Obesity and medical conditions associated with being overweight have become epidemic in the United States.1 Other countries are seeing similar trends as they adopt the Western lifestyle, experiencing the labor-saving devices and high-calorie foods that Americans have enjoyed for decades. Bodybuilders exist at the opposite extreme of the morbidly obese, but share the desire to decrease body fat stores. In the case of bodybuilders, that would be to the absolute minimum. This common goal makes obesity treatment drugs and methods topics of great interest to these athletes, as well as performance athletes, celebrities, models and others who are concerned about their physical health and appearance.

Pharmaceutical approaches have focused upon two methods of decreasing body fat stores, or fat mass. Those are increasing energy expenditure (number of calories burned) or decreasing calories consumed (appetite suppressants, enzyme blockers or binders). These methods have had little effect upon the obesity epidemic, particularly as few are approved for long-term use. In fact, two of the most effective pharmaceutical drugs (fenfluramine and dexfenfluramine) have been removed from the market due to serious, even fatal, side effects. All these drugs depend on the fat cells releasing fat to meet the caloric needs of the body. Unfortunately, failure is only a buffet away.

    A Symbiotic Relationship
An interesting area of study was recently reviewed in the journal Nutrition Reviews.2 Researchers have been investigating the relationship between blood vessel growth and fat stores, reporting several very interesting discoveries. There is a body of evidence demonstrating that fat tissue is not a fixed number of "bags" that empty or fill passively based on the overall energy balance. Rather, we now know fat cells communicate with the rest of the body, signaling when fat stores are too high or too low. Hormones released by the fat cell, such as leptin and adiponectin, are of great interest to scientists, as they have been shown to alter other functions and behaviors, such as feeding, metabolic rate and body temperature.

Less well known and understood is the ability of fat cells to "remodel."3 Fat cells (adipocytes) are commonly thought to be fixed in number. In other words, you have the same number of fat cells your entire life. They merely increase or decrease in size depending upon how much fat is stored. Despite hearing this from every diet expert, even plastic surgeons who claim liposuction will permanently remove fat, it is wrong.

From test tubes to animal studies, scientists have discovered that immature fat cells coexist with vascular endothelial cells (cells later forming blood vessels).3-5 Mature adipose tissue, also called white adipose tissue, is composed of large, fully developed adipocytes and its accompanying blood supply (microvasculature). White adipose tissue is the subcutaneous fat that blurs muscle definition.

As fat develops, the formation of new fat cells and blood vessels are closely related. Even once the fat is fully matured, the blood supply expands to meet the metabolic needs of the growing fat mass.6 This relationship goes beyond the development of a blood supply to deliver oxygen. In fact, fat cells secrete hormones and growth factors into the surrounding area that directly stimulate the growth and formation of new blood vessels. A number of different growth factors have been identified, including vascular endothelial growth factor (VEGF) and monobutyrin.7,8

The communication between the fat cells and endothelial cells is two-way, as endothelial cells secrete a number of growth factors that target immature adipocytes. These growth factors stimulate immature fat cells to develop and multiply.9-11 This relationship is symbiotic, as the growth of each type of cell is supported by, and dependent upon, the other. In other words, as fat cells grow and flourish, so do endothelial cells and vice versa. However, if either should be prevented from signaling to the other, both would suffer and dwindle.

This relationship led researchers to investigate whether blocking new blood vessel growth would have an effect on body fat stores. As would be expected, with their new understanding of the relationship between fat cells and blood vessel development, blocking new blood vessel growth causes a reduction in body weight, with nearly all the weight loss coming from fat loss.12 In animal studies, no adverse effects were noted, nor were there any organ changes associated with drugs known to block blood vessel growth.12

    Angiogenesis Inhibitors: Great Promise?
These drugs, called angiogenesis inhibitors, are used in clinical medicine to treat cancerous tumors. Angiogenesis inhibitors are able to reduce malignant tumors by preventing blood vessels from directly supplying a tumor, thereby starving it and preventing its growth.

When genetically obese lab animals were treated with angiogenesis inhibitors, they experienced a rapid and dose-dependent reduction in weight and fat mass. The reduction in body weight was very specific to the fat compartment, with little effect on lean body mass.12

Other effects were noted during the administration of the angiogenesis inhibitors. The basal metabolic rate was increased with a shift in substrate utilization to fatty acids.12 This means the rats burned more calories at rest, with more of the calories burned coming from fat calories. The weight loss effect of angiogenesis inhibitors was noted in rats of all ages, not just newborn or juvenile rats. This suggests that the vascular supply of fat tissue is maintained in an immature state, so as to be responsive to changes in the environment, and is continually sensitive to inhibitors.2 One question that needs to be evaluated is the effect of angiogenesis inhibitors upon skeletal muscle, particularly during periods of growth (resistance training, steroid hormones, etc). It would be of little value to athletes if these drugs were developed for fat loss, but prevented muscle hypertrophy or strength increases.

While the angiogenesis inhibitors did decrease appetite initially, food intake returned to normal during the study. It's suggested that the decrease in appetite comes from the greater number of calories made available from releasing and burning fatty acids, as opposed to carbohydrates.

Once the obese rats reached a normal weight, fat loss plateaued. While the angiogenesis inhibitors were very effective in weight reduction, it's believed other mechanisms involved in weight maintenance countered further fat loss.2

This area of research holds great promise. Angiogenesis inhibitors may represent another, possibly better, method of treating obesity. Considering how this class of drugs appears to be specific in causing fat loss, without reducing lean body mass, and has no reported adverse effects to date, it is highly likely that several major pharmaceutical companies will be developing new drugs. Once the resources of these manufacturing giants are put in place, angiogenesis inhibitors with more rapid effect and greater potency are certain to be discovered. Not only will the obese benefit, but also people at risk for adult-onset diabetes, as angiogenesis inhibitors have been found to lower blood glucose and insulin levels, improving insulin sensitivity.12

Questions Remain
It is entirely too soon to make any declaration as to whether angiogenesis inhibitors may one day provide another weapon in the pharmaceutical arsenal against obesity or aid athletes in reducing fat stores. While the early research is very promising in terms of correcting pathologic conditions (severe obesity, adult-onset diabetes, etc.), several questions need to be answered before this avenue of pursuit can be recommended to professionals working with healthy adults and athletes. As mentioned previously, it's unknown if angiogenesis inhibitors would block the growth of blood vessels to skeletal muscle, preventing muscle hypertrophy, strength gains or endurance benefits under conditions of muscle growth. It is possible that the angiogenesis inhibitors could block the training effect of both endurance training and strength training, as the greater metabolic demand of the working skeletal muscle may not be met if new blood vessels cannot be formed.

Though no adverse effects have been noted in animal studies, it's important to see if any side effects occur in larger clinical trials involving humans. One drug in this class, Thalidomide, was responsible for an epidemic of severe, disfiguring birth defects. Children born to mothers who used Thalidomide had arms and legs that did not develop.13 These children were called "flipper babies," as the deformed limbs resembled the flippers of a seal, rather than arms or legs. Also, it's likely that any true benefit for athletes will have to await the development of newer, more potent drugs. The angiogenesis inhibitors available currently appeared to plateau once normal body weight and fat stores were achieved. It is probable that one or more chemical analogs will be developed that continue to decrease fat mass down to levels more suited for bodybuilders and athletes.

The authors of the review noted that two compounds present in the diet have angiogenesis inhibitor effects. Green tea catechins (EGCG) and soy isoflavones have been identified as anti-angiogenic.14,15 It is unlikely that this effect, using green tea or soy extracts, would be strong enough to cause weight loss. However, this may explain some of the fat loss effect seen using these compounds.

These drugs represent an exciting breakthrough, as they involve a new pathway for combating obesity. As the pharmaceutical industry works to develop these drugs, bodybuilders, athletes and the media will be watching with interest.

References
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2.    Liu L, Meydani M. Angiogenesis inhibitors may regulate adiposity. Nutr Rev, 2003;61(11):384-7.
3.    Aoki S, Toda S, et al. Coculture of endothelial cells and mature adipocytes actively promotes immature preadipocyte development in vitro. Cell Struct Funct, 2003;28:55-60.
4.    Crandall DL, Hausman GJ, et al. A review of the microcirculation of adipose tissue: anatomic, metabolic and angiogenic perspectives. Microcirculation, 1997;4:211-32.
5.    Poissonnet CM, Burdi AR, et al. Growth and development of human adipose tissue during early gestation. Early Hum Dev, 1983;8:1-11.
6.    Castellot JJ (Jr), Karnovsky MJ, et al. Potent stimulation of vascular endothelial cell growth by differentiated 3T3 adipocytes. Proc Natl Acad Sci U.S.A., 1980;77:6007-11.
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8.    Dobson DE, Kambe A, et al. 1-Butyrl-glycerol: a novel angiogenesis factor secreted by differentiating adipocytes. Cell, 1990;61:223-30.
9.    Brooks RA, Burrin JM, et al. Characterization of release of basic fibroblast growth factor from bovine retinal endothelial cells in monolayer cultures. Biochem J, 1991;276:113-20.
10.    Varzaneh FE, Shillabeer G, et al. Extracellular matrix components secreted by microvascular endothelial cells stimulate preadipocyte differentiation in vitro. Metabolism, 1994;43:906-12.
11.    Lau DC, Shillabeer G, et al. Paracrine interactions in adipose tissue development and growth. Int J Obes Relat Metab Disord, 1996;20:S16-25.
12.    Rupnick MA, Panigrahy D, et al. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U.S.A., 2002;99:10730-5.
13.    Shannon M. Thalidomide. J Toxicol Clin Toxicol, 1996;34(5):636.
14.    Cao Y, Cao R. Angiogenesis inhibited by drinking tea. Nature, 1999;398:381.
15.    Joussen AM, Rohrscheider K, et al. Treatment of corneal neovascularization with dietary isoflavonoids and flavonoids. Exp Eye Res, 2000;71:483-7.