We live in an exciting time of unparalleled breakthroughs in medical science. Investigation into human genetics and the human genome promise great things. Undoubtedly, this genetic research will be very fruitful for bodybuilders. The better we understand the complexities of our bodies, the better able we will be to control the anabolic aspects of our biochemistry. The notion that we must play with the genetic hand dealt us may soon change.  

On of the most promising genetic breakthroughs for bodybuilders is the discovery of the protein leptin. In 1994, researches investigating obese mice found an obesity gene. The mutation of this gene resulted in the mice no longer producing leptin (from the greek Leptos; meaning thin) which researchers concluded was what lead to the obesity observed in the mice. Of course, the logical thing to do was to inject our chubby little friends with exogenous leptin. The results were impressive, the mice's appetite decreased, their metabolisms increased, and they lost weight. Furthermore, it was not only mouse leptin that worked, human leptin produced the same the response in the obese mice.  

Immediately everyone was wondering if leptin would produce similar results in obese humans. Could they have discovered the magic bullet that would eliminate obesity? A study conducted by Considine, et al. published in 1996 in the New England Journal of Medicine (NEJM) examined this question. The conclusions were disappointing to say the least. They found that obese people had an average of four times the amount of leptin as normal weight individuals. As there was a reduction in their fat, leptin levels dropped sharply. This means that the action of leptin is far more complex in humans then in mice. Mice suffer from a lack of leptin and could be easily treated with exogenous leptin injections. But human obesity is not from a lack of leptin. While a lot of information was learned from animal research, the application of leptin therapy to humans has many important and unanswered questions.  

Fat (adipose tissue) is not just ugly. It does perform, surprisingly enough, many important functions that effect metabolic and endocrine systems. Adipose tissue produces, among other important proteins, leptin. Leptin exerts a strong effect on the central nervous system. Leptin interacts with numerous hypothalamic neuropeptide systems with the end result of influencing eating patterns and overall energy output[1].  

Leptin is expressed mostly by adipocytes, which supports the theory that the body senses total fat mass. Cells in the epithelium of the stomach and in the placenta also secrete smaller amounts of leptin. Leptin receptors are highly expressed in areas of the hypothalamus known to be important in regulating body weight. Leptin is an important component in the long term regulation of body weight. Recent studies with obese and non-obese humans demonstrated a strong positive correlation of serum leptin concentrations with percentage of body fat, and also that there was a higher concentration of ob (the obesity gene) mRNA in fat from obese compared to thin subjects. It appears that as adipocytes increase in size due to accumulation of triglycerides, they synthesize more and more leptin. In short, leptin appears to provide the body with an idea of overall nutritional status, no doubt an important evolutionary precaution. 

Leptin's effects on body weight are mediated through effects on hypothalamic centers that control feeding behavior and hunger, body temperature and energy expenditure. Daily injections of recombinant mouse or human leptin into ob/ob mice (the obese mutant mice without the natural ability to produce leptin with homozygous recessive genes for obesity) led to a dramatic reduction in food intake within a few days. In the slightly longer term the injected leptin lead to roughly a 50% reduction in body weight within a month. Weight loss resulting from administration of leptin appears to result from a combination of at least two fundamental effects: Decreased hunger and food consumption, mediated at least in part by inhibition of neuropeptide Y synthesis. Neuropeptide Y is a very potent stimulator of feeding behavior. The second mode of action was increased energy expenditure, measured as increased oxygen consumption, higher body temperature and loss of adipose tissue mass. Even when leptin was administered to genetically normal mice, there was profound weight loss and depletion of adipose tissue. There was also an apparent increase in lean body mass.

Let’s return briefly to how leptin works to reduce fat. Researchers observed that mice treated with leptin remained at a their new lean weight long after the treatment ended. To understand how leptin works I must explain apoptosis. Apoptosis is the “programmed” death of cells. This is the way in which the body eliminates damaged or redundant cells. When researchers looked at what happened to fat cells when leptin was administered it looked like the cells were dying; they were experiencing apoptosis. Further research appears to support this conclusion, in mice leptin causes fat cells to die and does not effect any other cells. This is an important breakthrough. Fat cells are normally not destroyed as the result of weight reduction. They merely shrink in size. Short of liposuction, no method of fat loss actually reduced the possibility of regaining the weight. It is therefore theoretically possible to develop a leptin treatment that permanently causes weight loss by eliminating fat cells from the body. But it has already been demonstrated that is it hard to transfer the results of animal tests to human beings.  

I would not write an article on some tantalizing new information if it didn't have practical application to physique or performance enhancement. Even though there is no leptin therapy available to humans, research has established correlations between insulin and insulin-like growth factor and leptin…in humans. Since it is possible for a bodybuilder to control their insulin and, to some degree, their IGF-1 levels, control over leptin and therefore weight loss seems possible. 

Originally it was shown that weight loss lowered leptin levels in humans. However, research into the effects of fasting on leptin produced evidence that serum leptin concentration is regulated by factors other then weight loss, namely insulin levels and/or glucose[2]. It appears that circulating leptin may be negatively linked with serum insulin levels. A marked decrease in serum insulin has been observed to lower leptin levels[3]. We already know that high insulin levels promote fat storage, which is why so many bodybuilders use low carbohydrate diets to stimulate weight loss. The correlation between insulin and leptin seems to offer further support to the already accepted idea that it is crucial to control insulin level to facilitate weight loss. In fact, insulin is appears to be the major regulator of leptin production in human adipose tissue.  

IGF-1 is a relatively new drug in bodybuilding circles. Very few people have used it (real IGF-1 that is) and most people are not impressed with it. However, IGF-1 appears to play a very important role in leptin inhibition[4] in the body, which would suggest IGF-1 to be helpful in losing weight. Obtaining biologically active IGF-1 may become much easier, as it has been recently approved for treatment of certain diseases and is available at some pharmacies. It appears that IGF-1 may help in weigh reduction along with supporting and facilitating other anabolic processes in the body.  

I think leptin manipulation will play a prominent role in the battle against obesity. While leptin is perhaps only part of the key, it certainly shows science that there is a valid genetic rationale behind weight-gain. Of course, people have been using genetics as an excuse for years; I’m fat because my parents were fat. However, as science continues to unlock the mysteries of the human genetic code, I am confident we will develop a host of vaccines and inhibitors that will be priceless as far as regulating weight gain.