AMERICA AND ADIPOCYTES: WHY LIPOSUCTION IS NOT THE ANSWER
Roughly 65% of Americans are overweight, 23% are obese, and not surprisingly these numbers continue to rise.[1] There are three classifications of obesity as published by the World Health Organization (WHO) utilizing the body mass index (BMI) which is computed by dividing weight in kilograms by height in meters. [2] Individuals with a BMI greater that 25 are considered overweight or of class I, people with a BMI greater than 30 are obese (class II), and those with a BMI over 40 are morbidly obese, and have an associated increased risk of death. [2]
The obesity problem translates into over 30 billion dollars yearly in spending on weight management products and services. [3] On an individual level, obesity can result in the development of various health problems and complications. The risk of acquiring heart disease, diabetes, dyslipidemia, arthritis, stroke and cancers such as breast, colon and kidney are increased in obese individuals. [4] Obese women are seven times more likely than women of normal weight to acquire type II diabetes. [2] Obesity may also have a detrimental effect on self esteem, which in turn often leads to depression. Obese individuals may suffer from discrimination from their peers and co-workers due to their physical appearance.
Despite these growing issues surrounding obesity, our scientific knowledge of how fat tissue is regulated in the body and our discovery of potential therapeutics for treating the condition is limited. When one considers the severity of the obesity condition, it’s surprising how very little is known about the regulation of fat cells and tissue, as well as the metabolism and signaling networks that occur within these cells.
So why is obesity such an increasing problem? There are many factors effecting obesity, such as genetics, diet, environment and exercise. [5] Although genetics has been suggested to account for approximately 50-90% of obese individuals, this does not explain the sharp increase in the number of obese individuals over the last 10-20 years. [6] Environmental changes such as diet and exercise, and the sedentary American lifestyle are most likely accountable for this increase. Although the ideal solution to the obesity epidemic would be to ban the western world from cars, elevators, McDonalds, computers and televisions, no one in this age of technology would be willing to make these sacrifices. Since it is difficult to alter high fat diets and change the increasingly sedentary American lifestyle, scientists and pharmaceutical companies have turned to studying the pesky adipocyte, or fat cell, for new approaches to combating obesity.
Although the development of fat cells, a process known as adipogenesis, begins in the womb, fat cell creation occurs throughout the human lifespan. [5] The process of adipogenesis begins with mesenchymal cells, which give rise to preadipocytes. [6] These preadipocytes differentiate into full fledged fat cells, or adipocytes. Adipocytes store triglycerides, also known as fats, when they are in excess and break down lipids into free fatty acids when they are needed by the body. These adipocytes store and uptake lipids, and can increase up to 1000x their original size if need be. [6] This adipocyte cell enlargement is known as hypertrophy. Once adipocytes reach a threshold size, they secrete factors such as hormones and growth factors that stimulate surrounding pre-adipocytes to differentiate irreversibly into new adipocytes. This process increases the total number of adipocytes, a process known as hyperplasia. [6] Adipocytes communicate with the brain and peripheral tissues through the use of adipokines, which send metabolic signals for food intake and energy usage. Adipokines signal for processes such as glucose production in the liver, glucose and lipid use in muscle and the release and mobilization of lipids from fat tissue. [7]
Pre-adipocytes and adipocytes can be grown in the laboratory to study the differentiation process from pre-adipocyte to adipocyte. These cell lines can also be used to study the metabolic processes and the effects of potential therapeutics on fat cells. Both pre-adipocytes and adipocytes can be taken from the adipose tissues of mice or other mammals, but it is difficult to grow and maintain these pre-adipocytes outside of the body in this manner, and as a result adipocytes do not survive well in this external cell culture environment. However, several pre-adipocyte cell lines have been created and are available, and these cells can be easily and consistently differentiated into adipocytes. Cell lines will grow and divide much longer outside the organism than normal cells as they have been treated and immortalized. Two cell lines are commonly utilized for studying fat cells; 3T3-L1, and 3T3-F442A, both of which are derived from mice. [8]
When 3T3-F442A cells were implanted into mice, they differentiated to give rise to a fat pad that was nearly identical to normal mouse adipose tissue. [9] As a result, this cell line allows researchers to efficiently differentiate and grow adipocytes in the laboratory that are virtually identical to real mouse fat cells. The ability to grow these cells in the laboratory, coupled with the availability of animal models of obesity, such as in mice, provide researchers with a variety of resources for understanding adipocyte function and for finding potential therapeutics.
Adipose tissue does not just consist of fat cells but also contains blood vessels, lymph nodes and nerves, which can also be targeted for obesity targeted drug development. Some potential therapeutic strategies for treating obesity include; inhibiting the differentiation/proliferation of pre-adipocytes, preventing blood vessel growth/expansion into fat tissue, targeting adipocyte cell death, and inhibiting adipokine production and secretion. [7]
Several areas of drug development and research entail blocking pre-adipocyte differentiation into adipocytes. Although an excess amount of fat is a health hazard, adipogenesis and fat tissue is required for functional and healthy adipose tissue. Lipotrophy, or a lack of fat tissue increases the risk of insulin resistance, type II diabetes and cardiovascular diseases. [7] Therefore it is important to keep in mind that preventing fat cell development may induce other problems and side effects.
Since fat cells have a low turnover rate in adult tissue, they may not die within a few months, years, and sometimes they will not turn over at all. Therefore, targeted killing of existing adipocytes may be a better option for therapeutics. [7] However this may result in a large release of lipid in a short period of time that would be difficult for the body to clear, and could have detrimental results.
Adipose tissue mass is dependent on both the number and size of adipocytes, and when these fat cells become saturated with lipid, adipogenesis is subsequently stimulated. This process could be avoided by developing a therapeutic that prevents lipid uptake by fat tissues. Unfortunately this tactic will probably increase lipid levels in other areas of the body, resulting in other complications.
Blood vessels supply vital nutrients and oxygen to adipocytes, and thus preventing blood vessel growth is an attractive method for maintaining a healthy amount of adipose tissue. Adipose tissue has a high concentration of blood vessels and it has been shown in an obese mouse model that preventing angiogenesis (also known as blood vessel growth) results in a loss of adipose tissue. [10] However it would be difficult to apply this method in a clinical setting, as inhibiting angiogenesis only within adipose tissue while maintaining normal blood vessel growth elsewhere in the body, will prove challenging.
Although there is significantly less known about adipocyte function and homeostasis then in many other cell types, they are still an important drug target. There are many questions that need to be answered when it comes to adipocyte research but once we understand some of these questions, finding a successful therapeutic will be much easier.
References:
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4 Mokdad, A. H., Ford, E. S., Bowman, B. A., Dietz, W. H., Vinicor, F., Bales, V. S. and Marks, J. S., Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001, Jama, 2003, 289: 76-79.
5 Daniels, J., Obesity: America’s epidemic, Am J Nurs, 2006, 106: 40-49, quiz 49-50.
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7 Nawrocki, A. R. and Scherer, P. E., Keynote review: the adipocyte as a drug discovery target, Drug Discov Today, 2005, 10: 1219-1230.
8 Otto, T. C. and Lane, M. D., Adipose development: from stem cell to adipocyte, Crit Rev Biochem Mol Biol, 2005, 40: 229-242.
9 Green, H. and Kehinde, O., Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line, J Cell Physiol, 1979, 101: 169-171.
10 Rupnick, M. A., Panigrahy, D., Zhang, C. Y., Dallabrida, S. M., Lowell, B. B., Langer, R. and Folkman, M. J., Adipose tissue mass can be regulated through the vasculature, Proc Natl Acad Sci U S A, 2002, 99: 10730-10735.