a role in obesity. In addition, they found new genetic regions involved in severe obesity and some involved in healthy thinness.

To see what impact these genes had on an individual’s weight, the researchers added up the contribution of the different genetic variants to calculate a genetic risk score.

“As anticipated, we found that obese people had a higher genetic risk score than normal weight people, which contributes to their risk of being overweight. ̽��ֱ��genetic dice are loaded against them,” explains Dr Barroso.

Importantly, the team also showed that thin people, had a much lower genetic risk score – they had fewer genetic variants that we know increase a person’s chances of being overweight.

“This research shows for the first time that healthy thin people are generally thin because they have a lower burden of genes that increase a person’s chances of being overweight and not because they are morally superior, as some people like to suggest,” says Professor Farooqi. “It’s easy to rush to judgement and criticise people for their weight, but the science shows that things are far more complex. We have far less control over our weight than we might wish to think.”

Three out of four people (74%) in the STILTS cohort had a family history of being thin and healthy and the team found some genetic changes that were significantly more common in thin people, which they say may allow them to pinpoint new genes and biological mechanisms that help people stay thin.

“We already know that people can be thin for different reasons” says Professor Farooqi. “Some people are just not that interested in food whereas others can eat what they like, but never put on weight. If we can find the genes that prevent them from putting on weight, we may be able to target those genes to find new weight loss strategies and help people who do not have this advantage.”

̽��ֱ��research was funded by the European Research Council and Wellcome.

Reference
Riveros-McKay, F, Mistry, V et al. Genetic architecture of human thinness compared to severe obesity. PLOS Genetics; 24 Jan 2019; DOI:10.1371/journal.pgen.1007603

In the largest study of its kind to date, Cambridge researchers have looked at why some people manage to stay thin while others gain weight easily. They have found that the genetic dice are loaded in favour of thin people and against those at the obese end of the spectrum.

It’s easy to rush to judgement and criticise people for their weight, but the science shows that things are far more complex

Sadaf Farooqi

MabelAmber

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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

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