Obesity and Immune Function

Obesity has long been associated with an increased risk for chronic diseases, such as diabetes and. Now, growing evidence also links obesity with a greater risk for acute infectious diseases.

Data collected between 1996 and 2008 in Ontario, Canada, found that obese people were more likely than healthy-weight individuals to be hospitalized for respiratory complications during influenza seasons.

Public health records for California residents during the 2009 H1N1 swine flu pandemic revealed that obesity was an independent risk factor for severe infection. Half of the adult Californians hospitalized for H1N1 were obese, which was 2.2 times the obesity rate of all adults in California at the time.

California health records from the 2009 H1N1 pandemic also showed that extreme obesity was associated with increased risk of death.

During the 2013-14 and 2014-15 influenza seasons, researchers at the University of North Carolina at Chapel Hill found that vaccinated obese adults had twice the risk of influenza or influenza-like illness as vaccinated healthy-weight adults.

Obesity not only appears to interact with the immune response to acute infections, but also may increase the risk for other immune-related conditions.

National Health and Nutrition Examination Survey (NHANES) data from 2005-06 showed that obesity was associated with an increased rate of allergies in children.

According to research published in 2011, obesity is associated with a greater risk of many types of cancer, along with more cancer-related deaths.

These sobering statistics beg the question: What are the mechanisms driving immune dysregulation in obesity? The answer is still unfolding. But through both human and animal models, researchers have discovered the following proposed mechanisms that may explain the connection between obesity and immune dysregulation.

Connection #1: Insulin Resistance

Obesity results from, and is associated with, a myriad of metabolic changes. Many obese patients also have elevated and triglycerides, along with insulin resistance. This metabolic environment contributes to low-grade that can disrupt the immune response.

One specific example of an interaction between insulin resistance and immune function involves T-cell activation. Whereas resting T cells have low energy needs, activated T cells increase their insulin-receptor expression and glucose transporters to meet a higher demand for energy. In people with insulin resistance, T cells may have trouble accessing the fuel they need, and the T cell response to pathogens may be impaired.

On the other side of the coin is the effect of elevated blood sugar on . Excessive glucose is associated with inflammation and a hyperactive immune response, and is linked to conditions like cancer and autoimmunity.

Connection #2: Leptin Resistance

Leptin is a hormone produced by fat cells that binds to receptors in the hypothalamus of the brain to signal a state of fullness. Obesity is not only associated with increased levels of leptin in circulation, but also leptin resistance. In obese people, leptin resistance has been proposed as one mechanism that drives hunger and increased calorie intake.

Leptin’s action, however, is not limited to its role in satiety. Leptin also plays a critical role in modulating the immune response. Leptin helps regulate the production of blood cells in bone marrow, the generation of T cells in the thymus, and the differentiation of T cells in the lymph nodes.

Leptin has been found to interact with macrophage activities, natural killer cell function, and the pro-inflammatory response of nonspecific immunity. Researchers propose that leptin resistance may interfere with the ability of the to mount an appropriate and effective response to pathogens.

Connection #3: Adipocyte Dysfunction

More commonly called fat cells, adipocytes are not simply benign storage depots. Instead, they collectively act as a distinct endocrine organ. Adipocytes secrete hormones, cytokines, and other proteins that influence metabolic and. Adipocytes also produce immune-related proteins, including leptin, tumor necrosis factor-alpha (TNF-alpha), and the macrophage migration inhibitory factor (MIF).

Fat cells in obese patients become engorged with lipids and activate a chronic, pro-inflammatory state within adipose tissue. Consequently, while macrophages represent only about 5 to 10 percent of cells in healthy adipose tissue, they can make up 50 percent of all cell types within obese adipose tissue. Also, hypertrophic adipose cells secrete higher levels of inflammatory mediators (such as IL-6) and lower levels of anti-inflammatory mediators (such as adiponectin).

The complete mechanisms have not yet been described, but researchers propose that the changes in adipocyte tissue function that occur in obesity may also interact with systemic immune-system regulation.

Connection #4: Fat Deposition in Lymphoid Tissue

In obese patients, fat deposition is not limited to adipose tissue. Lipids also accumulate in metabolic tissues, including two tissues that are critical to immune function: bone marrow and the thymus.

Throughout our lifespans, bone marrow continuously replenishes cells that develop into T cells, B cells, natural killer cells, macrophages, and other immune cells. T cells further develop and mature in the thymus. The generation of these immune cells depends on healthy tissue architecture of the bone marrow and thymus.

By increasing lipid deposition, obesity alters the cellular environment within lymphoid tissues and disrupts tissue integrity. Studies show that obesity is associated with thymic involution in animal models and accelerated thymic aging in humans. The result is compromised immune-cell development, migration, and diversity.

Connection #5: Dysfunctional Immune-Cell Activation

The above four mechanisms ultimately exert influence on the immune system by disrupting immune-cell activity. In addition to the immune effects already described, studies have detected the following changes in humans:

Decreased thymic output of naive T cells in obesity and insulin resistance
Increased white blood cell count in obesity and decreased white blood cell count with weight loss
Increased CD4+ cells and decreased CD8+ peripheral T cells in obesity
Increased NF-kappa B activation in peripheral blood mononuclear cells (PBMCs) in obesity
Increased peripheral TH2 and Treg cells in morbid obesity

More research is needed to fully understand the connections between obesity and immune function. In the meantime, should be considered a priority not only for the prevention of chronic illnesses, but also to support a healthier immune response to acute and infectious diseases.