Drugs targeting blood vessels may be candidates for treating Alzheimer’s

University of British Columbia researchers have successfully normalized the production of blood vessels in the brain of mice with Alzheimer’s disease (AD) by immunizing them with amyloid beta, a protein widely associated with the disease.

While AD is typically characterized by a build-up of plaques in the brain, recent research by the UBC team showed a near doubling of blood vessels in the brain of mice and humans with AD.

The new study, published online last week in Scientific Reports, a Nature journal, shows a reduction of brain capillaries in mice immunized with amyloid beta – a phenomenon subsequently corroborated by human clinical data – as well as a reduction of plaque build-up.

“The discovery provides further evidence of the role that an overabundance of brain blood vessels plays in AD, as well as the potential efficacy of amyloid beta as basis for an AD vaccine,” says lead investigator Wilfred Jefferies, a professor in UBC’s Michael Smith Laboratories.

“Now that we know blood vessel growth is a factor in AD, if follows that drugs targeting blood vessels may be good candidates as an AD treatment.”

AD accounts for two-thirds of all cases of dementia. The number of Canadians living with dementia is expected to reach 1.4 million by 2013, according to the Alzheimer’s Society of Canada.

New Study Validates Longevity Pathway

A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models.

What’s more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion. Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.

These findings are published in the March 8 issue of Science.

For the last decade, the science of aging has increasingly focused on sirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging. Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age. By recharging the batteries, SIRT1 can have profound effects on health.

Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.

“In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1,” said David Sinclair, Harvard Medical School professor of genetics and senior author on the paper. “Almost all drugs either slow or block them.”

In 2006, Sinclair’s group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol. (Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company, and remains a scientific advisor. Sirtris currently has a number of sirtuin-activating compounds in clinical trials.)

But while numerous studies, from Sinclair’s lab and elsewhere, underscored a direct causal link between resveratrol and SIRT1, some scientists claimed the studies were flawed.

The contention lay in the way SIRT1 was studied in vitro, using a specific chemical group attached to the targets of SIRT1 that fluoresces more brightly as SIRT1 activity increases. This chemical group, however, is synthetic and does not exist in cells or in nature, and without it the experiments did not work. As a response to this, a paper published in 2010 surmised that resveratrol’s activation of SIRT1 was an experimental artifact, one that existed in the lab, but not in an actual animal. SIRT1 activity in mice was, the paper claimed, at best an indirect result of resveratrol, and perhaps even a sheer coincidence.

As a result, a debate erupted over the particular pathway that resveratrol and similar compounds affected. Does resveratrol directly activate SIRT1 or is the effect indirect? “We had six years of work telling us that this was most definitely not an artifact,” said Sinclair. “Still, we needed to figure out precisely how resveratrol works. The answer was extremely elegant.”

Sinclair and Basil Hubbard, then a doctoral student in the lab, teamed up with a group of researchers from both the National Institutes of Health and Sirtris Pharmaceuticals to address this question.

First, the team addressed the problem of the fluorescent chemical group. Why was it required for resveratrol to rev up SIRT1 in the test tube? Instead of dismissing the result as an artifact, the researchers surmised that the chemical might be mimicking molecules found naturally in the cell. These turned out to be a specific class of amino acid, the building blocks of proteins. In nature, there are three amino acids that resemble the fluorescent chemical group, one of which is tryptophan, a molecule abundant in turkey and notable for inducing drowsiness. When researchers repeated the experiment, swapping the fluorescing chemical group on the substrate with a tryptophan residue, resveratrol and similar molecules were once again able to activate SIRT1.

“We discovered a signature for activation that is in fact found in the cell and doesn’t require these other synthetic groups,” said Hubbard, first author of the study. “This was a critical result, which allowed us to bridge the gap between our biochemical and physiological findings.

“Next, we needed to identify precisely how resveratrol presses on SIRT1’s accelerator,” said Sinclair. The team tested approximately 2,000 mutants of the SIRT1 gene, eventually identifying one mutant that completely blocked resveratrol’s effect. The particular mutation resulted in the substitution of a single amino acid residue, out of the 747 that make up SIRT1. The researchers also tested hundreds of other molecules from the Sirtris library, many of which are far more powerful than resveratrol, against this mutant SIRT1. All failed to activate it.

The authors propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive.

Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1—and how to break it—they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.

“This was the killer experiment,” said Sinclair. “There is no rational alternative explanation other than resveratrol directly activates SIRT1 in cells. Now that we know the exact location on SIRT1 where and how resveratrol works, we can engineer even better molecules that more precisely and effectively trigger the effects of resveratrol.”

The researchers plan on continuing academic-industry collaborations with the goal of bringing to fruition drugs that treat diseases associated with aging.

When food is scarce, a smaller brain will do

A new study explains how young brains are protected when nutrition is poor. The findings, published on March 7th in Cell Reports, a Cell Press publication, reveal a coping strategy for producing a fully functional, if smaller, brain. The discovery, which was made in larval flies, shows the brain as an incredibly adaptable organ and may have implications for understanding the developing human brain as well, the researchers say.

The key is a carefully timed developmental system that ultimately ensures neural diversity at the expense of neural numbers.

"In essence, this study reveals an adaptive strategy allowing the reduction of the number of neurons produced in the face of sub-optimal nutritional conditions, while preserving their diversity," said Cedric Maurange of Aix-Marseille Université in France. "This is a survival strategy permitting the developing brain to produce the minimal set of neurons necessary to be functional, at the minimum energetic cost."

Most of the neurons in the human brain are produced well before birth, as the developing fetus grows and changes in the womb. But how the young brain copes with adversity is an unresolved question. If a mother doesn’t have enough food to eat, what happens to the brain of her baby?

To find out, Maurange and his colleagues looked to the fruit fly, a workhorse of biology. The much shorter lifespan of fruit flies means that they reach the equivalent of toddlerhood in just four days’ time.

Their developmental studies in the fly visual system reveal an early sensitivity to the availability of amino acids, ingredients that are the building blocks of proteins. They found that a fly with all the amino acids it needs ends up with a larger pool of neural stem cells than one lacking those nutrients. Later, when those neural stem cells start to produce the many different types of neurons, that nutrient sensitivity goes away. The end result is a brain that is functional but smaller. In some flies, the optic lobe contained 40 percent fewer neurons and still worked.

"We were surprised to realize that the optic lobe can have such a drastically reduced number of neurons under dietary restriction and yet remains functional," Maurange said.

The findings may help to explain well-documented patterns of brain growth in humans. The human brain is protected over other organs when nutrients are lacking late in fetal development, producing a brain that is large relative to organs such as the pancreas or intestine. But when nutrients are limited early in larval development, the brain remains small along with the rest of the body. Those growth patterns are known as asymmetric and symmetric intrauterine growth restriction (IUGR), respectively.

"Our work suggests new avenues to investigate how early nutrient restriction affects mammalian brain development and may help in understanding the mechanisms underlying symmetric and asymmetric IUGR in humans," Maurange said.

To Make Mice Smarter, Add A Few Human Brain Cells

For more than a century, neurons have been the superstars of the brain. Their less glamorous partners, glial cells, can’t send electric signals, and so they’ve been mostly ignored.

Now scientists have injected some human glial cells into the brains of newborn mice. When the mice grew up, they were faster learners. The study, published Thursday in Cell Stem Cell, not only introduces a new tool to study the mechanisms of the human brain, it supports the hypothesis that glial cells — and not just neurons — play an important role in learning.

The scientific obsession with neurons really began at the end of the 19th century. Spanish anatomy professor Santiago Ramon y Cajal used a special dye to stain brain tissue. Under the microscope, neurons were revealed in exquisite detail. “A dense forest,” Ramón y Cajal called it — a field of little branching cells that would soon be named neurons.

With beautiful ink drawings, Ramón y Cajal painstakingly mapped neural networks and slowly developed the theory that neurons are the telegraph lines of thought (an idea later embraced by Schoolhouse Rock). Every idea and memory — every aspect of learning — could be traced back to the electric signals sent between neurons. Ramón y Cajal won the Nobel Prize for his work, and scientists focused on neurons for the next century.

But neurons aren’t the only cells in the brain.

"We’ve overlooked half the brain," says Douglas Fields, a neuroscientist at the National Institutes of Health. "We’ve only been studying one kind of cell in the brain." The other kind of cell — glial cells — are at least as abundant as neurons. But early scientists thought they were so boring they didn’t even merit a singular noun. "Glia is plural — there is no singular," Fields says. "We have ‘neuron’ but we don’t have ‘glion.’ "

Glial cells lacked the ability to send electric signals, and most scientists thought they were housekeeping cells, helping provide nutrients and insulation.

It was only in the last decade or so that scientists realized glial cells were more than that. Special types of glial cells, called astrocytes, which are named for the star-like patterns of their cellular structure, have their own form of chemical signaling. They have the potential to coordinate whole groups of neurons. “Glia are in a position to regulate the flow of information through the brain,” Fields says. “This is all missing from our models.”

And there’s something else. This type of glial cell, these astrocytes, have changed a lot as humans have evolved, while neurons have pretty much stayed the same. A mouse neuron and a human neuron look so much alike, even experienced neuroscientists can’t tell them apart.

"I can’t tell the differences between a neuron from a bird or a mouse or a primate or a human," says Steve Goldman, a neuroscientist at the University of Rochester who has studied brain cells for decades. But Goldman says glial cells are easy to tell apart.

"Human glial cells — human astrocytes — are much larger than those of lower species," he says. "They have more fibers and they send those fibers out over greater distances."

The thought is maybe these glial cells have played a role in making humans smarter. So Goldman teamed up with this wife, Maiken Nedergaard, to test this idea.

They injected some human glial cells into the brains of newborn mice. The mice grew up, and so did the human glial cells. The cells spread through the mouse brain, integrating perfectly with mouse neurons and, in some areas, outnumbering their mouse counterparts. All the while Goldman says the glial cells maintained their human characteristics.

"They very much thought that they were in the human brain, in terms of how they developed and integrated," he says.

So what are these mice like, the ones with brains full of functioning human cells? Their neural circuitry is still just the same, so they act completely normal. They still socialize with other mice and still seem interested in mousey things.

But the researchers say these mice are measurably smarter. In classic maze tests, they learn faster. “They make many fewer errors, and it takes them less time to come to the appropriate answer,” Goldman says.

It might take a normal mouse four or five attempts to learn the correct route, for example. But a mouse with human brain cells could get it on the second try. Glial cells — those boring glial cells — somehow enhance learning.

In fact, they could be changing what it means to be a mouse, and that raises ethical questions for this kind of research.

"Maybe bioethicists have been a little bit too cavalier assuming that a mouse with some human brain cells in it is just your normal old mouse," says Robert Streiffer, a bioethicist from the University of Wisconsin-Madison. "Well, it’s not going to be human, but that doesn’t mean it’s a normal old mouse either."

Streiffer says it’s not just that these mice can get through a maze more quickly — they’re better at recognizing things that scare them. And perception of fear is one of the things bioethicists must weigh when they decide the types of experiments you can do on an animal.

"So you have to sort of step back and do some hardcore philosophy," he says. Like, will these types of human-animal hybrids eventually get close enough to humanity that we would feel uncomfortable performing experiments on them?

The researchers in this study say we’re really, really far from that point. And if you want to investigate the role of glial cells, these hybrid mice are the best tools available.

Researchers discover workings of brain’s ‘GPS system’

Just as a global posi­tion­ing sys­tem (GPS) helps find your loca­tion, the brain has an inter­nal sys­tem for help­ing deter­mine the body’s loca­tion as it moves through its surroundings.

A new study from researchers at Prince­ton Uni­ver­sity pro­vides evi­dence for how the brain per­forms this feat. The study, pub­lished in the jour­nal Nature, indi­cates that cer­tain position-tracking neu­rons — called grid cells — ramp their activ­ity up and down by work­ing together in a col­lec­tive way to deter­mine loca­tion, rather than each cell act­ing on its own as was pro­posed by a com­pet­ing theory.

Grid cells are neu­rons that become elec­tri­cally active, or “fire,” as ani­mals travel in an envi­ron­ment. First dis­cov­ered in the mid-2000s, each cell fires when the body moves to spe­cific loca­tions, for exam­ple in a room. Amaz­ingly, these loca­tions are arranged in a hexag­o­nal pat­tern like spaces on a Chi­nese checker board.

“Together, the grid cells form a rep­re­sen­ta­tion of space,” said David Tank, Princeton’s Henry L. Hill­man Pro­fes­sor in Mol­e­c­u­lar Biol­ogy and leader of the study. “Our research focused on the mech­a­nisms at work in the neural sys­tem that forms these hexag­o­nal pat­terns,” he said. The first author on the paper was grad­u­ate stu­dent Cristina Dom­nisoru, who con­ducted the exper­i­ments together with post­doc­toral researcher Amina Kinkhabwala.

Dom­nisoru mea­sured the elec­tri­cal sig­nals inside indi­vid­ual grid cells in mouse brains while the ani­mals tra­versed a computer-generated vir­tual envi­ron­ment, devel­oped pre­vi­ously in the Tank lab. The ani­mals moved on a mouse-sized tread­mill while watch­ing a video screen in a set-up that is sim­i­lar to video-game vir­tual real­ity sys­tems used by humans.

She found that the cell’s elec­tri­cal activ­ity, mea­sured as the dif­fer­ence in volt­age between the inside and out­side of the cell, started low and then ramped up, grow­ing larger as the mouse reached each point on the hexag­o­nal grid and then falling off as the mouse moved away from that point.

This ramp­ing pat­tern cor­re­sponded with a pro­posed mech­a­nism of neural com­pu­ta­tion called an attrac­tor net­work. The brain is made up of vast num­bers of neu­rons con­nected together into net­works, and the attrac­tor net­work is a the­o­ret­i­cal model of how pat­terns of con­nected neu­rons can give rise to brain activ­ity by col­lec­tively work­ing together. The attrac­tor net­work the­ory was first pro­posed 30 years ago by John Hop­field, Princeton’s Howard A. Prior Pro­fes­sor in the Life Sci­ences, Emeritus.

The team found that their mea­sure­ments of grid cell activ­ity cor­re­sponded with the attrac­tor net­work model but not a com­pet­ing the­ory, the oscil­la­tory inter­fer­ence model. This com­pet­ing the­ory pro­posed that grid cells use rhyth­mic activ­ity pat­terns, or oscil­la­tions, which can be thought of as many fast clocks tick­ing in syn­chrony, to cal­cu­late where ani­mals are located. Although the Prince­ton  researchers detected rhyth­mic activ­ity inside most neu­rons, the activ­ity pat­terns did not appear to par­tic­i­pate in posi­tion calculations.

Star-Shaped Glial Cells Act as the Brain’s “Motherboard”

The transistors and wires that power our electronic devices need to be mounted on a base material known as a “motherboard.” Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.

But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University’s Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.

Using models designed to mimic brain signalling, De Pittà’s research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually “smart” in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain’s circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.

Transcending boundaries

"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."

Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.

De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.

Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.

These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.

A break in communication

According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain’s communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.

In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer’s disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.

Epigenetics: Neurons remember because they move genes in space

How do neurons store information about past events? In the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, a mechanism unknown previously of memory traces formation has been discovered. It appears that at least some events are remembered thanks to… geometry.

Neurons are the most important cells of the nervous system. Scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw have shown that during neuron stimulation permanent changes are observed with respect to genes’ arrangement within the cell nucleus. This discovery, reported in the “Journal of Neuroscience”, one of the most prestigious journals in the field of neurobiology, is significant for developing a better understanding of the processes going on in the mind and disorders of the nervous system, especially the brain.

“While conducting experiments on rats after epileptic seizures we have observed that a gene may permanently move deeper into the neuron’s cell nucleus. Since modification of the geometrical structure of the nucleus leads to changes in gene expression, this is how the neuron remembers, what happened”, explains Prof. Grzegorz Wilczyński from the Laboratory of Molecular and Systemic Neuromorphology at the Nencki Institute.

New clues to causes of peripheral nerve damage

Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.

Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.

Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.

The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists report March 6 in the journal Neuron.

“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” says senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”

The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.

In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.

The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.

Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.

And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.

“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt says. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”

The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons.

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.