Recently, an article entitled “Loss-of-function mutations in ADCY3 cause monogenic severe obesity” was published in Nature Genetics. This research highlighted ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity. The research contents are as follows.
The scientists identify and functionally characterize homozygous mutations in the ADCY3 gene in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent.
When mutations occur in ADCY3, adenylate cyclase 3 it codes for forms abnormally and doesn’t function properly. This leads to abnormalities relating to appetite control, diabetes, and even sense of smell.
“Early studies into ADCY3 tested mice that were bred to lack that gene, found that these animals were obese and also lacked the ability to smell, known as anosmia. When we tested our patients, we found that they also had anosmia, again showing a link to mutations in ADCY3.” said Professor Philippe Froguel, from the Department of Medicine at Imperial.
Based on the results, the researchers continue to study the possible mechanism. They entered their results into GeneMatcher, described by Professor Froguel as a “dating agency for genetics”. This led to another group of scientists in the Netherlands contacting the team with their own ADCY3 findings in one of their patients with obesity. This new European patient inherited different mutations on the same ADCY3 gene from both parents, so the ADCY3 gene of the offspring was not functioning properly, leading to obesity.
Further connections were made with a group of Danish scientists, studying the Inuit population of Greenland. Whilst not traditionally consanguineous (as in close family marriages), this population is small, so inbreeding is likely to have occurred.
Research into the genetic causes of obesity, and related conditions, could be incredibly valuable in finding ways to treat them. Currently, there are some drugs available or being tested, but knowing what specific mutations cause obesity allows scientists to create drugs that target them specifically.
‘’Obesity is not always gluttony, as is often suggested, and I think we should have a positive outlook considering the new treatments that are becoming possible.’’ said Professor Philippe Froguel, Chair in Genomic Medicine.
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