If you find obesity and its associated comorbidities then inflammation is sure to be close by. The connections between these three spin such a web it is hard to tell where the start, middle, and end of the obesity web are. For example, does obesity cause comorbidity and inflammation independently or are the three dominoes in a line. To further complicate the predicament classically associated obesity comorbidities can be caused by inflammation without obesity. For example, the gram negative bacteria cell associated lipopolysaccharide, activating the tried and true TLR->NFKB->gene expression->cytokine pathway ( or down regulation of PAPP-gamma according to the literature you read, both of which suppress GLUT 4 by different means) results in type 2 diabetes. Wow, if that doesn’t make you scratch your head I don’t know what will, and it gets better. Preadipocytes can exhibit phagocytic activity, secrete cytokines, and can become adipocytes or macrophages. At this point you should be having a mid-life immunologic crisis. Rest assured though, with reductionism to the rescue we will tackle the inflammation obesity predicament piece by piece, one at a time. For example obesity can cause fat deposition in the liver. Many proinflammatory cytokines such as CRP are produced by the liver (one possibility for the source of chronic inflammation.).
Sometimes the obesity web actually makes sense. In the obese state a large number of macrophages infiltrate the adipose tissue possibly to clear necrotic adiposity. Secreting TNF-alpha the macrophages inhibit insulin receptors and suppress GLUT 4 expression causing insulin resistance. According to Ping et. al. in the obese state macrophages in adiposity are in the M1 polarization alternatively macrophages in the lean state are of the M2 polarization suggesting obesity is proinflammatory. Macrophages in the proinflammatory state also cause atherosclerosis.
To be a large cell such as a growing adipocyte you need a lot of oxygen. One theory to the systemic inflammation associated with obesity is that as adipocytes get too large they no longer receive adequate oxygen. They might die because of it causing the large influx of macrophages which in turn cause inflammation. Or alternatively they might release cytokines to self induce insulin resistance so they wont get any larger which causes a secondary systemic inflammation.
Systemic inflammation associated with obesity is multifaceted. Macrophages and adipocytes are the primary source of the inflammation but there are many secondary and treachery contributors making pointing the finger to the culprit difficult but this knowledge helps to delineate solutions to the problem.
-Randy, who has a serious case of blogitis and is amused that despite agreeing with his 495 partner Elham to blog on different topics still managed to cover the same material. Seriously, not my bad yall.
Citations:
Jia0, Ping. "Adipose inflammation: cause or consequence of obestiy-related insulin resistance." Diabetes, Metabolic Syndrome, and Obesity Dove Medical Press 2008;1 25-31
O'rourke, Robert. "Inflammation in obesity-related diseases." Surgical Research Review
Mosby inc 2009; 255-259
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I share the sentiment of this post.
ReplyDeleteAfter reading the Nystrom and Sjoholm article "Inflammation and the Etiology of Type 2 Diabetes", I felt like I was caught in a web trying to figure out what was underlying cause of type 2 diabetes.
When examining the connection between inflammatory activity and the risk for developing type 2 diabetes, the WOSCOPS study found Prvastatin reduced the relative risk of developing diabetes by 30% compared to the placebo.
Pravastatin is a cholesterol (LDL) reducing drug, but the article hinted at a desire to claim Pravastatin's antiinflammatory properties explain why it reduced the risk of Diabetes in the WOSCOPS study. And though it seemed logical, the article went on to report many drugs that interfere with cholesterol production, inflammation, Angiotensin Converting Enzyme, etcc, and their benefits to preventing/treating type 2 diabetes. It's helpful to treat the inflammation, but are they treating the problem? Tres interesant.
Love,
Ben
Hey Ben,
ReplyDeleteI remember you saying were a grad student so you are probably accustomed to overlapping and conflicting theories. In most of the papers I read the therapy targeted prevention of diseases that arose from the inflammation like activating kinases that inhibit cytokine production or IgG specifit towards proinflammatory cytokins. I think the “cure” to all this would be to lose the weight which seems to be the source of the chronic inflammation causing so much trouble. Actually one theory is that type 2 diabetes is the adipocytes way of trying to avoid getting any bigger so in a way these therapies could do more harm by allowing more obesity which would result in more inflammation.
Peace,
Randy