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.

Mesoblast Clinical Trial Shows Stem Cell Treatments Improve Glycemic Control in Type 2 Diabetics

Mesoblast Ltd has announced the results of their clinical trial in type 2 diabetics at the annual meeting of the American Diabetes Association.

Mesoblast has developed a proprietary adult stem cell they call a mesenchymal precursor cell or MPC, which they are attempting show can be used as an “off the shelf” medical product. MPCs seem to act like immature mesenchymal stem cells that can modulate the immune response and have greater flexibility.

In this trial, Mesoblast was banking of the ability of administered MPCs to suppress inflammation. Type 2 diabetes results from an insensitivity of tissues to secreted insulin. Consequently, cells do not receive enough of the insulin signal to take up sugar and make protein, glycogen, and fat. Another prominent feature of type 2 diabetes is chronic, low-level inflammation, which is largely due to the chronically high blood glucose concentrations that damages cells, blood vessels, nerves, and connective tissue. By treating type 2 diabetics with MPCs, Mesoblast was hoping to ascertain the ability of MPCs to quell chronic inflammation.

The trial was conducted across 18 sites in the US. 61 patients with type 2 diabetes received either one intravenous infusion of 0.3, 1.0 or 2.0 millions MPCs per kilogram body weight over 12 weeks. One group of patients were given a placebo. Patients had suffered from diabetes an average of 10 years and had poor control with the drug metformin (Glucophage), which is one of the most widely-used drugs for type 2 diabetes.

The results were largely positive:
When it comes to safety, there were no safety issues observed during the 12-week study period. The MPC cell infusions were well tolerated (with a maximal dose of 246 million cells). With regard to efficacy, there were dose-dependent improvement in glycemic control as evidenced by a decrease at all time points after week 1 in hemoglobin A1c (HbA1c) in MPC- treated patients compared with an increase in HbA1c in placebo treated subjects. HbA1c is a blood test that determines how much damage the high sugar levels are doing to the body. The test uses the blood protein hemoglobin to assess the damage that high glucose levels are doing to the rest of the body. In this clinical trial, significant reductions in HbA1c were observed after 8 weeks in the 2 M/kg MPC group compared to placebo (p<0.05) which was sustained through 12 weeks. The reduction in HbA1c was most pronounced in subjects with baseline HbA1c ≥ 8% (i.e. those patients with relatively poorer glucose control).

Fasting insulin levels were reduced in the 1 million and 2 million/kg groups compared to placebo (P<0.05), and reduced levels of inflammatory cytokines TNF-alpha and IL-6 (which are made at high levels during inflammation) were observed at 12 weeks in MPC groups compared to placebo.

The scientists and physicians involved in this clinical trial concluded there was sufficient evidence to support further evaluation into the use of MPCs in the treatment of type 2 diabetes and its complications. They also thought that there were grounds for exploring other therapeutic venues in which MPCs might prove useful.

Mesoblast Chief Executive Silviu Itescu said: “We are very pleased with these results which are consistent with an immunomodulatory mechanism by which our MPCs may have glucose-lowering effects in patients with type 2 diabetes. We are evaluating whether similar effects may be seen with the use of MPCs in the treatment of kidney disease and other complications of type 2 diabetes.”

While it is improbable in the extreme that this one-time treatment will improve the long-term clinical outcomes of diabetics, it is possible that repeated treatments will provide better Glycemic control for poorly controlled diabetics, and that these repeated treatments will produce long-term improvements in the health of these patients.

Umbilical Cord Stem Cells Normalize Blood Glucose Levels in Diabetic Mice

Diabetes mellitus results from an insufficiency of insulin (Type 1 diabetes) or an inability to properly respond to insulin (Type 2 diabetes). Type 1 diabetes is caused by an attack by the patient’s own immune system on their pancreatic beta cells, which synthesize and secrete insulin. It is a disease characterized by inflammation in the pancreas. This suggests that abatement of inflammation in the pancreas might provide relief and delay the onset of diabetes.

Mesenchymal stem cells isolated from umbilical cord connective tissue, which is also known as Wharton’s jelly (WJ-MSCs), have the ability to reverse inflammatory destruction and might provide a way to delay or even reverse the onset of Type 1 diabetes.

To test this possibility, Jianxia Hu, Yangang Wang, and their colleagues took 60 non-obese diabetic mice and divided them into four groups: a normal control group, a normal diabetic group, a WJ-MSCs prevention group that was treated with WJ-MSCs before the onset of diabetes, and a WJ-MSCs treatment group that was treated with WJ-MSCs after the onset of diabetes.

After their respective treatments, the onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose levels and C-peptide (an indication of the amount of insulin synthesized), regulation of cytokines, and islet cells were examined and evaluated.

After WJ-MSCs infusion, fasting and fed blood glucose levels in WJ-MSCs treatment group decreased to normal levels in 6-8 days and were maintained for 6 weeks. The levels of fasting C-peptide of the WJ-MSC-treated mice was higher compared to diabetic control mice. In the WJ-MSCs prevention group, WJ-MSCs protected mice from the onset of diabetes for 8-weeks, and the fasting C-peptide in this group was higher compared to the other two diabetic groups.

Other comparisons between the WJ-MSC-treated group and the diabetic control group, showed that levels of regulatory T-cells (that down-regulate autoinflammation), were high and levels of pro-inflammatory molecules such as IL-2, IFN-γ, and TNF-α. The degree of inflammation in the pancreas was also examined, and pancreatic inflammation was depressed, especially in the WJ-MSCs prevention group.

These experiments show that infusions of WJ-MSCs can down-regulate autoimmunity and facilitate the recovery of islet β-cells whether given before or after onset of Type 1 Diabetes Mellitus. THis suggests that WJ-MSCs might be an effective treatment for Type 1 Diabetes Mellitus.

See March 2014 edition of the journal Endocrine.