̽��ֱ�� of Cambridge - brown 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

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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

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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

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