Qatar researchers mark major step towards understanding triggers of monogenic obesity

A study engineered lab-based hormones that control satiety and outcompete dysfunctional counterparts.

Researchers from the Qatar-based Sidra Medicine Hospital said they found a treatment for monogenic obesity, making a revolutionary step towards personalised and effective interventions.

Monogenic Obesity – a single gene mutation-based deficiency – is caused by changes in leptin – a hormone that regulates appetite. As such, children affected by this form of Obesity show little satiety and could have delayed pubertal development.

Acquired leptin resistance due to obesity without a known genetic cause is characterized by increased levels of serum leptin. Persistently high leptin levels lead to partial antagonism and reduced bioactivity. 7/10 pic.twitter.com/9zzeBOz5SX
— NEJM (@NEJM) June 21, 2023

The study by Sidra Medicine uses leptins found in two unrelated children. The leptins showed antagonistic behaviour because they worked against the regular leptin in the children’s bodies.

Leptin inhibits orexigenic neurons (that control eating) by attaching itself to receptors in the brain’s hypothalamus. The study looked at leptins, which could attach to these receptors but didn’t perform their function. According to the researcher, they didn’t send the right signals as regular leptins, and when regular leptin was present, these new types of leptin competed for attachment.

Two children with severe obesity and pathogenic LEP variants had no response to initial treatment with metreleptin. Understanding the antagonistic nature of the variants informed a successful treatment regimen. https://t.co/p7UfJemUeR
— NEJM (@NEJM) June 14, 2023

Another study hypothesised the reason for the antagonism as “posttranslational changes in the leptin molecule or alteration as leptin transports across the blood–brain barrier.”

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Regardless, to solve the issue, Sidra’s researchers provided a special kind of leptin made in a lab to the subjects. They started providing high amounts of this recombinant leptin but then slowly decreased the amount over time when enough changes were observed. Eventually, the children attained average weight.

“Over the period of 18 months, we discovered that by markedly increasing the dose of leptin by nearly 50 percent, we could successfully overcome the effects of the antagonist leptin and reduce her weight to a normal, healthy level,” said Professor Hussain lead researcher of the project.

While there was some resistance from the children, including the development of antidrug antibodies, this didn’t affect the efficacy of the treatment.

“This is the first study from the MENA region to be published on monogenic obesity and we hope it can provide insights into what is triggering the problem and what might help reverse it,” Professor Hussain added.

“Our research indicates there may be other children with this genetic disorder that are undiagnosed and that measuring leptin levels can provide the key to understanding some genetic malfunctions or deficiencies. Childhood obesity is a challenging clinical condition, and our research can help drive new discoveries and new treatments.”

Qatar has been battling obesity for a while. In a 2018 study of 164,963 school children aged between the ages of 5 to 19, the overall prevalence of overweight and obesity stood at 21.2% and 21.5%, respectively.