Obesity and Inflammation
Obesity and Inflammation
The connection between inflammation and the obesity, depression, diabetes and heart disease epidemics
What is inflammation and why is it bad?
Acute inflammation is a series of reactions that occur within and between the cells of our bodies when an irritant or infection attacks our system. The process starts when the irritant (whether chemical or biological) damages our cells, releasing oxygen free radicals. These free radicals incite an inflammatory “cascade” of chemical reactions. In these chemical reactions, certain proteins called cytokines are generated by immune cells which attack and clear away damaged cells. When this happens in short bursts to deal with occasional threats to the body, the system is beneficial to us. However, when our bodies are constantly bombarded by irritants, a state of chronic inflammation (also called silent inflammation-because you cannot feel it happening) develops. Chronic inflammation causes untoward damage to our organs. It is well known that visceral (meaning around our organs) and abdominal fat actually produce some of the most “pro-inflammatory” hormones and proteins, creating this state of chronic inflammation. This continuous cycle damages our organs leading to diabetes, heart disease, strokes, and many cancers. These are the “epidemic” diseases that plague our modern western culture, and the culprit is the abundance of food, especially foods containing high amounts of sugar and saturated fat.
How does the inflammatory process work?
What follows is a simplified explanation of an extremely complex system, which is still being investigated. In fact, scientists still have not unraveled all of the details concerning the causes and effects of chronic inflammation.
First, cells are damaged, resulting in the release of oxygen free radicals. The free radicals then activate a substance in the cell membranes called arachidonic acid (AA). AA signals the release proteins called cytokines that perpetuate the inflammatory reactions. One of the first proteins activated and released is called Nuclear factor kappa B (NfkB). NfkB goes to the nucleus of the cell and instructs the DNA to make inflammatory proteins like Interleukin-1 (IL-1), Interleukin-6 (IL-6), C-Reactive Protein (CRP) and Tumor Necrosis Factor (TNF). Under periods of acute inflammation, these proteins breakdown and clear away damaged cells. In states of chronic inflammation, however, these inflammatory proteins cause continuous damage to many cells in the body. For example, damage to beta cells of the pancreas, which make insulin, eventually leads to diabetes. Damage to neurons in the brain can lead to Alzheimer’s disease, and damage to the endothelial cells, which line our blood vessels, can cause heart disease and strokes.
NfkB has another significant effect within our bodies. It blocks the effect of insulin, which bring glucose and amino acids from protein into our cells to be used as energy. When insulin is not as effective, more insulin needs to be secreted by the pancreas to handle the increasing blood sugar. What follows is a state of “insulin” resistance. Insulin is also “pro-inflammatory” and triggers the release of more NfkB. Insulin also promotes the storage of more body fat and prevents its breakdown for use as fuel by blocking the production of an enzyme called hormone sensitive lipase or HSL. HSL is necessary to release free fatty acids from triglycerides (stored fat) for their use as energy.
How is excess body fat involved in inflammation?
It used to be thought that excess body fat was inert, meaning it acted as little else than cushion for our organs. However, research over the past decade reveals that fat is actually a highly active endocrine organ. In fact, body fat releases chemical messengers called adipokines. These adipokines have pro-inflammatory effects. We have talked about some of these adipokines already, namely NfkB, IL-1, IL-6, CRP and TNF. However, the discovery of another adipokine called leptin in 1994 clearly established body fat as an endocrine organ. Leptin communicates with the hypopthalamus in the brain signaling the status of our energy stores. In short, it tells our brains that we have enough energy stores, resulting in a decrease in appetite, and increase in energy expenditure. Yet another adipokine, called adiponectin, has an “anti-inflammatory” effect in that it decreases the production of TNF. It has been observed that levels of leptin and adiponectin (both anit-obesity and anti-inflammatory) are decreased in obesity. While the other adipokines that are “pro-inflammatory” and “pro-obesity” (such as CRP, TNF and the interleukins) all rise in obesity. One proposed theory as to why these pro-inflammatory cytokines are released in obesity is that as the fat mass grows, the tissue becomes relatively hypoxic, meaning the cells are low on oxygen. This results in the release of cytokines that stimulate the growth of more blood vessels to nourish the fat mass, which are the very same “pro-inflammatory” cytokines that cause damage to other tissues. This theoretical model has been likened to the growth of tumors, which release the same cytokines to increase the growth of blood vessels to nourish them.
The constant state of increased inflammation as described above then brings another hormone into play. That hormone is cortisol. Our adrenal glands react to this constant state of low grade inflammation by pumping out high amounts of cortisol. Under short periods of stress, cortisol is actually anti-inflammatory. It results in increases in blood sugar which gives us energy to fight a predator or a disease. However, when the body is constantly bombarded with high levels of cortisol, such as under chronic low-grade stress from work or social pressures, several deleterious effects occur. The first is that a “catabolic state” is created resulting in the breakdown of our muscle tissue for energy. This then triggers appetite, causing us to consume more calories than are needed. These excess calories are primarly stored as fat (especially visceral fat), due to high circulating levels of pro-inflammatory proteins like NfkB which block the effect of insulin, creating insulin resistance. High circulating levels of insulin promote further fat storage and prevent breakdown of stored fat. This will be discussed in more detail later in this handout.
What are the consequences of chronic inflammation?
In 1997, a Harvard study found that healthy middle-aged men with the highest CRP(an inflammatory protein) levels were three times more likely to suffer a heart attack in the next 6 years than those with lower CRP levels. In fact, subsequent research has shown that women with high CRP levels are at even greater risk of suffering a heart attack. Many forward thinking cardiologists are now routinely testing CRP levels in patients. In 2000, researchers discovered that patients taking celebrex for arthritis were less likely to develop intestinal polyps that have the potential to become cancerous. Celebrex is an anti-inflammatory drug that inhibits an inflammatory protein called COX-2. By blocking COX-2, the inflammatory process is halted. This has led researchers to study the role of COX-2 in the development of colon cancer.
Another fascinating association between inflammation and disease came with the discovery that patients taking aspirin for heart disease or arthritis tended to develop Alzheimer’s disease much later than a cohort of patients not taking aspirin. In the brains of Alzheimer’s patients, glial cells, which are responsible for secreting inflammatory cytokines, are chronically activated. The result is an accumulation of plaques and tangles that destroy the neurons. Preliminary research shows that low dose aspirin as well as fish oil capsules reduce the risk of developing the disease.
In the 1990’s, studies in the Netherlands came across an association between depression and certain infections and cancers. However, when the immune cells of these patients were examined under the microscope, they were found to be over active, spewing out more inflammatory cytokines than normal. This finding of chronic inflammation also fit into the finding that people with depression are 3 times more likely to suffer a heart attack, also thought to be caused by inflammation in the arteries of the heart, than non-depressed people. Further studies found that drugs like interferon and IL-2, used to treat infections such as Hepatitis C and conditions such as rheumatoid arthritis, induced depression in 1/3 of treated patients. The effect was not due to the patients simply dealing with an illness, considering the depressive symptoms were specific to the medications taken. Patients on IL-2 tended to have more memory problems, and patients on interferon had slower reaction times. Also, patients treated with an antidepressant similar to prozac at the same time they received their immune boosting drug, were less likely to develop depression. It is now theorized that some antidepressants actually have anti-inflammatory actions. A recent study published in September 2006 from Emory University found that depressed patients had elevated “resting levels” of the inflammatory cytokines IL-6 and NfkB. Furthermore, when these patients were exposed to a stressful situation, they also exhibited greater increases in these inflammatory cytokines than their non-depressed counterparts.
Two other chronic diseases linked to inflammation are Metbolic Syndrome and Type 2 Diabetes. The prevalence of Metabolic syndrome among Americans between 60-70 years old is 43% and Type 2 Diabetes has reached epidemic proportions. Before the isolation of insulin in the 1920’s, doctors used high doses of salicylates (an aspirin like compound) to treat diabetes. This treatment had many negative side effects such as headaches, dizziness, ringing in the ears and intestinal bleeding. However, the blood sugars did come under better control. Although salicylates are no longer used as treatment for diabetes, researchers are reexamining the role of inflammatory cytokines in the development of type 2 diabetes. Just as in heart disease, higher levels of CRP are associated with the development of diabetes. Current treatments for metabolic syndrome and diabetes, such as metformin, may actually work by exerting an anti-inflammatory effect.
Another class of medications called statins, used to treat high cholesterol, are recognized to have significantly potent anti-inflammatory effects as well. In fact, these medications are not only effective in reducing the incidence of heart attacks in patients with high cholesterol, they are also being studied in the treatment of Alzheimer’s disease and sickle-cell anemia.
What can we do to combat inflammation, obesity and chronic disease?
As research continues, new treatments will increasingly focus on combating the underlying process of inflammation that contributes to our modern epidemics of obesity, type 2 diabetes, heart disease and depression. However, research is already confirming the powerful benefits of anti-inflammatory and anti-oxidant supplements and foods. Per haps the most compelling results come from studies showing how an increase in Omega-3 fatty acids in our diet, coupled with a decrease in sugar and saturated fat from red meat and full-fat dairy, such as cheese, can dramatically reduce chronic inflammation. Several startling laboratory discoveries examining the role of omega-3 have been made over the past decade. For starters, diets high in omega-6 fatty acids (found in grains, eggs and red meat) and low in omega-3 fatty acids are associated with higher levels of circulating PE-2, a potent pro-inflammatory cytokine, according to a study from the American Journal of Clinical Nutrition published in 2000. It has also been observed that an over consumption of omega-6 fatty acids in the form of egg yolks, meat and other animal products, promotes the entire chronic inflammatory cascade because of higher circulating levels of arachidonic acid (AA). AA is actually one form of omega-6 fatty acid. Further studies confirm that EPA, one of the omega-3 fatty acids found in fatty cold water fish, is a competitive inhibitor of the conversion of AA to PE-2. Therefore, the entire inflammatory cascade can be dampened by consuming omega-3 fatty acids. Omega-3 fatty acid has also been shown to block the release of a protein called SREBP-1. This protein switches on a gene which codes for the release of a substance called fatty acid synthase. By blocking the production of fatty acid synthase, less energy is stored as fat and more is stored as glycogen in the liver. This stored glycogen can then be used for immediate energy needs. When less energy is stored as fat, less chronic inflammation is observed, as we have outlined above. Furthermore, omega-3 fatty acids are also known to bind to receptors in our cell walls called PPAR’s. Once bound, a gene is activated that turns on a substance called uncoupling protein-3, which causes us to burn more energy in the form of heat (called thermogenesis) after we consume a meal containing these essential fatty acids.
Other anti-oxidant and anti-inflammatory foods and supplements have also been found to dampen the chronic inflammatory response and treat many chronic diseases. Further discussions or handouts will review some of the exciting research around supplements such as CLA, CoQ-10, chromium and glutamine, as well as regular exercise and how they can all aid in our defense against chronic inflammation and disease.
