Sunday, 1 April 2012

How a Single Gene Mutation Leads to Uncontrolled Obesity


On March 18 2012, Baoji Xu; PhD and Associate Professor of Pharmacology and Physiology at Georgetown University Medical Centre, along with his research team, published their most recent findings: Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin (Xu, 2012). An article titled: How a Single Gene Mutation Leads to Uncontrolled Obesity was published by Science Daily and outlines the main findings of their work. Xu and his team were attempting to find “strategies to help the brain control body weight” (Xu, 2012).



     Dr Baoji Xu (Senior Investigator)
   Georgetown Medical Centre, 2012.

They conducted research by studying mice that had a mutation of the Brain-Derived Neurotrophic Factor (Bdnf) gene. It was found that any mice which had this mutation would, during protein synthesis, produce ineffective Brain-Derived Neurotrophic Growth Factor (BDNF) (Science Daily, 2012). BDNF is a protein which helps synapses to form and mature, ensuring that information from neurons is passed to and from the brain successfully. “This is the first time protein synthesis in dendrites, tree-like extensions of neurons, has been found to be critical for control of weight” (Xu, 2012).

Leptin is a hormone which plays a key role in regulating energy intake and expenditure, such as appetite and metabolism (Natural News, 2011). Insulin is another hormone produced by the pancreas which regulates carbohydrate and fat metabolism, and takes up glucose from the blood to store it as glycogen in the liver. It also stops the use of fat as an energy source by inhibiting the release of glucogen. Xu and his team found that neurons in mice deficient in BDNF did not “effectively pass leptin and insulin chemical signals through the brain” (Xu, 2012). Hence Xu concluded that continuous eating was caused by a failure of signals to reach the “correct locations in the hypothalamus. If there is a problem with the Bdnf gene, neurons can't talk to each other, and the leptin and insulin signals are ineffective, and appetite is not modified” (Xu, 2012).

    
           Georgetown Medical Centre, 2012.
                                 Left, mouse whose leptin and insulin intake signals are ineffective.
                                 Right, mouse whose leptin and insulin signals function effectively.


Upon further research, Xu discovered that BDNF plays a key role in forming and maturing synapses (Science Daily, 2012). One short transcript and one long transcript are generated by the Bdnf gene. Furthermore Xu discovered that when the long transcript is absent, BDNF growth factor is not synthesised in the dendrites, only in the neuron cell body (Science Daily, 2012). Therefore the BDNF cannot be transmitted via electrochemical signalling to the hypothalamus. The result of this poor synthesis of BDNF means the neuron produces synapses which are not mature enough for learning and memory recollection in mice. Xu also concluded that “the mice with the same Bdnf mutation grew to be severely obese” (Xu, 2012).

                           Science Daily, 2012.

According to Xu’s data, both insulin and leptin stimulate the synthesis of BDNF in dendrites (Xu, 2012).The idea being to move chemical messages from one neuron to another via synapses. Once the signals have moved to the correct locations of the brain the hormones will switch on a program that suppresses appetite. Researchers the world-over began to investigate the Bdnf gene in humans, and “large scale genome-wide association studies showed Bdnf gene variants are, in fact, linked to obesity” (Xu, 2012). Scientists are now aware that BDNF regulates movement of insulin and leptin signals via brain neurons, “the question is whether a faulty transmission line can be repaired” (Xu, 2012).

 Scientists are now currently looking at procedures to help reduce obesity in humans with this gene mutation. Possible strategies include virus-based gene therapy, and using drugs to stimulate gene expression in the hypothalamus (Xu, 2012). “We have opened the door to both new avenues in basic research and clinical therapies, which is very exciting” (Xu, 2012).

Daniel Sharp       42882028

Science Daily: How a Single Gene Mutation Leads to Uncontrolled Obesity, http://www.sciencedaily.com/releases/2012/03/120318143904.htm, 18/3/2012.   

Natural News: Starvation and Obesity, http://www.naturalnews.com/033376_starvation_obesity.html, 20/8/2011.

Georgetown University Medical Centre: Gene with a thousand faces, http://gumc.georgetown.edu/, 18/3/2012.

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