Immunometabolism: The New Frontier

Immunometabolism: The New Frontier

Immunometabolism: The New Frontier

Byron J. Richards, CCN

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 the abstracts of these studies:

Linking T cells and Glucose Uptake by Fat Cells – A study explaining changes in T cells that directly influence metabolism.

Study Title:

Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.

Study Abstract:

Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4+ Foxp3+ T regulatory (Treg) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these Treg cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of Treg cells to inhibit elements of the metabolic syndrome may have therapeutic potential.

Study Information:

Markus Feuerer, Laura Herrero, Daniela Cipolletta, Afia Naaz, Jamie Wong, Ali Nayer, Jongsoon Lee, Allison B Goldfine, Christophe Benoist, Steven Shoelson & Diane Mathis. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Medicine  2009 July  
1.Immunology and Immunogenetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

How Fat Inflammation Gets Going – A study explaining how these changes in T cells cause inflammation.

Study Title:

CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.

Study Abstract:

Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8+ effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4+ helper and regulatory T cells were diminished. The infiltration by CD8+ T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8+ T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8+ T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8+ T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8+ T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation.

Study Information:

Satoshi Nishimura, Ichiro Manabe, Mika Nagasaki, Koji Eto, Hiroshi Yamashita, Mitsuru Ohsugi, Makoto Otsu, Kazuo Hara, Kohjiro Ueki, Seiryo Sugiura, Kotaro Yoshimura, Takashi Kadowaki & Ryozo Nagai. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.  Nature Medicine  2009 July  
1.Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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).

Study Title:

Normalization of obesity-associated insulin resistance through immunotherapy.

Study Abstract:

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4+ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon- (IFN-)-secreting T helper type 1 (TH1) cells, overwhelming static numbers of TH2 (CD4+GATA-binding protein-3 (GATA-3)+) and regulatory forkhead box P3 (Foxp3)+ T cells. CD4+ (but not CD8+) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through TH2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab’)2 fragment, reduces the predominance of TH1 cells over Foxp3+ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4+ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

Study Information:

Shawn Winer, Yin Chan, Geoffrey Paltser, Dorothy Truong, Hubert Tsui, Jasmine Bahrami, Ruslan Dorfman, Yongqian Wang, Julian Zielenski, Fabrizio Mastronardi, Yuko Maezawa, Daniel J Drucker, Edgar Engleman, Daniel Winer & H.-Michael Dosch. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine  2009 July  
1.Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto Departments of Pediatrics & Immunology, Toronto, Ontario, Canada.

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. 

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