A Summary of Immunology and Genetics in Obesity

Dr. Dana F. Flavin, M.S., M.D. Med uni (Innsbruck)

There are two main parameters in obesity. Both relate to inflammation. One is the immune system that shows a shift from the Th-2 lymphocytes to the Th-1 lymphocytes particularly as the patients begin to border on diabetes. Adipose tissue is now recognized to be a multifunctional organ. It has a major endocrine function secreting several hormones notably leptin and adiponectin. There are also a diverse range of other protein factors or signals, which have been given the collective name adipocytokines or adipokines. Those adipokines involved in inflammation are TNF alpha, IL-1 beta, IL-6, IL-8 and IL-10, Transforming growth factor beta, nerve growth factor and the acute-phase response, plasminogen activator inhibitor-1, haptoglobin, and serum amyloid A. Most likely an involvement in the oxygen radicals in inflammation also polays a major role in obesity as arginine has been shown to reverse obesity and its mechanism is most likely via the generation of nitric oxide from the anti-inflammtory endothelial nitric oxide synthase enzyme.

Essentially it is viewed by many experts that obesity is a chronic low grade inflammation. It is further suggested that these chain of events are preceded by hypoxia, activating the transcription factor, hypoxia inducible factor-1. Although the T regulatory cells, particularly CD4(+) lymphocytes are seen in adipose tissue form humans, they should regulate inflammation. In the metabolic syndrome with insulin resistance associated with diabetes, there is a reduction in these regulatory cells. In obesity, the adipose tissue,shows an increase in CD8(+) effector T cells that helps to pull in macrophages. When these CD8(+) cells are decreased, the inflammation is decreased and the systemic insulin resistance is ameliorated. CD8(+) T cells appear to play a major role in the development of inflammation and insulin resistance. In mice, CD3-specific antibodies or its F(ab’)(2) fragment reduced the predominance of the TH1 cells over the Foxp3+ cells and reversed insulin resistance for months despite a high fat diet. In Humans, the Th-1 family of lymphocytes is markedly increased in obese children dominated by the production of interferon gamma and related to insulin resistance correlating with the Th-1 family of cytokines, also NF-Kappa B and JNK-1 systems, measured in obesity including and associated with inflammation and diabetes.

Although there are many genes involved in the regulation of fat metabolism and obesity some of the major ones relate to thyroid(TSHR), peroxisome proliferator-activated receptor (PPAR) gamma genes, adiponectin receptor genes (AdipoR1) and from Histone H3 lysine 9, the histone demethylase JHDM2-a as a regulator of genes involved in energy metabolism. Methylation also plays a role in many factors in obesity, including the PPAR activity and leptin levels shich can be influenced by diet induced obesity. In relation to the genes regulating cytokines and Metaloproteinases, the most expressed genes are from TNF alpha treated human adipocytes are: Eotaxin-1, monocyte chemoattractant protein(MCP-1), Vascular cell adhesion molecule 1(VCAM1) which are all uprelated in obesity. The down regulation of by TNF alph treatment is seen in IL-1 family members, Thrombospondin motifs-1, fibronectin 1 isoforms 1 preprotein(FN1) and finally matrix metalloproteinase 15 preproteint(MMP15) .

The invovelment of the inflammatory factors and gene regulation alteations in obesity is a complicated balance that through proper modification can reverse obesity in animal models and potentially humans. In addition to controlling these factors for reversing and/or preventing obesity, they also have the potential to alter the insulin response and reestablish normal insulin receptor sensitivity. Many receptors and enzymes involved in the development of obesity have been up regulated or down regulated to effect the development or progression of obesity. These include the Cide family of protein receptors, adiponectin receptors, and enzymes such as stearoyl CoA desaturase, inosine monophosphate dehydrogenase, and constitutive androstane receptor (CAR) activation to decrease obesity and increase insulin sensitivity.