Hi everyone! As you all know, our topic this week is the inflammatory processes involved with obesity and diabetes. The rate of obesity in the U.S. has increased dramatically since the 1990's and has contributed to many metabolic disorders, especially diabetes. Diabetes is marked by chronically high levels of glucose in the blood due to the insensitivity of our cells to insulin. People with diabetes are unable to take up glucose into their cells because they have acquired insulin resistance.
The paper I focused on this week was the review article on inflammation and metabolic disorders. It covered obesity and diabetes along with a slew of other metabolic disorders including hypertension and atherosclerosis. One of the things about the article that I found intriguing was the discussion of two key regulatory hormones involved in obesity: leptin and adiponectin. Obesity itself is mediated by leptin, which is a
hormone that controls food intake and body weight through its binding and
activation of leptin receptors (OBR). High levels of leptin usually promote
weight loss, but in obese people, high levels of leptin have no effect. This
is referred to as leptin resistance and is associated with diabetes.
In regard to inflammation, leptin regulates components
of innate and adaptive immunity, including T lymphocytes and monocytes.
Leptin also has structural and functional resemblance to proinflammatory
cytokines, such as IL-6 and may regulate C-reactive protein (CRP).
It is referred to as an adipocytokine. Leptin has been found to be
an insulin-sensitizing hormone, but increased amounts of non-functional
leptin in the circulation of obese people is associated with hyperinsulinemia
and insulin resistance.
Adiponectin is a hormone secreted from
fat tissue that increases insulin sensitivity. However, as body mass increases, serum
adiponectin levels decrease. Less circulating adiponectin means that insulin sensitivity is
decreased, which can lead to diabetes. Adiponectin also normally inhibits the
expression of proinflammatory cytokines such as TNF-alpha, but with less
adiponectin being produced, these cytokines are more highly expressed, leading
to an inflammatory state.
The article also briefly discussed the role of lipid oxidation in inflammation, but they didn't do a very thorough job in explaining it. So, I thought this would be a great question to pose to all you bloggers! How does the process of lipid oxidation work? How are reactive oxygen and nitrogen species involved? And what are the consequences of having these oxidized lipids in our circulation? How does the process promote inflammation??
Hopefully this will give everyone some food for thought!
With regards to your questions, the reactive oxygen species and nitrogen species are examples of free radicals. What these free radicals do is steal the electron from the lipid portion of cell membranes, and this process is called lipid oxidation or lipid peroxidation. This is a really unfortunate event because when the oxidation happens, the cells get damage and eventually die. With these damaged cells present, we can expect immune responses and inflammatory cytokine responses which cause inflammation that may last for a short time or a long time.
ReplyDeleteGoing over what you said in the first part of you blog, the body has a lot of supportive mechanisms that keeps the body in good shape, however, many mechanisms we have encountered throughout our physiology courses have showed us that many of these mechanisms have thresholds and the prolonged exposure to these mechanisms usually results in the resistance development. It seems like when your body develops these resistances, they are saying that they have given up and it is up to the person as a whole to make changes and get the system back to work properly.
Thanks for your response! I don't think I realized just how prevalent lipids are in the body, due to their structural function as the major component of all cell membranes. Since the oxidation is happening to the lipids within the membrane, it makes a lot of sense that the cell will be subject to serious damage and eventually death after this oxidation event. The membrane is what holds the entire cell together, after all!
ReplyDeleteAnd you make an interesting point about how resistance develops! I completely agree; I believe that our bodies can only handle a certain amount of certain compounds and signals, and after so long, the normal mechanisms that regulate them are not able to function properly. It's like our body's way of telling us that it's had enough.
I was doing some research on CVD for another class and came across an article related to lipid oxidation that I thought was interesting.
ReplyDeleteThe article I found talks about the effects of cranberry juice, which has known antioxidant properties, on people that have been diagnosed with metabolic syndrome. They found that the dose of cranberry juice given to the subjects with Metabolic Syndrome reduced the amounts of oxidized LDL and MDA in their plasma, which are markers of oxidative stress and have become strongly correlated with Metabolic Syndrome. In this specific study there was not any notable differences that the cranberry juice had on markers of inflammation, but they hypothesized based on other similar studies that larger doses of cranberry juice may reduce markers of inflammation such as IL-6 which is often associated with Metabolic Syndrome.
I just thought it was interesting that the effects of lipid oxidation can be modified so easily by something as simple as our diet and that there is new research going on to investigate how we can control the inflammatory responses associated with Metabolic Syndrome.
Basu A, Betts NM, Ortiz J, et al. Low-energy Cranberry Juice decreases Lipid Oxidation and increases plasma antioxidant capacity in Women with Metabolic Syndrome. Nutrition Research. 2011;30:190-196
ReplyDeleteAfter reading the article, I decided to do some more research on lipid oxidation and how it affects those with metabolic syndrome as well as hypertension and atherosclerosis. We already know that with Metabolic Syndrome, there is a large amount of oxidized lipids, specifically oxidized LDL. This leads to higher levels of circulating oxidized LDL and this can contribute to an increased risk of myocardial infarction. I found an article titled “Metabolic Syndrome, Inflammation, and Atherosclerosis.” While reading the article for class, I realized there hasn’t been much information as to how the hormone adiponectin contributes to atherosclerosis. As Kelly mentioned, normally adiponectin decreases macrophage phagocytic activity. According to the article I found, this is done by decreasing the endothelial expression of adhesion molecules (intercellular adhesion molecule-1[CAM-1], vascular cell adhesion molecule-1[VCAM-1], P-selectin). On the other hand, resistin, a protein that is expressed primarily in macrophages and is correlated with markers of inflammation, increases the expression of these adhesion molecules. As a result, adiponectin and resitin interfere with monocyte adherence to vascular endothelium, promoting monocytic migration to the subendothelial space. This event contributes to atherosclerosis. Sometimes I need to know more about the mechanism in order to understand the process. Hopefully this article I found helps you understand the topic as well.
Paoletti, Rodolfo, Chiara Bolego, Andrea Poli, and Andrea Cignarella. "Metabolic
Syndrome, Inflammation and Atherosclerosis." Journal of Vascular Health and Risk Management 2.2 (2006): 145-52. Web.
.
Ok.. sorry for the long blog, but I went into a lot of detail.
ReplyDeleteLipid oxidation AKA: Lipid peroxidation is the process of breaking down lipids. It occurs when free radicals (An uncharged molecule (typically highly reactive and short-lived) having an unpaired valence electron) take electrons from the cell membrane lipids. This in turn, causes damage to the cell because they’re stealing electrons from the lipid which promotes lipid degeneration. Therefore, this has a huge effect on the plasma membrane since one of the key elements to the plasma membrane is its lipid bilayer.
Lipid oxidation mechanism involves a free radical chain reaction mechanism between a radical and a non-radical species. This mechanism is described in three steps: initiation, propagation and termination.
The first step, initiation involves reactive oxygen species (ROS- chemically reactive molecules containing oxygen.) colliding with H+ atoms to produce a fatty acid radical. To state clearer, ROS’s such as OH and HO2 combine with an H+ to make H20 and an unstable fatty acid radical.
During the second step propagation, the fatty acid radical that has been produced acts on the O2 because of its unstable nature and creates peroxyl-fatty acid radical which elicits instability as well. This instability allows for the unstable reactive species to react readily with another non-radical species which in this case is another free fatty acid. The interaction between the peroxyl fatty acid radical and the free fatty acid (non-radical) produces a different fatty acid radical and lipid peroxide.
The last step termination occurs when two radical reactions react with one another to produce a non-radical species. Normally, when a radical chain reaction occurs it is stimulated by the reaction between a radical and a non-radical to produces another radical which keeps the reaction going. But as seen in the termination sequence, with the presence of two radicals producing a non-radical species, the radical chain reaction stops. This mainly happens when the concentration of radicals increases to a high enough concentration that the probability of collision between the two radicals is higher than the probability of a radical colliding with a non-radical.
If termination is not sped up then damage to the cell membrane can occur because of the loss of high concentration of lipids in the membrane. With this decrease the cell membrane will become damaged and cause a release of phospholipids E2 out of the cell. This release calls in macrophages and WBC. Macrophages will eat the debris and the WBC will release a chemical called hypochlorite which will not only sterilize the area but all damage adjacent cell membrane thus resulting in the release of more phospholipids E2 worsening the problem. Without the “balancing” aspects of prostaglandins 1 and 3 (which are found in high concentrations within the plasma membrane and are termed “good”) inflammation can erupt.
http://www.backtolifehealth.com/Inflammation.htm
http://en.wikipedia.org/wiki/Lipid_peroxidation
Wow! After reading all of your comments, I can really say I have a good handle on the process of lipid oxidation and the real effects it has on the process of atherosclerosis. April, I thought it was really interesting that you were able to find a simple lifestyle change that can lower the risk of atherosclerosis and other cardiovascular risk associated with diabetes. It's empowering to know that there is always something we can do to reverse aberrant processes in our bodies.
ReplyDeleteZinnia, I completely agree, it's really helpful to know some background information in order to understand the complicated mechanisms involved in diabetes and cardiovascular disease. I thought it was interesting that the two different compounds, adiponectin and resistin, work in different ways to cause the same effect, which is the interference of monocyte adhesion and migration. It goes to show how different mechanisms work in tandem to cause the problems we see in metabolic disease.
And Nicole, I really got a lot out of your blog! It's helpful to understand what is happening on the molecular level in order to see the effects it has on our bodies as a whole. I thought it was interesting that the process can be continually propagated, leading to the nasty cycle that eventually causes the inflammatory events you discussed. It's scary to think that these oxidation events could be going on in our bodies as we speak!
Thanks for all of your wonderful comments, I learned a lot and enjoyed your insights!