̽��ֱ�� of Cambridge - fat

Study in mice suggests drug to turn fat ‘brown’ could help fight obesity

cjb250 — Mon, 26 Nov 2018 13:51:16 +0000

While their study was carried out in mice, they hope that this finding will translate into humans and provide a potential new drug to help fight obesity.

Obesity is a condition in which individuals accumulate more and more fat until their fat stops functioning. This can lead to diseases such as diabetes. However, not all fat tissue is bad: the fat that accumulates in obesity is known as ‘white fat’, but a second form of fat known as ‘brown fat’ could be used to treat obesity.

Both brown and white fat are made up of fat cells known as adipocytes, but in brown fat, these cells are rich in mitochondria – the ‘batteries’ that power our bodies – which give the tissue its brown colour. Brown fat also contains more blood vessels to allow the body to provide it with oxygen and nutrients.

While white fat stories energy, brown fat burns it in a process known as ‘thermogenesis’. When fully activated, just 100g of brown fat can burn 3,400 calories a day – significantly higher than most people’s daily food intake and more than enough to fight obesity.

We all have some brown fat – or brown adipose tissue, as it is also known – in our bodies, but it is found most abundantly in newborns and in hibernating animals (where the heat produced by brown fat enables them to survive even in freezing temperatures). As we age, the amount of brown fat in our bodies decreases.

Just having more brown fat alone is not enough - the tissue also needs to be activated. Currently, the only ways to activate brown fat are to put people in the cold to mimic hibernation, which is both impractical and unpleasant, or to treat them with drugs known as adrenergic agonists, but these can cause heart attacks. It is also necessary to increase the number of blood vessels in the tissue to carry nutrients to the fat cells and the number of nerve cells to allow the brain to ‘switch on’ the tissue.

In 2012, a team led by Professor Toni Vidal-Puig from the Wellcome Trust-MRC Institute of Metabolic Science, ̽��ֱ�� of Cambridge, identified a molecule known as BMP8b that regulates the activation of brown fat in both the brain and the body’s tissues. They showed that deleting the gene in mice that produces this protein stopped brown fat from functioning.

Now, in a study published today in the journal Nature Communications, an international team of researchers led by Drs Vanessa Pellegrinelli and Vivian Peirce, and Professor Vidal-Puig has shown that increasing how much BMP8b mice can produce increases the function of their brown fat. This implies that BMP8b, which is found in the blood, could potentially be used as a drug to increase the amount of brown fat amount in humans as well as making it more active. Further research will be necessary to demonstrate if this is the case.

To carry out their research, the team used mice that had been bred to produce higher levels of the protein in adipose tissue. As anticipated, they found that increasing BMP8b levels changed some of the white fat into brown fat, a process known as beiging and thus increased the amount of energy burnt by the tissue.

They showed that higher levels of BMP8b make the tissue more sensitive to adrenergic signals from nerves – the same pathway target by adrenergic agonist drugs. This may allow lower doses of these drugs to be used to activate brown fat in people, hence reducing their risk of heart attack.

Unexpectedly, but importantly, the team also found that the molecule increased the amount of blood vessels and nerves in brown fat.

“There have been a lot of studies that have found molecules that promote brown fat development, but simply increasing the amount of brown fat will not work to treat disease – it has to be able to get enough nutrients and be turned on,” says Professor Vidal-Puig, lead author of the study.

Co-author Dr Sam Virtue, also from the Institute of Metabolic Science, adds: “It’s like taking a one litre engine out of a car and sticking in a two litre engine in its place. In theory the car can go quicker, but if you only have a tiny fuel pipe to the engine and don’t connect the accelerator pedal it won’t do much good. BMP8b increases the engine size, and fits a new fuel line and connects up the accelerator!”

̽��ֱ��research was funded by the British Heart Foundation, Medical Research Council, European Research Council, WHRI-Academy and Wellcome.

Read more on ̽��ֱ��Conversation website: Could this be a solution for the obesity crisis?

Reference
Pellegrinelli, V et al. Adipocyte-1 secreted BMP8b mediates adrenergic-induced remodeling of the neurovascular network in adipose tissue. Nature Communications; 26 Nov 2018; DOI: 10.1038/s41467-018-07453-x

Our bodies contain two types of fat: white fat and brown fat. While white fat stores calories, brown fat burns energy and could help us lose weight. Now, scientists at the ̽��ֱ�� of Cambridge have found a way of making the white fat ‘browner’ and increasing the efficiency of brown fat.

There have been a lot of studies that have found molecules that promote brown fat development, but simply increasing the amount of brown fat will not work to treat disease

Toni Vidal-Puig

TeroVesalainen

Weight loss nutrition

̽��ֱ��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.

Yes

Licence type:

Public Domain

Stored fat fights against the body’s attempts to lose weight

cjb250 — Tue, 24 Nov 2015 09:22:25 +0000

Most of the fat cells in the body act to store excess energy and release it when needed but some types of fat cells, known as brown adipocytes, function primarily for a process known as thermogenesis, which generates heat to keep us warm. However, an international team of researchers from the Wellcome Trust-Medical Research Council Institute of Metabolic Sciences at the ̽��ֱ�� of Cambridge, UK, and Toho ̽��ֱ��, Japan, have shown that a protein found in the body, known as sLR11, acts to suppress this process.

Researchers investigated why mice that lacked the gene for the production of this protein were far more resistant to weight gain. All mice – and, in fact, humans – increase their metabolic rate slightly when switched from a lower calorie diet to a higher calorie diet, but mice lacking the gene responded with a much greater increase, meaning that they were able to burn calories faster.

Further examinations revealed that in these mice, genes normally associated with brown adipose tissue were more active in white adipose tissue (which normally stores fat for energy release). In line with this observation, the mice themselves were indeed more thermogenic and had increased energy expenditure, particularly following high fat diet feeding.

̽��ֱ��researchers were able to show that sLR11 binds to specific receptors on fat cells – in the same way that a key fits into a lock – to inhibit their ability to activate thermogenesis. In effect, sLR11 acts as a signal to increase the efficiency of fat to store energy and prevents excessive energy loss through unrestricted thermogenesis.

When the researchers examined levels of sLR11 in humans, they found that levels of the protein circulating in the blood correlated with total fat mass – in other words, the greater the levels of the protein, the higher the total fat mass. In addition, when obese patients underwent bariatric surgery, their degree of postoperative weight loss was directly proportional to the reduction in their sLR11 levels, suggesting that sLR11 is produced by fat cells.

In their paper the authors suggest that sLR11 helps fat cells resist burning too much fat during ‘spikes’ in other metabolic signals following large meals or short term drops in temperature. This in turn makes adipose tissue more effective at storing energy over long periods of time.

There is growing interest in targeting thermogenesis with drugs in order to treat obesity, diabetes and other associated conditions such as heart disease. This is because it offers a mechanism for disposing of excess fat in a relatively safe manner. A number of molecules have already been identified that can increase thermogenesis and/or the number of fat cells capable of thermogenesis. However to date there have been very few molecules identified that can decrease thermogenesis.

These findings shed light on one of the mechanisms that the body employs to hold onto stored energy, where sLR11 levels increase in line with the amount of stored fat and act to prevent it being ‘wasted’ for thermogenesis.

Dr Andrew Whittle, joint first author, said: “Our discovery may help explain why overweight individuals find it incredibly hard to lose weight. Their stored fat is actively fighting against their efforts to burn it off at the molecular level."

Professor Toni Vidal-Puig, who led the team, added: “We have found an important mechanism that could be targeted not just to help increase people’s ability to burn fat, but also help people with conditions where saving energy is important such as anorexia nervosa.”

Jeremy Pearson, Associate Medical Director at the British Heart Foundation (BHF), which helped fund the research, said: “This research could stimulate the development of new drugs that either help reduce obesity, by blocking the action of this protein, or control weight loss by mimicking its action. Based on this promising discovery, we look forward to the Cambridge team’s future findings.

“But an effective medicine to treat obesity, which safely manages weight loss is still some way off. In the meantime people can find advice on healthy ways to lose weight and boost their heart healthy on the BHF website.”

̽��ֱ��study was part-funded in part by the British Heart Foundation, the Wellcome Trust, the Medical Research Council and the Biotechnology and Biological Sciences Research Council.

Reference
Whittle, AJ, Jiang, M, et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nature Communications; 20 November 2015

̽��ֱ��fatter we are, the more our body appears to produce a protein that inhibits our ability to burn fat, suggests new research published in the journal Nature Communications. ̽��ֱ��findings may have implications for the treatment of obesity and other metabolic diseases.

Our discovery may help explain why overweight individuals find it incredibly hard to lose weight. Their stored fat is actively fighting against their efforts to burn it off at the molecular level

Andrew Whittle

Alan Cleaver

Lose weight now

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

Yes

Licence type:

Attribution

Scientists identify protein that stimulates brown fat to burn calories

gm349 — Fri, 11 May 2012 09:30:22 +0000

Scientists have identified a protein which regulates the activation of brown fat in both the brain and the body’s tissues. Their research, which was conducted in mice, was published today, Friday 11 May, in the journal Cell.

Unlike white fat, which functions primarily to store up fat, brown fat (also known as brown adipose tissue) burns fats to generate heat in a process known as thermogenesis. ̽��ֱ��research, led by scientists at the ̽��ֱ�� of Cambridge Metabolic Research Laboratories at the Institute of Metabolic Science, discovered that the protein BMP8B acts on a specific metabolic system (which operates in the brain and the tissues) to regulate brown fat, making it a potential therapeutic target.

̽��ֱ��scientists believe that activating brown fat could help to support current weight loss programmes, which individuals often struggle to maintain.

Dr Andrew Whittle, one of the authors of the paper from the Institute of Metabolic Science, said: “Other proteins made by the body can enhance heat production in brown fat, such as thyroid hormone but often these proteins have important effects in other organs too. Therefore they are not good targets for developing new weight loss treatments. However, BMP8B seems to be very specific for regulating the heat producing activity of brown fat, making it a more ideal mechanism for new therapies.”

̽��ֱ��experiments showed that when mice lacked the protein BMP8B they found it more difficult to maintain their normal body temperature. They also became much more obese than normal mice, particularly when fed a high-fat diet. Additionally, when the researchers treated brown fat cells with BMP8B they responded more strongly to activation by the nervous system. Furthermore, when BMP8B was administered to specific parts of the brain it increased the amount of nervous activation of brown adipose tissue. ̽��ֱ��result was that these BMP8B-treated brown fat cells burned more fat and mice given BMP8B in the brain lost weight.

Professor Toni Vidal-Puig, lead author of the study from the Institute of Metabolic Science and a member of the MRC Centre for Obesity and Related Metabolic Diseases, said: “A major feature of current weight-loss strategies is that people lose a lot of weight early on, but then reach a plateau despite continuing to follow the same diet regime. This is because the human body is incredibly good at sensing a reduction in food consumption and slows the metabolic rate to compensate. A strategy to increase brown fat activity could potentially be used in conjunction with current weight loss strategies to help prevent the typical decrease in a person’s metabolic rate.

“One could be sceptical that techniques to increase metabolic rate might just be compensated by the body trying to make you want to eat more, to fuel this increased metabolism. But our findings showed that treating mice with Bmp8b did not have this effect, it simply made them lose weight by burning more fat in their brown adipose tissue.

“There are obvious differences between mice and humans, and from a therapeutic perspective this work is preliminary. Validation will be necessary to see if manipulating BMP8B would be safe and effective in humans.”

̽��ֱ��research was funded by the Medical Research Council (MRC), the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council (BBSRC).

Protein highlights ‘ideal mechanism’ for development of new therapies to fight obesity.

Other proteins made by the body can enhance heat production in brown fat, such as thyroid hormone but often these proteins have important effects in other organs too. Therefore they are not good targets for developing new weight loss treatments. However, BMP8B seems to be very specific for regulating the heat producing activity of brown fat, making it a more ideal mechanism for new therapies.

Dr Andrew Whittle, one of the authors of the paper from the Institute of Metabolic Science

Dr. Miguel Lopez, from the ̽��ֱ�� of Santiago de Compostela in Spain

Brown fat

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes

You are what you eat: Investigating nutrition and cancer

bjb42 — Sun, 01 Apr 2007 15:59:45 +0000

Genetic factors are known to be important in determining propensity to develop cancer but there is strong evidence that the worldwide variation in cancer incidence is mainly due to our lifestyle and environmental factors such as the food we eat. A deeper understanding of this relationship is being afforded by the largest study of diet and health ever undertaken, involving over half a million people in ten countries. Researchers at the Medical Research Council (MRC) Centre for Nutritional Epidemiology in Cancer Prevention and Survival (CNC), in the ̽��ֱ�� of Cambridge's Department of Public Health and Primary Care, are building on these findings under the directorship of Professor Sheila Bingham.

Cancer incidence worldwide

Geographically, when age is taken into account using world-standardised rates, there are up to 100-fold variations in the incidence of particular cancers in different regions of the globe. ̽��ֱ��incidence of colon cancer, as an example, varies 20-fold between the highest (USA) and the lowest (India) incidence. Even across Europe there are marked differences in cancer rates, with incidence rates in Greece being about half those of Germany.

Worldwide, about 10 million people are diagnosed annually with cancer and more than 6 million people die of the disease.
̽��ֱ��most common cancers worldwide (excluding non-melanoma skin cancer) are lung (12.3%), breast (10.4%) and colorectal (9.4%).
In developed countries, the main cancers are of the lung, large bowel, breast, prostate and bladder.
In developing countries, the main cancers are of the cervix, liver, stomach and mouth.
In sub-Saharan Africa, cancer of the large bowel, breast and lung are virtually absent.
'Hot spots' exist for cancers at certain sites: oesophageal cancer in parts of Iran and nasopharyngeal cancer in parts of South-East Asia.

Studies of migrants moving from a low- to a high-risk area have shown that the migrants acquire the cancer pattern of the host country within a relatively short period of time – as swiftly as within a single generation.

Over the past 40 years in Japan, colon cancer has increased enormously and the incidence of bowel cancer in Japanese men is now twice that of men in the UK, despite being extremely rare only 40 years ago. It's clear that changes in the gene pool cannot account for such rapid changes in Japan. A more likely explanation is that the Japanese population have a susceptibility to this cancer that has been unmasked by their rapidly changing diet.

What is the link with nutrition?

There are very strong links between the amount of certain dietary items consumed, together with the dietary practices used in various populations, and the incidence rates for common cancers. On the basis of such comparisons, it has been estimated that 32–35% of cancers could be attributed to nutrition, although the contribution of diet to specific types of cancer varies from as low as 10% for lung cancer to as high as 80% for cancer of the large bowel.

Even so, there is a complex interaction between genetic factors, individual metabolic characteristics and diet. By themselves, common variants in genes that regulate the metabolism of food constituents are unlikely to confer large cancer risks, but they could do so in individuals who smoke, drink or have a particular dietary pattern. Links between diet and cancer can therefore only be found by measuring not only gene variants but also dietary exposure in populations. To do this, you need to study as large a number of people as possible – which can only be made possible through significant collaboration.

An EPIC study

̽��ֱ��European Prospective Investigation into Cancer and Nutrition (EPIC) is the largest study ever to investigate specifically the relationship between diet, metabolic and genetic factors, and certain types of cancer. EPIC includes 519,978 volunteers (366,521 women and 153,457 men) who have been recruited to 23 regional or national centres in 10 countries across Europe. Blood was collected from approximately 400,000 subjects at enrolment and the different fractions were stored under special conditions as straws in liquid nitrogen pending further analysis. By studying people in different countries with differing diets, it is anticipated that specific information about the effect of diet on long-term health will be discovered.

EPIC is an enormous resource and, since its inception in 1992, numerous papers have been published by the study collaborators, at a fast increasing rate as more and more cancers develop within the cohort; 75 papers were published in 2006. Of these, two key published findings have been that an approximate doubling of dietary fibre intake is associated with a 40% reduction in colorectal cancer incidence and that red and processed (but not white) meat is associated with an increase in risk of colorectal cancer, whereas fish is protective. A further finding was that eating vegetables and fruits did not appear to protect against breast cancer.

Collaborating centres in the UK

In the UK, there are two EPIC collaborating centres, one based in Oxford and the other at the ̽��ֱ�� of Cambridge's Institute of Public Health (EPIC Norfolk; www.epic-norfolk.org.uk), which has recruited 25,000 men and women from Norfolk. EPIC Norfolk has taken an important lead in the biostatistical handling of data, in collaboration with the MRC Biostatistics Unit, and in developing nutritional methods for measuring diet on such large population samples. One of the important findings of EPIC Norfolk has been the demonstration that fat could be an important risk factor in breast cancer, a finding that has been replicated in a subsequent study in the USA.

̽��ֱ��search continues

CNC, a new MRC Centre awarded to the Institute of Public Health, builds on the success of the Europe-wide EPIC collaboration, and is the focus of a unique consortium of cohorts of approximately 100,000 participants from several UK universities investigating how diet can prevent cancer. Cancer survival in relation to diet is being assessed in the SEARCH (Studies of Epidemiology And Risk Factors in Cancer Heredity) study of cancer genetics in breast, bowel, prostate and ovarian cancer survival and prognosis. CNC also fosters epidemiological biomarker studies into the mechanisms whereby nutritional factors are involved in DNA alterations leading to mutation and ultimately tumour development.

Cancer is still one of the most common causes of death in western countries, including the UK. As a significant number of cancers may be the result of diet, studies at EPIC Norfolk and the CNC will provide a crucial focus for nutritional epidemiology and our future understanding of the link between nutrition and cancer.

'32–35% of cancers could be attributed to nutrition.... from as low as 10% for lung cancer to as high as 80% for cancer of the large bowel.'

For more information, please contact the author Professor Sheila Bingham (sheila.bingham@srl.cam.ac.uk) at the CNC (www.srl.cam.ac.uk/cnc).

We all know that a good diet is key to good health, but it's now clear that certain foods we eat can unmask underlying susceptibilities to cancer.

ollesvensson from Flickr

apples

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes

Why are we so fat?

bjb42 — Sun, 01 Apr 2007 15:56:04 +0000

One of the most important public health issues of today is obesity. Why do people gain weight? Is it simply about eating too much food and taking too little exercise? Why do some people gain a lot of weight while others stay thin yet share the same environment? Dr Sadaf Farooqi, working with Professor Stephen O’Rahilly in the ̽��ֱ�� Department of Clinical Biochemistry, is helping to answer some of these questions.

Obesity is defined as an excess of body fat that’s large enough to result in adverse consequences for health – the most common being high blood pressure, type 2 diabetes, coronary heart disease and certain cancers. Although calculating exactly how much body fat a person has requires sophisticated techniques, we usually use body mass index or BMI (weight in kilograms/height in metres squared) as a measure of heaviness as it correlates reasonably well with body fat content. Obesity is defined as a BMI greater than 30 kg/m2.

In the UK, current estimates of obesity indicate that 23% of men and 24% of women are obese. ̽��ֱ��World Health Organization has warned that obesity has reached epidemic proportions globally, with more than 1 billion adults overweight and is now ‘a major contributor to the global burden of chronic disease and disability.’

Why is obesity on the increase? We live in an age of increased availability of palatable, energy-dense foods and yet we have a reduced requirement for physical exertion during our working and domestic life. All this contributes to a state of positive energy balance, which over a period of time is enough to shift the mean BMI of a population. Obesity can run in families, which might point to the sharing of a common lifestyle but might also point to a genetic link. In fact, the heritability of body weight and fat mass is very high, at 40–70%, based on studies in twins and adopted children. How can we find the genes that control body weight?

Finding the ‘fat’ genes

Dr Sadaf Farooqi and her colleagues have made progress in uncovering the molecular basis of obesity by focusing on patients who have severe forms of the condition. Many of the patients they study are extremely obese from a young age, with excessive food consumption beyond what is needed for their basic energy requirements – a type of behaviour known as hyperphagia.

̽��ֱ��story began a decade ago, with the finding of two severely obese Pakistani cousins with uncontrollable appetites. Dr Farooqi’s studies revealed that the children had undetectable levels of a protein called leptin in their serum and further analysis showed that they carried homozygous mutations in the leptin gene. ̽��ֱ��story unfolded as other families were identified with mutations either in this gene or in the receptor that binds leptin. When the patients were given daily injections of synthetic leptin in a clinical trial, dramatic beneficial effects were seen: within two weeks, the uncontrollable food-seeking behaviour had normalised, and their body weight and fat mass slowly reduced to normal levels.

To date, the team have identified seven genes that, when defective, result in severe obesity in children. All are part of the leptin–melanocortin system and all are involved in the control of appetite. One of these, the gene encoding the melanocortin receptor MC4R, is turning out to be the commonest single gene disorder causing obesity, with mutations found in 0.1% of the general population, a prevalence higher than for cystic fibrosis. Dr Farooqi and colleagues have studied 2000 severely obese individuals as part of the Genetics of Obesity Study (GOOS), discovering that as many as 5–6% of participants have pathogenic mutations in this gene.

Unfortunately no therapy yet exists for patients with MC4R deficiency, although much has been learnt about how mutations change the structure and function of the receptor and also about the range of associated clinical problems. By studying over 150 patients with MC4R deficiency, Dr Farooqi and colleagues have shown that when MC4R doesn’t work at all, this leads to a more severe form of the disease. This is even reflected in the amount of food eaten. People with a defective MC4R eat much more when given free access to food at a test meal, compared with people in whom the MC4R gene is working at 50%. This shows that MC4R acts as a brake on food intake and suggests that targeting MC4R may be useful as a treatment for obesity.

It’s all in the mind

Eating behaviour results from the innate drive to eat. Although this is genetically determined, it’s also influenced by the hedonic or rewarding properties of food – which can override the biological cues that govern hunger and fullness and result in hyperphagia. Eating behaviour is unique in that some of the key molecular determinants of the drive to eat are being identified. ̽��ֱ��genetic disorders involving the leptin–melanocortin pathway studied by Dr Farooqi affect a signalling pathway that starts with leptin released from fat calls and leads back to the hypothalamus in the brain. Studies in patients with defects in the proteins involved in this pathway should provide the opportunity to find out how the biological pathways link with the reward pathways to influence eating behaviour.

̽��ֱ��drive to eat: what’s next?

Progress towards defining the molecular basis of obesity in some patients has helped not only to suggest treatment strategies but also to highlight that, for many people, theirs is a medical condition. ̽��ֱ��seven disorders found so far are likely to be joined by the identification of many other gene defects that lead to severe obesity. These findings provide insights into the pathways that regulate body weight, which in turn is a starting point for developing treatments that may well be applicable to more common forms of obesity.

Although several groups in the UK have recently identified the first gene, FTO, that increases the risk of common obesity in the population, uncovering the basis of common forms of obesity or more subtle genetic defects will undoubtedly prove harder, and new approaches to assessing obesity are an attractive option. One new avenue of research has been to look directly at what is happening in the brain in response to food. Considerable experience exists in Cambridge in the use of imaging techniques to study brain function and to assess human behaviour in conjunction with biological correlates. Recent advances in these technologies are helping scientists to understand the brain pathways involved in eating behaviour. Dr Farooqi is working with Dr Paul Fletcher in the Department of Psychiatry and Drs Andrew Lawrence and Andy Calder at the Medical Research Council (MRC) Cognition and Brain Sciences Unit on one such technique. They are using functional magnetic resonance imaging (fMRI) to measure patterns of brain activity when people see images of food compared with everyday items such as toys, trees and trains. It is hoped that these studies will shed light on the areas of the brain involved in food reward and explain why some people have uncontrollable urges to eat.

For more information, please contact the author Dr Sadaf Farooqi (isf20@cam.ac.uk) at the Department of Clinical Biochemistry. This research is supported by the Wellcome Trust and the MRC, and the functional imaging studies are supported by an endowment from the WOCO Foundation.

For some people, the urge to eat is uncontrollable. Cambridge scientists have taken us a step closer to understanding the causes of obesity by studying a group of patients for whom overeating is an everyday event.

Dr Sadaf Farooqi

Functional MRI scan

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes