Biosingularity

Possible new drug target for obesity treatment

Posted on: February 4, 2009

Scientists have discovered a gene that when mutated causes obesity by dampening the body’s ability to burn energy while leaving appetite unaffected.

The new research could potentially lead to new pharmacologic approaches to treating obesity in humans that do not target the brain, according to study senior author Yi Zhang, Ph.D., professor of biochemistry and biophysics in the University of North Carolina School of Medicine.

The findings also add new knowledge to the burgeoning field of epigenetics, in which heritable changes in gene expression or physical appearance are caused by mechanisms besides changes in the underlying DNA.

The gene in question encodes for a specific epigenetic factor, an enzyme called Jhdm2a. In 2006, Zhang showed that Jhdm2a was able to demethylate, or remove, a methyl group from one of four histone proteins bound to all genes. Because they are so intimately associated with DNA, even slight chemical alterations of histones can have profound effects on nearby genes.

The new study focused on a line of so-called “knockout” mice that lacked the Jhdm2a gene. Zhang found impairment in two molecular signaling pathways important for normal function in brown fat tissue and muscle cells. Both pathways exert a major influence on metabolism, the body’s conversion of food to energy. Without the enzyme, the mice had reduced metabolisms, becoming visibly obese.

To Zhang’s knowledge, this is the first mouse model to exhibit obese traits that do not resulting from an alteration in appetite, which is largely a brain function. “Given that this gene is not expressed in the brain, any drug that targets this gene would not have an effect on brain function,” he said. “Therefore, we are really looking for a pure effect on metabolism.”

With that in mind, Zhang anticipates that the study, published online February 4, 2009 in the journal Nature, could be of great interest to pharmaceutical companies eager to develop new anti-obesity drugs aimed at a novel, new molecular target expressed in non-brain tissues.

Zhang said his group will continue to look for more detailed mechanisms involved in how the enzyme regulates the relevant genes and changes in the metabolic rate.

“My lab has a long-term interest in identifying histone-modifying enzymes,” said Zhang. “Three years ago, we discovered the jumanji family of histone demethylase, which is a huge family and brought big interest in the field to study this group of genes.”

That body of work has contributed significantly to a new understanding that mutations in epigenetic factors such as histone demethylase enzymes can have profound physiologic effects. The team had already zeroed in on the Jhdm2a enzyme, showing in a 2007 Nature publication that the Jhdm2a gene is highly expressed in mouse testes and plays an important role in spermiogenesis, the final step in the production of a functional sperm cell. Male mice with the gene knocked out were infertile.

That discovery has provided researchers with a new potential cause for male infertility, just as the current study shows that the same genetic defect leads to obesity in both male and female animals, shedding new light on the role of epigenetics in regulating metabolism.

“So this gene has at least two biological functions,” Zhang said. “One is control of spermiogenesis; the other is control of metabolism.”

This finding was not necessarily expected by the researchers. “Nobody could have predicted that this gene had this particular function in regulating metabolism,” Zhang said. “The histone-modifying enzymes actually have broad effect – every gene is packaged by histones. Therefore, when modifying histones, you can’t necessarily predict what function will be affected.”

In addition to being obese, the Jhdm2a knockout mouse also developed other characteristics related to human metabolic disorder, such as hyperlipidemia (raised lipid levels) and insulin resistance. Whether the mouse results will be mirrored in humans remains to be seen. “We don’t know whether this gene is defective in some of the obese or metabolic syndrome patients – those are things that need to be investigated,” Zhang said.

One of the lines of research Zhang and his colleagues will pursue is to conduct experiments with “conditional” knockout mouse models, in which the gene of interest is functionally removed from specific tissues, such as, in this case, brown fat or muscle tissue. According to Zhang, “that way we can ask specific questions and can pinpoint the specific tissue or cell types…then we can also pinpoint the specific molecular mechanism.”

University of North Carolina School of Medicine

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3 Responses to "Possible new drug target for obesity treatment"

Thoughts about Obesity

Obesity has been defined as when excess body fat accumulates in one to where their physical overgrowth makes the person unhealthy to varying degrees. Obesity is different than being just overweight, as it is of a more serious concern.
As measured by one’s body mass index (BMI), one’s BMI of 25 to 30 kg/m is considered overweight. If their BMI is 30 to 35 kg/m, they are class I obese, 35 to 40 BMI would be class II obese, and any BMI above 40 is class III obesity. Presently, with obesity affecting children progressively more, the issue of obesity has become a serious public health concern.
Approximately half of all children under the age of 12 are either obese are overweight. About twenty percent of children ages 2 to 5 years old are either obese are overweight. The consequences of these stats on our children are very concerning, considering the health issues they may or likely experience as they get older.
Worldwide, nearly one and a half billion people are either obese or overweight. In the United States, about one third of adults are either obese or overweight. Women of low socioeconomic status are likely to be twice as obese compared with those who are not at this status. It is now predicted that, for the first time in about 150 years, our life expectancy is suppose to decline because primarily of this obesity problem.
Morbid obesity is defined as one who has a body mass index of 30 kg/m or greater, and this surgery, along with the three other types of surgery for morbid obesity, should be considered a last resort after all other methods to reduce the patient’s weight have chronically failed. Morbid obesity greatly affects the health of the patient in a very negative way. It has about 10 co-morbidities that can develop if the situation is not corrected. Some if not most of these co-morbidities are life-threatening.
One solution beneficial in many cases of morbid obesity if one’s obesity is not eventually controlled or corrected is what is known as gastric bypass surgery. This is a type of bariatric surgery that essentially reduces the volume of the human stomach in order to correct and treat morbid obesity by surgical re-construction of the stomach and small intestine.
Patients for such surgeries are those with a BMI of greater than 40, or a BMI greater than 35 if the patient has co-morbidities aside from obesity. This surgery should be considered for the severely obese when other treatment options have failed. The standard of care illustrating as to whether this surgery is reasonable and necessary should be clarified.
There are three surgical variations of gastric bypass surgery, and one is chosen by the surgeon based on their experience and success from the variation they will utilize. Generally, these surgeries are procedures related to gastric restrictive operations or mal-absorptive operations.
Over 200,000 gastric bypass surgeries are performed each year, and this surgery being performed continues to progress as a suitable option for the morbidly obese. There is evidence that this surgery is particularly beneficial for those obese patients that have non-insulin dependent Diabetes Mellitus as well.
It is believed that the results of this surgery to correct morbid obesity greatly limits or prevents such co-morbidities associated with those who are obese. Yet about two percent of those who undergo this surgery die as a result from about a half a dozen complications that could occur. However, the surgery reduces the overall mortality of the patient by 40 percent or so, yet this percentage is debatable due to conflicting clinical studies at times.
Age of the patient should be taken into consideration, as to whether or not the risks of this surgery outweigh any potential benefits for the patient who may have existing co-morbidities that have already caused physiological damage to the patient. Also what should be determined by the surgeon is the amount of safety, effectiveness, and rationale for a particular patient regarding those patients who are elderly, for example.
Many feel bariatric surgery such as this should be considered as a last resort when exercise and diet have failed for a great length of time.
If a person or a doctor is considering this type of surgery, there is a website dedicated to bariatric surgery, which is: http://www.asmbs.org,

Dan Abshear

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