New research published in the New England Journal of Medicine discovered two novel gene mutations—or leptin variants—responsible for extreme hyperphagia, severe obesity, and high leptin levels in two unrelated children.

Funcke JB, Moepps B, Roos J, et al. Rare antagonistic leptin variants and severe, early-onset obesity. N Engl J Med. 2023;388(24):2253-2261.

 

 

 

A brief look at leptin

 

Leptin is a hormone released from the body’s fat cells and encoded by the obese (ob) gene. “Leptin plays a key role in regulating hunger…and acts on specific receptors in the hypothalamus,” explains Dr. Praveen Guntipalli, an internal medicine and obesity MD, as well as the director of Sanjiva Medical Spa in Dallas, TX. In action, the hormone regulates fat storage and balances how much food a person eats with how much energy they expend, Dr. Guntipalli explains.

Dornbush S, Aeddula NR. Physiology, leptin. In: StatPearls. StatPearls Publishing; 2023.

 

 

Dr. Guntipalli also says plasma leptin levels reduce when a patient loses weight. This leads to a stimulated appetite. On the other hand, he says leptin levels rise when weight is gained, which can keep appetite levels lower until weight is lost. But with leptin dysfunction, the system is off. 

“Congenital leptin deficiency and dysfunction are rare, autosomal recessive forms of severe, early-onset obesity caused by changes in the leptin gene,” the authors write. 

 

Two unrelated young patients with leptin dysfunction

 

The report shares the case of two children—patient A (a 14-year-old boy of European descent whose parents are second-degree cousins) and patient B (a two-year-old girl of Arabic descent whose parents are first-degree cousins)—who presented with leptin dysfunction, including intense hyperphagia, impaired satiety, and severe, early-onset obesity. The children’s parents were heterozygous (meaning they had different alleles for a particular trait) for the variants.

Heterozygous. Genome.gov.

 

Previous research has found 21 leptin gene variants, most of which cause defects in the production or secretion of the hormone, while others cause receptor issues. In this case, the researchers sequenced the children’s LEP gene and found two novel variants—P64S (patient A’s variant) and G59S (patient B’s variant), both pathogenic in nature, causing congenital leptin dysfunction characterized by hormone antagonism. 

“Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of non-variant leptin, the variants act as competitive antagonists,” the authors write. This, of course, led to the patients’ insatiable hunger and weight gain. 

However, at 0.03 mg, no effect was noted—underscoring the need for higher doses in order to overcome the variants’ antagonism. Patient A then received 0.14 mg per kilogram on day two of treatment, and increased to 0.70 mg per kilogram on day five. 

Patient B’s dose was increased to 0.15 mg per kilogram on day two of treatment. More so, the patients underwent “vigorous fasting” as well as exercise programs intended to lower the endogenous leptin production while improving the effects of the exogenous leptin, the researchers write. 

This resulted in increased (yet therapeutic) circulating leptin levels as well as normal satiety and hunger cues. Patient A saw notable reduction in fat mass and dropped to a “near-normal” weight after 1188 days of treatment, while patient B had a “near-normal” weight of 1260 days of treatment.  

“We observed a transient rise in aminotransferase and insulin levels, findings similar to observations in patients with leptin deficiency treated with much lower doses of metreleptin,” the researchers noted. 

After treatment, the patients saw remarkable weight loss—which led to reduced levels of endogenous leptin variant productions. The team then reduced the patients’ doses of metreleptin. 

“The new antagonistic variants described herein add further complexity to the diagnosis and treatment of congenital leptin dysfunction,” the authors write. “The phenotypes of patients with antagonistic and biologically inactive leptin variants are indistinguishable from one another before hormone replacement, although the phenotypes diverge after the administration of metreleptin.”

The researchers point out that while certain patients with leptin deficiency or biologically in' \]/. cvvcghjl;''active variants may see improvement with lower metreleptin doses, higher doses are essential for patients with antagonistic variants; the goal is to take over the competitive antagonism of the endogenous hormone.

The researchers submitted the leptin variants to the ClinVar repository. They can be  searched for under accession numbers SCV003761543 and SCV003761542.