In the past, fat tissue was considered to be inert—a place where excess energy was stored in the form of triglycerides to be released in time of need, such as starvation. The discovery of leptin by Friedman and colleagues1 at Rockefeller University in 1995 resulted in a paradigm shift in this thinking. Leptin is a hormone that is exclusively produced by fat cells and regulates the brain to modulate food intake and energy expenditure. Subsequently, fat cells and other components of fat tissue, such as stromal cells, have been found to produce many hormones that can modulate the body’s immune responses. These proteins are termed “adipokines.” Plasminogen activator inhibitor-1, or PAI-1, is one such adipokine that plays a role in breaking down blood clots and increases the risk of heart disease. Some adipokines can be potentially harmful to the body, while others may be beneficial.
In 2005, a report by Ferrante2 and colleagues described that fat tissue of obese animals was infiltrated by an intriguing type of inflammatory cell known as the macrophage. They found that rodents with a genetic form of obesity or those fed a high fat diet displayed a state of chronic inflammation and accumulated these macrophages in their fat tissue. These cells produced large amounts of inflammatory cytokines. In an article published at the same time, Xu and colleagues3 confirmed these findings and demonstrated that such an accumulation of macrophages was associated with the development of insulin resistance (a condition that precedes the development of type 2 diabetes).
In a recent report published in “Science Translational Medicine”4 we describe that elevated amounts of fat molecules (called free fatty acids) circulating in the blood, as seen in obesity and type 2 diabetes, can directly increase important markers of cardiovascular disease risk. This seems to be due to the activation of macrophages that congregate in fat tissue when people become obese. Under normal circumstances, these cells (macrophages) may have health-maintaining functions, such as to fight off an infectious process. We have shown that increased circulating free fatty acids cause these cells to become activated and produce potentially harmful cytokines (signaling molecules). It is now believed that elevated levels of circulating cytokines increase the risk of diabetes and heart disease. Moreover, substances secreted locally by the fat tissue seem to work together with the elevated, circulating, free fatty acids to activate these macrophages.
We infused a fat mixture in the veins of overweight but otherwise healthy, nondiabetic adults in order to raise their circulating free fatty acids levels to those characteristically seen in obesity and type 2 diabetes. With a larger number of fatty acids, their bodies did not respond effectively to insulin (i.e. they became insulin resistant). In addition, an inhibitor that serves as an important marker of cardiovascular risk known as PAI_1 was increased in circulation. This confirmed findings of other investigators and provided further support for the link between obesity and increased risk of cardiovascular events.
More importantly, we examined subcutaneous fat tissue from these individuals and showed that the specialized inflammatory cells within fat tissue (macrophages) produced more of this particular cardiovascular marker when exposed to increased fatty acids. We found that exposing macrophages to extract from fat cells or free fatty acids in a dish resulted in their activation. Interestingly, this activation was significantly higher when we combined the fat extract and free fatty acids, suggesting that fat tissue and fatty acids worked in synergy to increase the activation of macrophages. This explains how macrophages residing within fat tissue become activated with weight gain, and how they ultimately contribute to the many consequences of obesity.
While inflammation is a normal, healthy process to fight infection, it can become inappropriately activated in obesity, with serious consequences. Many chronic diseases such as heart disease,5 type 2 diabetes,6 and even many types of cancer7 may be related to chronic inflammation. This research is an attempt to understand the inter-relationships between these conditions and their relationship to the inflammatory processes. These new findings in human subjects help to explain why fat tissue becomes inappropriately inflamed in obesity, and highlight the importance of circulating free fatty acids, as well as fat tissue, in increasing the risks of diabetes and cardiovascular diseases. Currently, free fatty acids are not considered a target for treatment with drugs, although some diabetes drugs or weight loss can somewhat reduce blood levels. Understanding these mechanisms and identifying the fat-derived factors that activate macrophages could lead to new targeted therapies for these conditions, which have increased to epidemic proportions globally.
This project was supported by the National Institutes of Health, Einstein’s Clinical Research Center, Einstein’s Diabetes Research and Training Center and the American Federation of Aging Research.
References
1Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.
2Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 Dec;112(12):1796-808.
3Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003 Dec;112(12):1821-30.
4P. Kishore, J. Tonelli, W. Li, Kehao Zhang, C. Weaver, U. Schubart, E. Goodman, and M. Hawkins. Activation of adipose tissue macrophages by FFA contribute to atherothrombotic risk. Science Translational Medicine 2010 Feb 2(20), p. 20ra15.
5Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–26, 1999.
6Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860-7, 2006.
7Coussens LM, Werb Z. Inflammation and cancer. Nature 420:860-7, 2002.
Original article:
“Adipocyte-Derived Factors Potentiate Nutrient-Induced Production of Plasminogen Activator Inhibitor–1 by Macrophages.”
Preeti Kishore1,2, Weijie Li1, Julia Tonelli1, Do-Eun Lee1, Sudha Koppaka1, Kehao Zhang1, Ying Lin3, Sylvia Kehlenbrink1, Philipp E. Scherer4 and Meredith Hawkins1,2
1Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
(This is a summary by one of the study’s co-authors. Full text appears in Science Translational Medicine, Feb. 24, 2010, Vol. 2, Issue 20, p. 20ra15.)