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Scientists at DDI discover a mutation in the kuwaiti population that causes obesity

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The Leptin-Melanocortin pathway is an important system in the regulation of food intake and energy

expenditure. It is unique because it can integrate neural, metabolic, and hormonal signals. One key

component of this system is a receptor called Melanocortin 4 Receptor (MC4R). MC4R is expressed in the brain and was shown to play an important role in controlling appetite. When the receptor is functioning properly, the feeling of hunger is under control, hence the weight is normal. When this

function is compromised and the activity of the receptor is reduced, this leads to increased appetite and food consumption eventually leading to weight gain. This receptor malfunction could be due to several factors but genetics are on top of this factors list. In fact, several studies on different ethnic groups reported that mutations in MC4R lead to obesity.

Generally, when a gene is mutated, there are two possibilities; it will either be a Loss of Function (LOF) or Gain of Function (GOF) mutation. Interestingly, a recent study from the UK biobank showed that LOF mutations in MC4R associate with higher BMI but GOF mutations are in fact protective from obesity.

In this paper, we report that people with a specific mutation in the MC4R have significantly higher BMI, DNAJC27, and ghrelin levels. Ghrelin is the hunger hormone, so it is well-documented that it correlates with obesity.

ddi-discover-a-mutation-in-kuwait-population

Previous studies from our department at DDI showed that DNAJC27 levels are elevated with obesity as well. However, how DNAJC27 affects body weight was still not known. Our cellular work in this article demonstrates that DNAJC27 can
reduce the signaling and hence the functional activity of MC4R. In addition, we report an association between this specific MC4R mutation and hypertension. “We knew that obesity naturally associates with high levels of Ghrelin (the hunger hormone), but this study suggests that it could be the mutation in MC4R that is causing the increase in
appetite.” Says Dr. Maha Hammad who headed this research. The good news is that the FDA recently approved a drug called Imcivree as the first treatment for weight management for people with certain rare genetic conditions. Imcivree is in fact a MC4R agonist (activator). Treatment of diseases is gradually moving from the traditional out-dated “One Size Fits All” approach to a more personalized medicine approach.

Now we know that the MC4R is a target of interest in the Kuwaiti population, and we know that the use of this new drug would be beneficial for those patients who carry MC4R mutations. Therefore, it is important to consider MC4R sequencing in the Kuwaiti population when drafting a weight management plan for a patient.

Hammad MM et al., MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort. Front Endocrinol. 2020; 11: 437. https://doi.org/10.3389/fendo.2020.00437

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