Brown Fat.

Caloric Restriction Turns White Fat Brown

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Limiting food intake leads to the conversion of white fat cells into more metabolically active brown fat cells through an immune response, a mouse study shows.

Image No 1Infrared imaging of a calorie-restricted mouse.In mice, severely restricting caloric intake promotes the transformation of white fat into brown fat, which contains cells that burn energy faster, according to a study published today (August 25) in Cell Metabolism. The innate immune system, researchers from the University of Geneva, Switzerland, and their colleagues reported, mediates this fat cell-transforming effect.

“The paper nicely characterizes this phenomenon,” said Ajay Chawla of the University of California, San Francisco, who was not involved in the work. “And it mechanistically seems to identify a pathway that we had identified.”

Whereas the present study found diet induced a “beiging” phenotype—in which white adipose tissue starts to express more energy-expending brown fat cells—Chawla and colleagues had previously shown that cold temperatures, another extreme condition, can produce the same effect.

Scientists are keenly interested in learning how to generate brown fat cells. A treatment could help stem the obesity epidemic. “Finding some mechanism to activate this response—ideally, in obese or diabetic individuals—is really attractive,” said postdoctoral researcher Salvatore Fabbiano of the University of Geneva who led the present study.

Several conditions are already known to make white fat tissue more brown—cold temperatures, microbe loss, and gastric bypass surgery among them. Fabbiano and colleagues hypothesized that the common feature of all these experiences was an increased expenditure of calories compared to intake.

Cutting calories by extreme amounts—say, 40 percent—has been linked in animal models to a longer lifespan and improved health outcomes, such as better liver and pancreas function. Fabbiano’s team surmised converting fat might be part of the way caloric restriction confers its benefits and that—as Chawla and others have proposed—an innate immune response might link the two.

To test their hypothesis, the scientists monitored how fat changed in calorie-restricted lean mice and obese (leptin-knockout) mice, examining the immune system’s role in changes to fat tissue composition.

After keeping a group of lean male mice on a calorie-restricted diet for four weeks, using PET-CT imaging, the team compared the animals’ subcutaneous and visceral fat stores against those of lean mice with free access to food. The researchers found both fat pads in the calorie-restricted mice contained more brown fat cells. Instead of a single large, lipid globule in their cell bodies, brown fat cells have multiple smaller droplets. These cells are also denser, and contain more mitochondria (all traits that make them appear darker, hence the “brown” moniker).

To confirm that the beiging fat was changing the animals’ metabolism, the team tested the mice in a cold environment (43 °F). Then, with infrared imaging, the researchers monitored how the mice regulated heat for 12 hours.

The calorie-restricted mice appeared to be burning more energy than their freely eating counterparts. Imaging from below revealed that, in the calorie-restricted mice, the beiging fat was also producing more heat than the fat found in control mice. When the team tested calorie restriction on leptin-knockout mice, their fat also beiged and the animals remained warmer in the cold.

Immune signaling within the calorie-restricted mice also changed, the team reported, with higher levels of interleukin-(IL) 4 and IL13, which are characteristic of the type 2 immune response. To test whether this reaction was responsible for converting the fat, the researchers removed the immune system entirely: they used radiation to kill stem cells in the bone marrow of mice, and transplanted bone marrow with either fully functional, wild-type immune system cells or defective ones (knocked out in the shared receptor subunit for IL4 and IL13).

Only mice with intact immune responses experienced beiging. Mice unable to mount a type 2 response still lost weight on a calorie-restricted diet, but in an atypical way. “The thing that was really amazing [was that] these mice don’t lose any weight in their subcutaneous fat, though their visceral fat decreases,” Fabbiano told The Scientist. “It means that to reduce the amount of fat in certain regions of the body, you need to have browning of that fat.”

Deborah Clegg, an internal medicine researcher at Cedars-Sinai Medical Center in Los Angeles, California, who has observed beiging fat in mice that have undergone gastric bypass surgery, said she was somewhat surprised by the model systems the team chose. “I think this is first time I’ve ever seen someone taking a lean mouse and making it leaner,” she told The Scientist. That the obese mice were genetic knockouts might also have influenced their responses, she added. “We do this so we can ask the question, how can we help the [hundreds of] millions of people who are obese lose weight? And this [mouse study] is not answering that question.”

Fabbiano maintained that the lean mice were a better choice for this work. “We needed a healthy model, immunocompetent and without any confounders to study the general response to caloric restriction first,” he said. “Of course, therapeutically it’s more interesting to use an obese mouse. But [they] may also conceal some general mechanism . . . impaired in them because of their obesity.”

Chawla said he thought the study was rigorous, but noted that Fabbiano and colleagues may have missed a second mediating mechanism: the effect of temperature. Animals become warmer when they eat, so mice on a calorie-restricted diet might feel cooler, he explained.

Indeed, the team observed that calorie-restricted mice had lower body temperatures, overall. So it could be temperature causing the animals’ fat to brown, Chawla said. “Clearly, on my part, it’s speculation,” he said. “But they haven’t formally excluded it.”

Is Serotonin The Obesity Hormone? Better Brown-Fat Burning Linked To Hormone Blockage

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serotonin
Through a series of blocked signals in the body, peripheral serotonin may be responsible for preventing normal calorie burns. 

Whenever you feel really happy (like too happy) or even just healthy and content, your brain is releasing the neurotransmitter serotonin. But while this form of serotonin is the most popular, it only makes up five percent of the body’s total supply. The other 95 percent, a new study finds, is busy regulating how well your body burns calories through brown fat.

Stored around your collarbone are deposits of brown adipose tissue (fat) that help burn energy. Brown fat is scarcer in obese people, and for years researchers have wondered about the mechanism behind the reduction. Recently, a team from McMaster University has found the presence of so-called “peripheral serotonin” makes brown fat less active due to enzyme blockage.

“Too much of this serotonin acts like the parking brake on your brown fat,” said Gregory Steinberg, a professor of medicine and the paper’s co-author, in a statement. “You can step on the gas of the brown fat, but it doesn’t go anywhere.”

Brown fat was once believed to be a vestige of evolution — similar to the appendix — that helped keep warm other mammals that do not shiver. But several years of research have begun confirming brown fat’s advantages, principally a role in speeding up the body’s metabolism. As we age, however, the stores of beneficial brown fat, which burn the “bad” white fat that accumulates on our bellies and thighs, begin to diminish. And depending on our diets, they could stop working entirely.

As of late, these concerns have multiplied for researchers involved with obesity. In the U.S. alone, more than one-third of adults, or 79 million people, are obese. The annual cost for treating the conditions associated with obesity, including heart disease, stroke, type 2 diabetes, and some types of cancer, totals $147 billion in 2008 dollars, the latest year for which data are available. Individually, medical costs for the obese are $1,429 higher than for those of a normal weight.

Given these concerns, Steinberg and his colleagues wanted to understand how exactly brown fat’s energy burning comes to a halt. Previous work in their lab had shown the enzyme tryptophan hydroxylase, or Tph1, was overrepresented in lighter mice. Using Tph1 in their follow-up studies, they fed a second group of mice a high-fat diet that was designed to mimic a traditional Western diet. Those with the enzyme mutation produced less serotonin than the normal mice, in turn keeping them healthier.

“What we discovered is that if we remove this enzyme either genetically or if we inhibit its activity using a chemical, a drug, the mice have low levels of serotonin and they didn’t develop diabetes, obesity, or fatty liver disease,” Steinberg said.

This finding holds great promise for future weight loss drugs, the team argued. Most of the current options rely on suppressing people’s appetites to achieve a desired amount of weight loss. They also produce severe side effects, including heart complications and risks for depression. Inhibiting the enzyme that triggers energy storage tackles the problem from the other direction, helping to increase the amount of energy people burn normally.

“Moving forward, we think it’s a much safer method to work with increasing energy expenditure instead of decreasing the appetite, which involves more risks,” Steinberg said. He and his team are currently at work on a pharmacological approach that could stand in as a substitute for traditional weight loss pills.

Source: Crane J, Palanivel R, Mottillo E, et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nature Medicine. 2014.

Researchers Find Healthy Brown Fat Regulates Your Blood Sugar.

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Story at-a-glance

  • People with higher levels of brown fat have a faster metabolism, better blood sugar control, and higher insulin sensitivity after being exposed to cold temperatures
  • Brown fat generates heat by helping you burn calories, and because of this it’s being explored as a tool for weight loss, healthy metabolism, and much more
  • The more brown fat, or the more activated brown fat, you have the better, as there are direct correlations between the activation of brown fat and metabolic measures of good health
  • Scientists have repeatedly found that they can activate brown fat in adults by exposing them to cold temperatures; exercise may also help to increase your brown fat
  • Consuming melatonin stimulates the appearance of “beige” fat, another type of heat-generating fat that is similar to brown fat

Healthy Diet

Your body fat percentage is a useful gauge to dictate metabolic health or dysfunction, with lower levels (to a point) generally associated with better health outcomes. This is referring to white fat (the kind that accumulates where you least want it).

Brown fat is most prominent in newborn animals (including human babies), where its main function is to generate body heat, helping newborns to regulate their temperatures.

Here’s where it gets interesting… brown fat generates heat by burning calories, and because of this, it’s being explored as a tool for weight loss, healthy metabolism, and much, much more.

Plus, newer research revealed that not only do adults have some brown fat, but it also appears to have physiological roles beyond heat generation. These roles are just now beginning to be explored…

Brown Fat May Help Regulate Blood Sugar

One of the latest studies on brown fat showed that people with higher levels have a faster metabolic rate, better blood sugar control, and higher insulin sensitivity.1 In the study, seven of the 12 participants had “high brown fat quotients” while five had low levels.

This in and of itself didn’t lead to the benefits, however, as brown fat must be activated to offer results. One known way to do this is via exposure to cold temperatures. The men in the study were exposed to mildly cold temperatures for up to eight hours to activate brown fat.

Those with higher brown fat levels then showed increases in resting metabolism, insulin sensitivity, and glucose processing, with the researchers stating brown fat may function as an anti-diabetic tissue in humans. One of the study’s authors noted:2

“We showed that exposure to mild cold raised whole body energy expenditure, increased glucose removal from the circulation and improved insulin sensitivity in men who have significant amounts of brown adipose tissue depots.”

Failing Brown Fat May Cause Middle-Age Spread

As you get older, the thermogenic activity of brown fat is reduced, similar to what happened with mice in one revealing study published in the FASEB Journal.3Mice that had a gene known as platelet-activating factor receptors (PAFR) knocked out became far more obese with age than the normal control mice.

The PAFR gene is responsible for inflammation and fat transfer, and it’s thought that deactivating it impaired the function of brown fat, causing the mice to become quickly obese. This “failing” of brown fat is likely a key reason why there’s a tendency to gain weight with age. The FASEB Journal’s editor-in-chief noted:4

“A common complaint is that older people have to work twice as hard with their diets and exercise to get half of the results of younger people. Now we have a much better idea why this is the case: Our brown fat stops working as we age.”

There’s also a type of fat known as beige fat that is sometimes used interchangeably with brown fat. While it appears the two are similar, they also are likely to have distinct beneficial functions in your body, and these are only in the beginning stages of discovery. As reported in the journal Nature Medicine:5

“A clear question is whether brown and beige fat cells have different functions. The answer to this question is still unknown and has not been well studied. However, a recent study has suggested that fully stimulated brown and beige adipocytes… have similar thermogenic capacities.

… Aside from thermogenesis, it is highly probable that beige and brown adipocytes have other cell type–specific actions that have yet to be studied. For example, beige adipocytes may secrete certain factors that affect WAT [white adipose tissue, or white fat] function, systemic metabolism or both.”

Characteristics of People with More Brown Fat

It’s now thought that virtually everyone has small amounts of brown fat in their body, but certain groups of people tend to have more brown fat than others. The more brown fat, or the more activated brown fat, the better, as there are direct correlations between the activation of brown fat and metabolic measures of good health. For example:

  • Slender people have more brown fat than obese people do
  • Younger people have more brown fat than elderly people
  • People with normal blood sugar levels have more brown fat than those with high blood sugar

Women also tend to have more brown fat than men, and people taking beta-blocker drugs to treat high blood pressure have less active brown fat. The latter is likely because catecholamines, which are hormones released as part of your body’s natural “fight or flight” response, are known to activate brown fat, but beta-blockers block catecholamines, thereby suppressing the activation of beneficial brown fat.6

3 Natural Methods to Raise Your Levels of Brown (and Beige) Fat

Given all the emerging benefits of brown fat, you’re probably wondering how you can get more of it.

Researchers are excited about the potential for a medical intervention that can help people develop more brown fat, but I would be cautious of any solution in a pill form. Instead, I’d suggest trying out some of the non-invasive methods that have been found to promote brown fat production and its activation.

1. Exposure to Cold

Scientists have repeatedly found that they can activate brown fat in adults by exposing them to cold temperatures. In one study, men burned more calories when cooled and lost white fat, the kind that causes obesity.7 According to the study’s authors:

“…metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity…”

Swedish research published in 2009 also found that cold temperatures increased the activity in the subjects’ brown fat regions.8 Cold-induced glucose uptake was increased by a factor of 15!

Based on animal models, researchers estimated that just 50 grams of brown fat (which is less than what most study volunteers have been found to have) could burn about 20 percent of your daily caloric intake—and more if “encouraged.” Tim Ferriss, author of The Four-Hour Work Week, gave the following suggestions for putting this into practice (they range from easy to hard core):

  • Place an ice pack on your upper back and upper chest for 30 minutes per day (you can do this while relaxing in front of the TV for example)
  • Drinking about 500 ml of ice water each morning
  • Cold showers
  • Immersing yourself in ice water up to your waist for 10 minutes, three times per week. (Simply fill your tub with cold water and ice cubes)

2. Exercise

In one mouse study, the animals converted white fat into brown fat simply by exercising. The study, published in the journalDisease Models and Mechanism,found that during exercise the animals’ muscles released an enzyme called irisin, which triggered the conversion of white fat cells to brown.9

It still wasn’t for certain whether this would hold true in humans… until preliminary studies presented at the 2013 annual meeting of the American Diabetes Association showed that both mice and men experienced beneficial “browning” of fat following exercise. Among men, the benefits were found after 12 weeks of training on an exercise bike. One of the researchers, a postdoctoral fellow at Joslin Diabetes Center, said:10

“Our results showed that exercise doesn’t just have beneficial effects on muscle, it also affects fat… It’s clear that when fat gets trained, it becomes browner and more metabolically active. We think there are factors being released into the bloodstream from the healthier fat that are working on other tissues.”

3. Melatonin

Consuming melatonin stimulates the appearance of “beige” fat, which, the researchers of one study believe, may explain why melatonin helps control body weight, along with its metabolic benefits.11 Science Daily reported:12

“The study… showed that chronic administration of melatonin sensitizes the thermogenic effect of exposure to cold, heightens the thermogenic effect of exercise and, therefore, constitutes excellent therapy against obesity. The fact is that one of the key differences between ‘beige fat,’ which appears when administering melatonin, and ‘white fat,’ is that ‘beige fat’ cell mitochondria express levels of UCP1 protein, responsible for burning calories and generating heat.”

It’s also well proven that lack of sleep is linked to obesity, and if you’re not getting enough sleep, there’s a good chance your melatonin production is not up to par either. The disturbance to your melatonin levels caused by lack of sleep (and exposure to light during the night) may be one more reason why disturbed sleep leads to weight gain, and this could have far-reaching impacts on your health. It is probably unwise to take melatonin supplements for this effect but far better to stimulate your own melatonin production as I’ve discussed in many previous articles.

Heat-Shock Proteins and the Sauna Connection

Heat-shock proteins (HSPs) are used by your cells to counteract potentially harmful stimulus. Whenever a cell is exposed to an unfriendly environment, the DNA separates in certain regions and begins to read the genetic code to produce these stress proteins. HSPs are actually beneficial, helping to both prevent and repair damaged proteins. Heat-shock proteins are induced by heat, and this is one reason why sauna use is so beneficial.

However, intriguing research suggests heat-shock proteins may also be cold-induced. In one animal study, cold exposure induced the expression of HSPs in brown fat,13 the implications of which are as yet unknown. It’s thought that cold-induced expression of heat-shock proteins may facilitate thermogenesis in brown fat,14 and, on a much broader scale, that exposing your body to reasonable amounts of both cold and heat stress may actually be beneficial.

Scripps Research Institute Scientists Find New Calorie-Burning Switch in Brown Fat.

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Biologists at The Scripps Research Institute (TSRI) have identified a signaling pathway that switches on a powerful calorie-burning process in brown fat cells.

The study, which is reported in this week’s online Early Edition of theProceedings of the National Academy of Sciences, sheds light on a process known as “brown fat thermogenesis,” which is of great interest to medical researchers because it naturally stimulates weight loss and may also protect against diabetes.

“This finding offers new possibilities for the therapeutic activation of brown fat thermogenesis,” said team leader Anastasia Kralli, associate professor in TSRI’s Departments of Chemical Physiology and Cell Biology.

‘Revving the Engines’

Most fat cells in our bodies are “white fat” cells that store fat as a reserve energy supply. But we and other mammals also have depots of “brown fat” cells. These apparently evolved not to store but to burn energy—quickly, as a way of generating heat and keeping the body warm in cold conditions, as well as possibly to get rid of excess caloric intake.

Human babies as well as mammals that hibernate have relatively extensive brown fat tissues. Scientists have found in recent years that many adult humans have significant levels of brown fat, which are located mostly in the neck and shoulders, and appear to help regulate body weight and blood sugar.

Low temperatures activate the brown-fat thermogenesis process via the sympathetic nervous system: Nerve ends in brown fat tissue release the neurotransmitter norepinephrine, and that triggers a shift in metabolism within the brown fat cells, which are densely packed with tiny biological energy reactors called mitochondria.

“The mitochondria start generating heat instead of useful chemical energy; it’s like revving the engines of a lot of parked cars,” said first author Marin Gantner, who was a graduate student in the Kralli laboratory during the study.

Given the potential medical applications—about 100 million people suffer from obesity or diabetes in the US alone—researchers are eager to understand brown fat thermogenesis and how it can be boosted artificially. One clue, reported by other scientists in 1998, is that norepinephrine instructs brown fat cells to express high levels of a protein called PGC-1α, which acts as a general amplifier of energy metabolism and also activates thermogenesis. The Kralli laboratory has shown in past studies that PGC-1α works by activating a molecule called ERRα. But this pathway can’t be the only one that triggers thermogenesis, because mice lacking PGC-1α in their fat cells, or ERRα, still show most of the usual thermogenesis response to cold.

A Serendipitous Discovery

In the new study, Gantner, Kralli and their colleagues discovered another thermogenesis activation pathway that works alongside PGC-1α and ERRα.

Originally, however, they were not examining brown fat thermogenesis, but instead were looking for clues to the function of ERRβ, a protein about which little was known at the time, except that it was closely related to ERRα, appeared in brown fat cells, and also worked as a so-called nuclear receptor—a molecular switch for gene activation that can be turned on by small lipophilic molecules or a signaling protein partner.

In the hope of finding ERRβ’s signaling partner, the team screened about 18,000 different proteins to see which could biochemically activate it. After accumulating a short list of “hits,” the scientists found that one of them, GADD45γ, is normally produced in mouse brown fat cells and becomes especially abundant after exposure to cold—hinting that GADD45γ and ERRβ, much like PGC-1α and ERRα, work together to switch on brown fat thermogenesis.

The team then detailed the signaling in this pathway, from cold-induced norepinephrine release, to upregulation of GADD45γ in brown fat cells, to the activation of ERRβ and another closely related protein, ERRγ, which turned out to be also prevalent in brown fat cells and relevant to thermogenesis. “We focused on ERRγ after that,” Gantner said.

The team confirmed that the GADD45γ-mediated activation of ERRγ leads to the metabolic shift in brown fat mitochondria that is characteristic of thermogenesis. The scientists also found that transgenic mice lacking GADD45γ can’t fully switch on thermogenesis under cold conditions.

In the experiments, GADD45γ acted synergistically with PGC-1α to activate brown fat cell activity. “You have to add them together to get the full effect,” said Kralli, suggesting that ideally, one would stimulate both pathways to boost brown fat thermogenesis.