Some Types of Obesity Might be Caused by a Faulty Immune System


When we think of our Immune systems, we normally entertain visions of white blood cells that fight off invading viruses and bacteria. However, recent work suggests that our immune systems may also being fighting a war against fat.

When laboratory mice are engineered to lack a specific type of immune cell, they become obese and show signs of high blood pressure, high cholesterol, and diabetes. Even though these findings have yet to be replicated in humans, they are already helping scientists understand the triggers of metabolic syndrome, a cluster of conditions associated with obesity.

A new study “definitely moves the field forward,” says immunologist Vishwa Deep Dixit of the Yale School of Medicine, who was not involved in the work. “The data seem really solid.”

Scientists have known for some time now that there is a correlation between inflammation—a heightened immune response—and obesity. Fat cells have the ability to release inflammatory molecules, which complicates these findings, since it is difficult to distinguish if the inflammation causes weight gain or is a side effect of weight gain.

Immunologist Yair Reisner of the Weizmann Institute of Science in Rehovot, Israel, came upon this new cellular link between obesity and the immune system while he was studying autoimmune diseases. Reinser was interested in an immune molecule called perforin, which kills diseased cells by boring a hole in their outer membrane. Reisner’s group suspected that perforin-containing dendritic cells might also be destroying the body’s own cells in some autoimmune diseases. To test their hypothesis, Reisner and his colleagues engineered mice that lacked perforin-wielding dendritic cells. Then they waited to see whether they developed any autoimmune conditions.

“We were looking for conventional autoimmune diseases,” Reisner says. “Quite surprisingly, we found that the mice gained weight and developed metabolic syndrome.”

Mice lacking the dendritic cells with perforin had high levels of cholesterol, early signs of insulin resistance, and molecular markers in their bloodstreams associated with heart disease and high blood pressure. Furthermore, the immune systems of these laboratory animals revealed that they also had a peculiar balance of T cells—a type of white blood cell that directs immune responses.

Reisner and his colleagues report online in the journal Immunity that when they removed these T cells from the mice, the absence of dendritic cells no longer caused the animals to become obese or develop metabolic syndrome.

The results, according to Reisner, suggest that the normal role of the perforin-positive dendritic cells is to keep certain populations of T cells under control. In the same way that perforin acts to kill cells infected with viruses, it can be directed to kill subsets of unnecessary T cells. When the brakes are taken off those T cells, they cause inflammation in fat cells, which leads to altered metabolism and weight gain.

“We are now working in human cells to see if there is something similar going on there,” Reisner says. “I think this is the beginning of a new focus on a new regulatory cell.” If these results turn out to be true in humans, they could point toward a way to use the immune system to treat obesity and metabolic disease.

Daniel Winer, an endocrine pathologist at the University of Toronto in Canada and the lead author of a January Diabetes paper that links perforin to insulin resistance, says the new results overlap with his study. Winer and his group found that mice whose entire immune systems lack perforin developed the early stages of diabetes when fed a high-fat diet. This new paper builds on that by homing in on perforin-positive dendritic cells and showing the link even in the absence of a high-fat diet. “It provides further evidence that the immune system has an important role in the regulation of both obesity and insulin resistance.”

Even if the results hold true in humans, however, a treatment for Type 2 diabetes, obesity or metabolic disease are far off. Dixit said. “Talking about therapeutics at this point would be a bit of a stretch.” Injecting perforin into the body could kill cells beyond those T cells that promoting obesity. We can’t live without any T cells at all, since they are vital to fight diseases and infections.

However, research on what these T cells are recognizing when they seek out fat cells and cause inflammation in fat tissue could eventually reveal drug targets.

Spanish Team Develops Anti-Obesity Treatment in Animal Models


A research team from the Spanish National Cancer Research Center (CNIO) has shown that partial pharmacological inhibition of the PI3K enzyme in obese mice and monkeys reduces body weight and physiological manifestations of metabolic syndrome, specifically diabetes and hepatic steatosis (fatty liver disease), without any signs of side effects or toxicities. They published their work in the journal Cell Metabolism. This collaborative project between the Tumor Suppression Group headed by Manuel Serrano at the CNIO (Madrid, Spain) and the Translational Gerontology Branch headed by Rafael de Cabo at the U.S. National Institute on Aging, National Institutes of Health (NIH, Baltimore, MD, USA), included the participation of the NeurObesity group of CIMUS led by Miguel Lopez at the University of Santiago de Compostela (Santiago de Compostela, Spain).

PI3K (phosphatidylinositol-3-kinase) is the name of an enzyme that regulates the balance between the biosynthesis of cellular components and the burning of nutrients to make energy in cells. Specifically, PI3K promotes cellular growth and biosynthesis, which can lead to the induction of growth and multiplication of cells, and ultimately could lead to cancer.

For this reason, scientists who investigate cancer have has a long-standing interest in designing pharmacological inhibitors of PIK3. CNIO, in fact, has developed its own experimental inhibitor, CNIO-PI3Ki, which is being studied for applications as a cancer treatment in combination with other compounds. As part of the characterization of the PI3K inhibitor and to understand how it affects the balance between the use and storage of nutrients in the body, the Serrano team decided to study the effects of CNIO-PI3Ki on metabolism.

“At this point we have veered away from the original anticancer aspects of these inhibitors. In our previous studies, we had seen that one of the normal physiological functions of the PI3K enzyme is to promote the storage of nutrients. We found this to be of particular interest because it is precisely this type of manipulation, regulation of the balance between storage and use of nutrients, that is sought after in treating obesity,” explains Ana Ortega-Molina, the first author of the study, who is working at the Memorial Sloan-Kettering Cancer Center in New York.

To test the effect of their PI3K inhibitor on metabolism, CNIO scientists administered small doses of the CNIO-PI3Ki inhibitor to obese mice for 5 months while those mice were fed a high-fat diet. During the first 50 days, the obese animals lost 20% of their body weight, at which point their weight stabilized. The treatment was administered for 5 months and during the whole time, these mice maintained a stable weight (20% below the weight of non-treated obese mice), despite continuing feeding with a high-fat diet. They also improved their pathological symptoms of diabetes (high glucose levels in the blood) and hepatic steatosis (fatty liver).

“When it comes to obesity, constant weight loss can be extremely dangerous. The ideal solution is to alter the balance between the use and storage of nutrients, to strike a new balance in which there is greater use and less storage,” explains Elena López-Guadamillas who, in collaboration with Ana Ortega-Molina, carried out most of the experimental work. This study showed that the drug had no side-effects and did not produce irreversible effects on metabolism, which is also desirable for its possible future use as a treatment in humans.

In non-obese animals that were fed a standard diet, the administration of the drug had no effect, which is another indication of its safety. “This shows that the activity of the PI3K enzyme is only relevant when there is an excess of nutrients, that is, a high-calorie or high-fat diet,” adds López-Guadamillas.

CNIO scientists then collaborated with the U.S. National Institutes of Health (NIH) in order to test the CNIO-PI3Ki compound on obese monkeys (macaques).  They used a very low dose to ensure higher safety margins, but even with these very high doses, the daily treatment of these obese animals over a 3-month period reduced the total amount of fatty tissue by 7.5% and improved the symptoms of diabetes.

Obesity is one of the most important risk factors within the spectrum of serious diseases that constitute the metabolic syndrome. Many pharmacological agents have been discovered that lead to weight loss, but these drugs often have unacceptable toxic effects (partly due to the fact that these previous agents act on the brain centers that control appetite). In this respect, CNIO-PI3Ki seems to be the exception, at least in animal models thus far, as no such side-effects have been observed, even after long-term treatments (5 months in mice and 3 months in monkeys).

A series of safety characteristics that have been demonstrated in mice is shown below:
1) Selective: CNIO-PI3Ki only produces weight loss in mice that receive an excess of nutrients and not in mice that eat a normal balanced diet. This shows that PI3K plays an important role in the storage of nutrients when food intake is excessive, but is not so important under a normal diet.
2) Weight loss in the mice is due exclusively to loss of fatty tissue; no losses occur in other tissues such as liver, muscle or bone.
3) It does not affect the brain: CNIO-PI3Ki does not cross the blood-brain barrier.
4) It does not affect the hypothalamus: The hypothalamus is a specialized structure of the brain that is exceptional because it lacks a blood-brain barrier (a structure that controls the entrance of substances from the blood to the brain) and it controls many metabolic processes, including appetite and satiety. No effects on the main neuropeptides produced by the hypothalamus related to appetite and satiety have been noted in the mice. These last studies have been carried out in collaboration with the research group led by Miguel López at the University of Santiago de Compostela.
5) It works on a long-term basis: The effects of CNIO-PI3Ki were maintained over at least a 5-month period of treatment in mice, which suggests that resistance mechanisms are not developed. This is very important, as it is a common problem found in other compounds that affect metabolism.
6) Reversibility: The effects of CNIO-PI3Ki were reversible, which means that when the treatment was interrupted and a high-fat diet maintained, the mice regained weight. This indicates that CNIO-PI3Ki does not cause irreversible changes.

The next logical step, once the beneficial effects of CNIO-PI3Ki have been demonstrated in obese mice and monkeys, is to perform clinical trials on humans. “The leap from animals to humans is complex, expensive and full of uncertainties. Many treatments that are promising in animals turn out not to be effective in humans or toxicities appear that were not observed in animals. But, obviously, in spite of the uncertainties, we have to give it a try,” says Manuel Serrano. “Clinical trials require large investments and are undertaken with the aim of marketing a treatment. We are very optimistic about the possibility of entering into an agreement soon with a multinational pharmaceutical company interested in carrying out clinical trials with CNIO-PI3Ki to treat obesity and metabolic syndrome in humans,” says Serrano.

Turning Muscle Stem Cells into Brown Fat


Michael Rudnicki’s laboratory at the Ottawa Hospital Research Institute has managed to convert stem cells from skeletal muscle into brown fat. Because brown fat burns calories, studies have shown that trimmer people tend to have more brown fat, Therefore, Rudnicki’s findings are being viewed as a potential treatment for obesity.

According to Rudnicki, “This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese. Rudnicki is a senior scientist and director for the Regenerative Medicine Program and Sprott Center for Stem Cell Research at the Ottawa Hospital Research Institute.

Obesity is the fifth leading risk death, globally speaking, and an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

in 2007, Rudnicki and his research team demonstrated the existence of a stem cell population in skeletal muscle. In this new publication, Rudnicki and others show that these adult muscle stem cells not only have the ability to produce muscle fibers, but can also make brown fat.

An even more important aspect of this paper (Yin, et al., Cell Metabolism 17(2) 2013: 210), is that it shows how adult muscle stem cells become brown fat. The main switch is a regulatory molecule called microRNA-133 or miR-133. When miR-133 is present, the muscle stem cells produce muscle fibers, but when the intracellular concentration of miR-133 is reduced, the muscle stem cells form brown fat.

Graphic Abstract

Rudnicki’s research staff developed a molecule that could reduce the concentration of miR-133 in cells. This molecule an antisense oligonucleotide or ASO that is complementary to miR-133. When injected into mice, the ASO caused the mice to produce more brown fat and prevented obesity. Additionally, when injected into the hind leg muscle, the metabolism of the mouse increased, and this effect lasted for four months after the ASO injection.

Even though antisense oligonucleotides are being used in clinical trials, such trials with miR-133 ASOs are still years away.

Rudnicki noted that “we are very excited by this breakthrough.” He continued: “While we acknowledge that it’s a first step there are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there any adverse effects we have not yet observed?”

Surely these questions will be addressed in good time, and Rudnicki’s lab is probably working on them as you read this entry.