Posts tagged fat cells
Articles and news from the latest research reports.
Obesity makes fat cells act like they’re infected
The inflammation of fat tissue is part of a spiraling series of events that leads to the development of type 2 diabetes in some obese people. But researchers have not understood what triggers the inflammation, or why.
In Cell Metabolism this month (cover), scientists from The Methodist Hospital report fat cells themselves are at least partly to blame — high calorie diets cause the cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals — they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.
"We did not know fat cells could instigate the inflammatory response," said principal investigator and Methodist Diabetes & Metabolism Institute Director Willa Hsueh, M.D. "That’s because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don’t just rely on local resident immune cells for protection — they play a very active role in their own defense. And that’s not always a good thing."
In pinpointing major histocompatibility complex II (MHCII) as a cause of inflammation, the researchers may have also identified a new drug target for the treatment of obesity. Blocking the MHCII response of adipocytes wouldn’t cure obesity, Hsueh said, “but it could make it possible for doctors to alleviate some of obesity’s worst consequences while the condition itself is treated.”
Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet?
"The expression of MHCII in adipocytes does not seem to be helpful to the body," said co-lead author Christopher Lyon, Ph.D. "It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet."
Hsueh added, “The bottom line is, you’re feeding and feeding these fat cells and they’re turning around and biting you back. They’re doing the thing they’re supposed to do — storing energy — but reacting negatively to too much of it.”
The scientists studied fat cells from obese, female humans (via biopsy) and overfed male mice. The researchers said that while they expect similar MHCII expression to occur in overweight male humans and female mice, further studies are needed to establish this.
The immunology of adipocyte inflammation is complex. It begins with the import of excess nutrients from the bloodstream, which are converted and stored as fat and stimulate the production of the hormone leptin. Excess leptin, spurred by a high calorie diet, excites CD4 T cells to produce a second signaling molecule, interferon gamma, which causes adipocytes to produce MHCII. This dialogue between adipocytes and T cells appears to initiate the inflammatory response to high fat diet — Hsueh and her group found that overfed mice lacking MHCII experienced less inflammation.
Interferon gamma from T cells exacerbates the inflamed adipocytes’ behavior and causes another type of immune cell, M2 macrophages, to be converted to their pro-inflammatory (M1) version.
"It was known that macrophages and T cells are major players," said lead author Tuo Deng, Ph.D. "But no one knew what the start signals were to ignite inflammation.
RNA was extracted from adipocytes purified from fat tissue biopsies and subjected to microarray analysis, which allowed the researchers to see what genes were increased in overweight subjects. The researchers found high expression of most MHCII complex and MHCII antigen processing genes. Similar gene expression patterns were observed in mice within two weeks of starting a high-fat diet, and this mirrored pro-inflammatory changes in fat tissue CD4 T cells. Hsueh says her group plans to investigate whether the inflammatory response in overfed mice can be blocked when MHCII expression is specifically reduced in adipocytes.
Hsueh says that if she and her group can identify the antigen(s) that MHCII is presenting to T cells in fat tissue, medical researchers would have a new approach to target adipose inflammation in obese patients. The hypothesis is that if a treatment can interfere with the production or MHCII presentation of these antigens, this would reduce the activation of fat tissue immune cells and thus reduce inflammation. Determining the MHCII antigen(s) involved in the inflammatory response of fat tissue to weight gain is one of her group’s next goals, she says.
The brain circuit that makes it hard for obese people to lose weight
Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.
While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.
Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.
The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.
“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.
“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”
“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”
“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”
“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”
“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”
Study uncovers protein key to fighting and preventing obesity
University of Florida researchers and colleagues have identified a protein that, when absent, helps the body burn fat and prevents insulin resistance and obesity. The findings from the National Institutes of Health-funded study were published online ahead of print Sunday, Jan. 6, in the journal Nature Medicine.
The discovery could aid development of drugs that not only prevent obesity, but also spur weight loss in people who are already overweight, said Dr. Stephen Hsu, one of the study’s corresponding authors and a principal investigator with the UF Sid Martin Biotechnology Development Institute.
One-third of adults and about 17 percent of children in the United States are obese, according to the Centers for Disease Control and Prevention. Although unrelated studies have shown that lifestyle changes such as choosing healthy food over junk food and increasing exercise can help reduce obesity, people are often unable to maintain these changes over time, Hsu said.
“The problem is when these studies end and the people go off the protocols, they almost always return to old habits and end up eating the same processed foods they did before and gain back the weight they lost during the study,” he said. Developing drugs that target the protein, called TRIP-Br2, and mimic its absence may allow for the prevention of obesity without relying solely on lifestyle modifications, Hsu said.
First identified by Hsu, TRIP-Br2 helps regulate how fat is stored in and released from cells. To understand its role, the researchers compared mice that lacked the gene responsible for production of the protein, with normal mice that had the gene.
They quickly discovered that mice missing the TRIP-Br2 gene did not gain weight no matter what they ate — even when placed on a high-fat diet — and were otherwise normal and healthy. On the other hand, the mice that still made TRIP-Br2 gained weight and developed associated problems such as insulin resistance, type 2 diabetes and high cholesterol when placed on a high-fat diet. The normal and fat-resistant mice ate the same amount of food, ruling out differences in food intake as a reason why the mice lacking TRIP-Br2 were leaner.
“We had to explain why the animals eating so much fat were remaining lean and not getting high cholesterol. Where was this fat going?” Hsu said. “It turns out this protein is a master regulator. It coordinates expression of a lot of genes and controls the release of the fuel form of fat and how it is metabolized.”
When functioning normally, TRIP-Br2 restricts the amount of fat that cells burn as energy. But when TRIP-Br2 is absent, a fat-burning fury seems to occur in fat cells. Although other proteins have been linked to the storage and release of fat in cells, TRIP-Br2 is unique in that it regulates how cells burn fat in a few different ways, Hsu said. When TRIP-Br2 is absent, fat cells dramatically increase the release of free fatty acids and also burn fat to produce the molecular fuel called ATP that powers mitochondria — the cell’s energy source. In addition, cells free from the influence of TRIP-Br2 start using free fatty acids to generate thermal energy, which protects the body from exposure to cold.
“TRIP-Br2 is important for the accumulation of fat,” said Dr. Rohit N. Kulkarni, also a senior author of the paper and an associate professor of medicine at Harvard Medical School and the Joslin Diabetes Center. “When an animal lacks TRIP-Br2, it can’t accumulate fat.”
Because the studies were done mostly in mice, additional studies are still needed to see if the findings translate to humans.
“We are very optimistic about the translational promise of our findings because we showed that only human subjects who had the kind of fat (visceral) that becomes insulin-resistant also had high protein levels of TRIP-Br2,” Hsu said.
“Imagine you are able to develop drugs that pharmacologically mimic the complete absence of TRIP-Br2,” Hsu said. “If a patient started off fat, he or she would burn the weight off. If people are at risk of obesity and its associated conditions, such as type 2 diabetes, it would help keep them lean regardless of how much fat they ate. That is the ideal anti-obesity drug, one that prevents obesity and helps people burn off excess weight.”
(Source: news.ufl.edu)
Study of link between night eating and the peculiar internal clock of fat cells
When researchers at the University of Pennsylvania messed with the internal clocks of mouse fat cells, a surprising thing happened.
The mice got fat.
Figuring out why led to more surprises. Mice usually eat at night, but the altered mice ate more of their food during the day. They got fat even though they ate the same number of calories as regular, nocturnal-feeding mice.
And when the researchers gave altered mice two of the key ingredients in fish oil, the animals didn’t get fat.
That’s a lot to digest, but it has potential implications for humans as we enter the season of stuffed refrigerators that beckon some to eat when they should be resting.
Fat cells store excess energy and signal these levels to the brain. In a new study this week in Nature Medicine, Georgios Paschos PhD, a research associate in the lab of Garret FitzGerald, MD, FRS director of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, shows that deletion of the clock gene Arntl, also known as Bmal1, in fat cells, causes mice to become obese, with a shift in the timing of when this nocturnal species normally eats. These findings shed light on the complex causes of obesity in humans.
The Penn studies are surprising in two respects. “The first is that a relatively modest shift in food consumption into what is normally the rest period for mice can favor energy storage,” says Paschos. “Our mice became obese without consuming more calories.” Indeed, the Penn researchers could also cause obesity in normal mice by replicating the altered pattern of food consumption observed in mice with a broken clock in their fat cells.
This behavioral change in the mice is somewhat akin to night-eating syndrome in humans, also associated with obesity and originally described by Penn’s Albert Stunkard in 1955.
The second surprising observation relates to the molecular clock itself. Traditionally, clocks in peripheral tissues are thought to follow the lead of the “master clock” in the SCN of the brain, a bit like members of an orchestra following a conductor. “While we have long known that peripheral clocks have some capacity for autonomy – the percussionist can bang the drum without instructions from the conductor – here we see that the orchestrated behavior of the percussionist can, itself, influence the conductor,” explains FitzGerald.
The absence of a specific type of neuron in the brain can lead to obesity and diabetes in mice report researchers in The EMBO Journal. The outcome, however, depends on the type of diet that the animals are fed.
A lack of AgRP-neurons, brain cells known to be involved in the control of food intake, leads to obesity if mice are fed a regular carbohydrate diet. However, animals that are deficient in AgRP-neurons but which are raised on a high-fat diet are leaner and healthier. The differences are due to the influence of the AgRP-neurons on the way other tissues in the body break down and store nutrients. Mice lacking AgRP-neurons adapt poorly to a carbohydrate diet and their metabolism seems better suited for feeding on fat.
The scientists wanted to show if a primary setting in the brain might directly affect the relative balance that exists in peripheral tissue between storage, conversion and utilization of carbohydrate and lipids. “The idea that we wanted to test in our experiments was whether the action of a specific type of brain cell known as the AgRP-neuron extended beyond its known influence on food intake. We found a new function for these cells, one that affects the communication with and activities of other tissues in the body including the liver, muscle and the pancreas,” added Luquet.
The researchers showed that mice that lacked AgRP-neurons from birth and which were fed on a regular carbohydrate diet had excessive body fat, increased amounts of the sugar-regulating hormone insulin, and normal levels of glucose in the blood. When the same animals were fed a high fat diet they showed a reduced gain in body weight and improved glucose clearance in the blood.