Diabesity

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The immunology of obesity

by Luke Kennedy Burke

Type 2 diabetes has long been thought of as primarily a metabolic disease. A series of recent studies have challenged this dogma and implicated an unlikely candidate system in the promotion of disease onset - the immune system. Mild inflammation of fat tissue in obese patients reportedly acts through immune-cell processes to impair insulin signalling in adipocytes. This work therefore provides a novel way of understanding the link between obesity and type 2 diabetes.

The development of insulin insensitivity involves the malfunction of several organs, however, this article will focus on the role of adipose tissue. Adipocytes have a duplicitous role in that they are both a storage depot and endocrine organ. Obesity is accompanied by a state of chronic, low-grade inflammation of adipose tissue (Feuerer et al., 2009). However, unlike other forms of inflammation which are subject to control mechanisms, fat inflammation appears to escape immune regulation. In the case of type 2 diabetes, it is the invasion of adipose tissue by cytokine-producing macrophages that can lead to insulin resistance. The mechanistic underpinning of this phenomenon have recently been the subject of both novel and intense investigation, the results of which have provided new understanding and therapeutic targets for obesity-induced type 2 diabetes. More specifically, several publications from Japanese, American and American groups have all pointed to a common culprit – T regulatory cells (Treg cells). These specialised members of the T cell family play a key role in suppressing inappropriate activation of the immune system. They do so by interacting with macrophages and regulating the inflammatory cascade (Nishimura et al., 2009). Feuerer et al. (2009) isolated a specific phenotype of T cell, CD4, which is enriched in the adipose tissue of lean mice but dramatically reduced in that of obese, insulin-resistant mice. Through loss-of-function experiments it was shown that CD4 cells are functionally active and their absence results in inflammatory cytokine production and reduced glucose uptake. Importantly, CD4 T cells were only shown to behave in this manner in visceral fat stores, which, unlike subcutaneous stores, are associated with the development of type 2 diabetes. A complementary study, performed by Winer et al. (2009), demonstrated that obesity-induced type 2 diabetes can be remedied by treatment with CD antibody treatment. This was even observed in mice who continued on a Western diet and offers therapeutic targets for future drug development. A separate study by Nishimura et al. (2009) revealed that CD8 effector T cells, a different phenotype of Treg cell, are responsible for the chronic inflammation observed in adipose tissue. The use CD-8 antibodies, however, reduces inflammation and the onset of insulin sensitivity.

Another aspect of the immune system that has been implicated in type 2 diabetes onset is mast cell function. Mast cells respond to allergic and parasitic challenge by releasing inflammatory mediators, thus playing an integral protective role. An abundance of mast cells beyond that of what is immunologically necessary can cuase the cells to become unstable, leading to instability and inflammation. The white adipose tissue of obese mice possesses a significantly greater number of mast cells when compared to that of lean equivalents. This led Shi et al. to ask whether the manipulation of mast cell number, achieved through genetic reduction and pharmacological equalization, can reduce the onset of obesity and type 2 diabetes. In the first set of experiments, genetically mast cell-deficient mice (Kit W-sh/ Kit W-sh) and control mice were fed on a Western-diet (4.5 kcal /gram) for three months. Loss of mass cell function appeared to be having the effect of lowering serum leptin, increasing glucose tolerance and increasing insulin sensitivity in comparison to the control group. In the second strand of experimentation, mice were treated with mast cell-stabilizing medication to ask whether diet-induced obesity and diabetes could be inhibited. After two months on a Western-diet, mice were either switched to a healthy diet, supplied with medication, or a combination of both. While the dietary adjustment caused minor improvements, the mast-cell stabilizing medication stimulated significant restitution and the combination allowed practically a full recovery in comparison to control group who continued on a Western-diet. Shi has since signed a contract with a pharmaceutical company to develop this mast cell-stabilizing drug for testing in humans.

Both of these drugs are already used to treat other medical conditions and are therefore both safe and available, however the question that remains to be answered is do Zaditor and cromolyn offer similar protection against diabetes in humans?

At present the application from model to human appears positive. A study into T cell concentration in human abdominal fat tissue by Winer et al. (2009) has revealed an abundance in normal weight individuals when compared to that of obese, diabetic patients. A similar reflection of mouse data was found when the number of macrophages was examined. Obese and diabetic fat tissue that was absent of Treg cells contained a large number of macrophages, which is in keeping with the understanding that Tregs are crucial in regulating macrophage number and thus preventing inflammation.

Key References

Normalization of obesity-associated insulin resistance through immunotherapy http://www.nature.com/nm/journal/v15/n8/full/nm.2001.html

Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice http://www.nature.com/nm/journal/v15/n8/full/nm.1994.html

Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters http://www.nature.com/nm/journal/v15/n8/full/nm.2002.html

CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity http://www.nature.com/nm/journal/v15/n8/full/nm.1964.html

The protein kinase IKKepsilon regulates energy balance in obese mice http://www.cell.com/retrieve/pii/S0092867409007934

T-ing up inflammation in fat http://www.nature.com/nm/journal/v15/n8/full/nm0809-846.html