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The image shows an ob/ob mouse in the right treated with
fatostatin while the mouse on the left did not receive the chemical.
Note the weight loss in the fatostatin treated mouse.
Kamisuki, S et al., (2009). “A small molecule that blocks fat synthesis
by inhibiting the activation of SREBP” Chem & Biol., 16; 882-892.
Over the last decade, there has been a trend towards an increase in the number and percentage of Americans in the US population that are classified as obese. The consequences of this grim fact may likely mean that more and more Americans will likely suffer and develop a myriad cardiovascular related diseases (stroke, atherosclerosis), cancer, and neurological disorders such as Alzheimer's disease in the ensuing years; thereby increasing the economic burden on our healthcare system and decreasing the mean life-span. There is a clear need to change our culture and eating habits in order to reverse this trend. Indeed, the benefits of caloric restriction on health and life-span have been previously highlighted and emphasized in another Examiner related article. In a practical sense, the chances of this ever happening are very slim to none. Although the eating habits and diet of most Americans may likely remain the same in the future, scientists and medical doctors are scrambling to find the magic pill that confers immediate effects in lowering cholesterol, fatty acid levels and weight in obese people. Although statins are very effective for lowering cholesterol levels, these drugs do nothing to lower weight, glucose or triglyceride levels. More importantly, it is worth noting that patients taking these drugs may develop serious side effects such as renal damage and rhabdomyolysis (muscle wasting).
There is a need to develop and find more compounds/drugs that may not only block cholesterol synthesis, but lowers blood glucose levels, triglycerides and also induces weight loss. Indeed, one such chemical has all of the aforementioned properties and has been termed fatostatin, previously named 125B11. This compound significantly inhibits the activation of “fat” genes by blocking the activity of a transcription factor known as sterol regulatory binding element protein (SREBP). Interestingly, this chemical was previously discovered not only to have anti-adipogenic effects but also possesses anti-carcinogenic effects against prostate cancer. By using a strain of mice that are prone to obesity, scientists wanted to study the effects of fatostatin in vivo. In brief, scientists found that giving the chemical in the diet of mice causes the animals to become leaner and loose weight. The findings on the effects of fatostatin on weight and cholesterol in mice was published in the Journal of “Chemistry and Biology” this month. Salih Wakil, a lead investigator in this study from Baylor College of Medicine, expressed his excitement about the recent findings by stating that “the chemical goes to the origin of fat synthesis by blocking the gene expression of fat-related genes”.
Fatostatin, the fat-lowering chemical used in this research, works very different from cholesterol-lowering statins such as Lipitor, which work by blocking a single enzyme or different enzymes in the cholesterol-synthesis pathway (HMG-CoA reductase, lowering mevalonate synthesis). Surprisingly, the chemical structure of fatostatin is somewhat related to the three-ring cyclic structure of other statins. Unlike the statins which block an enzyme or multiple enzymes required for cholesterol synthesis, fatostatin works by blocking the activity of transcription factor SREBP, master regulator of gene expression for fat related genes, and thereby inhibiting the first step required for the synthesis of fat and cholesterol related genes. The study showed that the long-term effects of inhibiting SREBP and fat/cholesterol related genes leads to a significant reduction in cholesterol and fatty-acid synthesis in vitro and in vivo. Supporting this observation, microarray (gene expression) studies in cell culture models showed that fatostatin significantly lowers the activity of 63 genes, including 34 directly associated with fatty acid or cholesterol synthesis. Many of those genes identified to be inhibited by fatostatin were known to be under the control of SREBP.
Moreover, cell biology studies were carried out to determine the mechanisms of action of fatostatin for blocking the activity of SREBP. The authors of this study found that fatostatin specifically binds to a binding partner of SREBP localized in the endoplasmic reticulum of cells called SREBP cleavage activating protein (SCAP). The binding of fatostatin to SCAP prevents the postranslational processing and maturation of SREBP in the endoplasmic reticulum, a critical step required for nuclear translocation of SREBP. In other words, since postranslational processing and maturation of SREBP is an important step required for its translocation to the nucleus, blocking SCAP causes a global shut down of fat and cholesterol related genes and eventually leads to a gradual decrease in cholesterol and triglyceride levels.
The authors of this study then wanted to investigate what are the physiological effects of administering fatostatin in ob/ob mice, a strain of mice that is prone to weight gain and used as an ideal model for obesity. The authors of the study found that a continuous infusion of this chemical in the diet of mice lead to a lost of upto 12 percent of their initial weight after four weeks of ingesting fatostatin. In addition, the levels of triglycerides, cholesterol, LDL and HDL, and glucose levels were decreased in fatostatin treated ob/ob mice compared to untreated ob/ob mice. Given these results, this study also suggest that fatostatin may have beneficial effects on people with type II diabetes.
What may this mean for human beings? The results in mice may actually translate into a human being loosing 12 percent of their weight after 2.5 years. In other words, these results in mice may be the equivalent of a 6 feet tall male human being that weights 204 pounds (about 24 pounds overweight) and loosing 24-27 pounds over a time span of 2.5 years or less if given fatostatin. Although this may not seem much of a groundbreaking weight loss in a period of 2.5 years, one has to consider that the compounding beneficial effects of this drug in conjunction with exercise may actually increase and speed the benefits of this chemical on obesity. Moreover, many obese people who exhausts many forms of weight loss therapy (even gastric bypass surgery) may see this as a promising tool to overcome a genetically form of obesity.
There is another surprising scientific finding regarding the effects of fatostatin in mice. The authors of this study found that mice undergoing this regimen, lost weight and kept the weight off throughout their lifetime, a feat that is very difficult to achieve in human beings. Surprisingly, the mice kept the weight off even after they were fed an ad-libidum diet (care-free). In other words, mice receiving the chemical were not subjected to a specific diet or exercise regimen and were allowed to eat as much as they wanted. Currently, fatostatin is expected to be tested in FDA approved clinical trials this year to study the impact of fatostatin on obesity and cancer.
For more info: For more information click on the following links.
Original and brief version of this report as published by the DailyScience news:
www.sciencedaily.com/releases/2009/08/090827123206.htm
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