Discover how rare genetic mutations disrupting leptin, the hormone that regulates hunger, led to insatiable appetite and severe obesity.
A case report highlights rare, never-before-seen genetic mutations as the cause of intense, insatiable hunger and overeating in two children. These mutations disrupt leptin, a critical hormone responsible for signaling fullness to the body.
Leptin, produced by white fat cells, communicates with the brainstem and hypothalamus to regulate appetite. Unlike the fluctuating “hunger hormone” ghrelin, leptin levels remain steady, reflecting the body’s total fat reserves. This hormone plays a vital role in indicating stored energy levels and triggering “starvation mode” when fat stores become too low.
Genetic mutations that impair leptin production, secretion, or brain sensitivity to the hormone are exceedingly rare. Before this report, only 21 genetic variants affecting leptin function had been identified, all linked to hyperphagia, or uncontrollable hunger.
The case describes two unrelated children, a 14-year-old and a 2-year-old, each carrying slightly different genetic mutations that disrupt leptin function. The findings were published on June 14 in The New England Journal of Medicine.
Elevated leptin levels in the blood were observed in both cases, corresponding with high body fat percentages. After ruling out Prader–Willi and Bardet–Biedl syndromes—two rare genetic conditions associated with increased appetite and weight gain in childhood—attention was directed to the leptin gene (LEP). Each child was found to carry a unique variant of the LEP gene, identified as P64S in one case and G59S in the other. These variants encoded slightly altered forms of leptin.
Lab studies using human cells revealed that while the modified leptin could bind to the brain’s leptin receptor, it triggered minimal, if any, signaling. Additionally, the altered leptin versions interfered with normal leptin’s ability to activate the receptor. Despite producing large amounts of leptin, the brain received no indication of adequate energy reserves, leaving hunger unregulated and the appetite unsatisfied.
Treatment involved metreleptin, a synthetic leptin substitute. Initial doses were higher than usual to counter the effects of the altered leptin. Alongside the treatment, fasting and exercise programs were introduced to reduce white fat levels, which ultimately lowered leptin production. Over time, these measures normalized food intake, increased satiety, and promoted weight loss.
Antibodies against metreleptin were detected in both cases, as anticipated, but this did not diminish the treatment’s effectiveness. No serious side effects were reported, and both individuals achieved near-normal weight, as noted in the case report.
https://www.nejm.org/doi/full/10.1056/NEJMoa2204041
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