C75, a Synthetic Fatty Acid Synthase Inhibitor, Decreases Appetite and Increases Energy Expenditure

New therapies for the treatment and prevention of obesity are, and will continue to be, in great demand. There are several approaches to a pharmaceutical battle against obesity. One approach is to alter metabolism; to somehow prevent the body from synthesizing and storing excess fat. Another approach might be to limit the calories consumed by altering the individual's appetite.This is the target of C75. The goal of C75 is to turn off the "hunger switch" so that less food is consumed. Fortunately, this new compound does not slow down metabolism. It decreases food intake but the body continues to act as if it is receiving sufficient amount of food: fasting pathways are not activated. C75 is a very potent anti-obesity drug in mice, however much needs to be known before it will be used in humans. One of the major concerns with C75 is its lack of specificity. The biochemical pathways that it modulates are involved in many cellular processes, so side-effects and are likely to occur. However, studies with C75 gives us new insight into the biochemistry of appetite.

C75 alters neuronal energy metabolism and subsequently regulates appetite. It has been known that the hypothalamus is a major regulatory site for food intake. The focus recent research is the effect of C75 on energy perception in the hypothalamus. C75 was designed as an analog to cerulenin, a natural fatty acid synthase (FAS) inhibitor as an anti-cancer drug. C75 also affects Acetyl-CoA Carboxylase (ACC). Surprisingly, it turned out to be one of the most promising anti-obesity compounds developed in the past few years. Recent studies show that C75 is also a carnitine palmitoyltransferase-1 (CPT-1) activator, and thus it increases long chain fatty acid oxidation. The hypothesis is that these fatty acid pathways in the brain control whole-body energy balance by regulating caloric intake.

Figure 1. The molecular structure of cerulenin, a natural fatty acid synthase (FAS) inhibitor and C75.

Diagram 1. C75 inhibits fatty acid synthesis and stimulated fatty acid oxidation in the brain. This alters energy perception in the brain and decreases appetite, resulting in weight loss.

Brain metabolism relies on glucose for energy, and not upon fatty acid metabolism as peripheral tissues do. The studies [Landree et al.(2004), Andersson et al. (2004), and Cha et al.(2004)] show the importance of fatty acid metabolism in brain metabolism and energy perception. All the main components of fatty acid metabolism are found in the brain. C75 and its profound effect on weight loss is evidence that fatty acid metabolism in the hypothalamus is involved in global energy balance.

C75's incredible effects on weight loss were discovered by accident when researchers at John Hopkins Medical Center were searching for an anti-cancer drug in mice. The mice began to loose weight and almost stopped eating. Figure 2 shows the weight loss of  mice treated with C75 compared to control mice and C75 mice (Cha et al.2004). Genetically obese (ob/ob) mice were observerd for 30 days. Pair-fed mice received the same amount of food as the C75 mice choose to eat. This was done as a control to se if the weight loss achieved by C75 mice was only due to decreased food intake. The data shows that the C75 mice lost more weight than the pair-fed mice despite having the same caloric intake, confirming that C75 alters metabolism and not just appetite. It is interesting to note that when comparing diet-induced mice (mice fed a high fat diet) and naturally lean mice only the diet-induced mice lost a significant amount of fat (Thupari et al. 2004). It is obvious that C75 is a potent anti-obesity drug in mice.

According to the Center for Disease Control (CDC) over 44 millionAmericans are considered obese. This number represents a 74% increase since 1991.

Table1. Health problems linked to obesity. Courtesy of www.CDC.gov.

Figure 2. Change in bodyweight and food intake of genetically obese (ob/ob) mice treated with C75, compared to control mice and pair-fed mice. Pair fed mice were given the same amount of food the C75 mice chose to eat. Results are from (Cha 2004).