��Ī - MRC Metabolic Diseases Unit

Map of brain’s appetite centre could enable new treatments for obesity and diabetes

Anonymous — Wed, 05 Feb 2025 16:00:15 +0000

Published today in Nature, this comprehensive resource, called HYPOMAP, provides an unparalleled view of the brain’s appetite centre and promises to accelerate the development of treatments for obesity and type 2 diabetes.

The hypothalamus is often described as the brain’s ‘control centre’, orchestrating many of the body’s most vital processes. While much of our knowledge of the hypothalamus comes from animal studies, especially in mice, translating these findings to humans has long been a challenge. HYPOMAP bridges this gap by providing an atlas of the individual cells within the human hypothalamus. This resource not only charts over 450 unique cell types but also highlights key differences between the human and mouse hypothalamus — differences that have major implications for drug development.

“This is a game-changer for understanding the human hypothalamus,” said Professor Giles Yeo, senior author of the study from the Institute of Metabolic Science-Metabolic Research Laboratories (IMS-MRL) and MRC Metabolic Diseases Unit, ��Ī.

“HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity. It gives us a roadmap to develop more effective, human-specific therapies.”

Together with researchers at the Max Planck Institute for Metabolism Research in Cologne, Professor Yeo and colleagues used cutting-edge technologies to analyse over 400,000 cells from 18 human donors. HYPOMAP allows researchers to pinpoint specific cell types, understand their genetic profiles, and explore how they interact with neighbouring cells. This detailed cellular resolution offers invaluable insights into the circuits that regulate appetite and energy balance, as well as other functions such as sleep and stress responses.

Comparison with a mouse hypothalamus atlas revealed both similarities and critical differences. Notably, some neurons in the mouse hypothalamus have receptors for GLP-1 — targets of popular weight-loss drugs like semaglutide — that are absent in humans.

"While drugs like semaglutide have shown success in treating obesity, newer therapies target multiple receptors such as GLP-1R and GIPR. Understanding how these receptors function specifically in the human hypothalamus is now crucial for designing safer and more effective treatments," said Dr Georgina Dowsett from the Max Planck Institute for Metabolism Research and formerly at the IMS-MRL.

“Our map of the human hypothalamus is an essential tool for basic and translational research,” added Professor Jens C. Brüning, Director at the Max Planck Institute. “It allows us to pinpoint which mouse nerve cells are most comparable to human cells, enabling more targeted preclinical studies.”

HYPOMAP’s open-access nature ensures that it will be an invaluable resource for scientists worldwide. By offering insights into the hypothalamus’s role in conditions ranging from obesity to cachexia (a wasting condition associated with several illness, which involves extreme loss of muscle and fat), it provides a foundation for tackling some of the most pressing health challenges of our time.

Dr John Tadross, Consultant Pathologist at Addenbrooke’s Hospital and lead author from IMS-MRL, said: “This is just the beginning. The atlas itself is a milestone, but what could really make a difference for patients is understanding how the hypothalamus changes in people who are overweight or underweight. This could fundamentally shift our approach to metabolic health and enable more personalised therapies.”

With HYPOMAP, researchers have a new tool to unlock the secrets of the human brain’s metabolic control centre. By better understanding the human hypothalamus, science takes a significant step toward combating obesity, type 2 diabetes, and related conditions.

Reference
Tadross, JA, Steuernagel, L & Dowsett, GKC et al. A comprehensive spatio-cellular map of the human hypothalamus. Nature; 5 Feb 2025; DOI: 10.1038/s41586-024-08504-8

Adapted from a story by the Institute of Metabolic Science-Metabolic Research Laboratories and the Max Planck Institute for Metabolism Research

Scientists have created the most detailed map to date of the human hypothalamus, a crucial brain region that regulates body weight, appetite, sleep, and stress.

HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity

Giles Yeo

Sander Dalhuisen

Person holding burger bun with vegetables and meat

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Are weight loss jabs the solution to the obesity crisis?

jg533 — Wed, 30 Oct 2024 10:50:43 +0000

Almost two thirds of UK adults are overweight or obese. Are weight loss drugs the solution? ��Ī experts share their opinions.

Scientists identify rare gene variants that confer up to 6-fold increase in risk of obesity

Anonymous — Thu, 04 Apr 2024 12:36:17 +0000

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 ��Ī.

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 obesity

Obesity 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 ��Ī, 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 data

The 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 research

Professor 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

��Ī 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 seen

Giles Yeo

World Obesity Federation

Woman with obesity washing food

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Genetic mutation in a quarter of all Labradors hard-wires them for obesity

jg533 — Wed, 06 Mar 2024 19:06:36 +0000

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 ��Ī’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 Raffan

A quarter of Labradors are hard-wired for obesity

Jane Goodall

Labrador retriever dog

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Female scientists lead ��Ī success in Royal Society awards 2021

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

Bell Burnell is one of twelve former and current ��Ī 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 ��Ī'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”.

The 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 ��Ī 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 University’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 ��Ī 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.

The 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

The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©��Ī 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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�������������Ī - MRC Metabolic Diseases Unit

Map of brain’s appetite centre could enable new treatments for obesity and diabetes

Are weight loss jabs the solution to the obesity crisis?

Scientists identify rare gene variants that confer up to 6-fold increase in risk of obesity

The brain’s role in obesity

The use of global data

Next steps for research

Genetic mutation in a quarter of all Labradors hard-wires them for obesity

A quarter of Labradors are hard-wired for obesity

Female scientists lead �������������Ī success in Royal Society awards 2021

��Ī - MRC Metabolic Diseases Unit

Female scientists lead ��Ī success in Royal Society awards 2021