Immunometabolism: The New Frontier

Every now and then rather jaw-dropping research is published, as is the case this week as the journal Nature Medicine published three groundbreaking articles linking the function of immune cells to obesity and diabetes – data which opens the door to solving all kinds of health problems including the obesity issue itself, inefficient immune response to the flu in overweight individuals, as well as obesity-related autoimmune problems.

It has been known for a number of years that the extra pounds of fat in an overweight person are generating significant amounts of immune-related inflammatory signals such as TNFa and IL6.  Such inflammation not only damages the stored fat so that it is less metabolically responsive, it has been shown to induce inflammatory damage around the body leading to increased rates of heart disease, diabetes, cancer, and joint destruction.

What hasn’t been understood are the changes within stored fat that result in this inflammatory state.  The new research goes a long way towards explaining exactly how this happens and the mechanism is startling.  It involves the function of various T regulator cells of the immune system, cells that until this point were never thought to have anything to do with metabolism and body weight.

Here are links to abstracts of these studies:
Linking T cells and Glucose Uptake by Fat Cells – A study explaining changes in T cells that directly influence metabolism.
How Fat Inflammation Gets Going - A study explaining how these changes in T cells cause inflammation.
Antihistamines Prevent Obesity and Diabetes – A study showing one way to help address this issue is with the use of antihistamines (one of the drugs tested is a synthetic version of quercetin, nature’s most potent natural anti-histamine).

We think of our immune system as our main defense against foreign invaders, which is of course true.  Science over the past decade has placed the immune system in the communication business in general, especially within the nervous system.  The immune system also orchestrates the repair process of your body during sleep.  Leptin, the hormone that is commander and chief of your metabolism, is structured like an immune cytokine, indicating a high likelihood of cross talk between immune cells and hormones relating to metabolism.

These new studies show that in animals that are not overweight there is a high level of T Helper cells (CD4*) and regulatory T cells in their white adipose tissue.  However, in the fat of overweight animals and obese diabetic humans this population of immune cells is virtually gone and has been replaced with a population of CD8+ T cells (also called cytotoxic T cells or T killer Cells),  Cytotoxic T cells kill cancerous cells and virally infected cells.  Here they are in excess amounts within stored fat – apparently responding to initial stress within white adipose tissue from too much extra fat.

While it is possible that in some cases the fat itself is virally infected (an issue not discussed in these studies), it was shown that these cytotoxic T cells were behind the recruitment of excessive macrophages into the extra pounds of fat.  The macrophages, in turn, generate the massive inflammation associated with being overweight or obese.  This problem, in turn, results in even more cyctoxic T cells and we end up with one large inflammatory party that is self-perpetuating as well as damaging the metabolism of calories in white adipose tissue (locking in excess pounds of stagnant fat that won’t budge).

This means that the proper T helper cells and regulatory T cells are needed to keep white adipose tissue in a non-inflammatory condition.  The researchers also showed that when this slides out of balance then glucose uptake by fat cells is dysregulated leading to perpetuation of obesity, a nasty catch 22 that most certainly applies to any person who is having trouble losing weight by eating and exercising.

The researchers showed that as part of this immune cell problem, there were excessive numbers of T Helper 1 cells and a lack of T Helper 2 cells within the fat.  Excess T Helper 1 cells are associated with autoimmune problems, allergy, skin problems, etc.  It is quite likely that just as excess inflammation coming from fat cells can wreak havoc around the body, so it is that fat may be tilting overall immunity into T Helper 1 excess, leading to multiple health problems.  Or, a T Helper 1 health problem may in reverse help set the stage for obesity.  Either way it is not a good situation.

Furthermore, a lack of T Helper 2 cells, especially if the body is tilted to T Helper 1 excess by obesity, would impair the formation of antibodies needed to fight an infection such as the Swine Flu.  As I mentioned in a recent posting, the CDC has warned that obesity is a specific risk factor for more severe Swine Flu.

The researchers also identified that mast cells were far more abundant in fat tissue from obese and diabetic humans and mice compared to those of normal weight.  Giving antihistamine drugs (Zaditor and cromolyn) to mice significantly improved their metabolism.  Cromolyn is a drug patterned after the quercetin molecule, which is the best natural antihistamine available (carnosine is another).

In their experiments the mice were divided into four groups. The first was the control group; the second group was simply switched to a healthy diet; the third was given cromolyn or ketotifen fumarate; and the fourth was both given the drug and switched to a healthy diet.

While symptoms of the second group improved moderately, the third group demonstrated dramatic improvements in both body weight and diabetes. The fourth group exhibited nearly 100 percent recovery in all areas.

To bolster these findings, researchers then took a group of mice whose ability to produce mast cells was genetically impaired. Despite three months of a diet rich in sugar and fat, these mice neither became obese nor developed diabetes.

These studies are indeed groundbreaking and open the door for new strategies to help individuals manage their weight, especially those who cannot get weight under control simply by eating better and exercising more.

Of course, all of the principles of the Leptin Diet still apply and this data does not supersede other data relating to how hormones function, etc.  Individuals with difficult weight problems often struggle with stress, thyroid problems, and toxicity as well.  What this data does is provide a new tool to the weight management arsenal.

A goal is to work on reducing inflammation as a priority, with a specific focus on reducing mast cell excess activity while losing weight, so that a normal immune profile within white adipose tissue has a chance of re-emerging.

The health benefits of restoring this system are not limited to weight loss – they will directly extend to all inflammatory diseases of aging associated with obesity.  This is a very realistic solution for very real health problems faced by millions of Americans.

The field of immunometabolism has now placed a stake in the ground.  Expect mountains of research on this topic in the coming years.