Obesity due to leptin receptor gene deficiency

Obesity due to leptin receptor gene deficiency (also known as LEPR deficiency or leptin receptor deficiency obesity) is an extremely rare monogenic form of severe, early-onset obesity caused by biallelic pathogenic variants in the LEPR gene, which encodes the leptin receptor. Leptin is a hormone produced by fat cells that signals to the brain to regulate appetite and energy balance. When the leptin receptor is non-functional, the brain cannot respond to leptin signals, leading to constant, insatiable hunger (hyperphagia) and rapid weight gain beginning in infancy or early childhood. The condition primarily affects the neuroendocrine system and metabolic regulation. Key clinical features include severe obesity from the first years of life, intense hyperphagia, hyperinsulinemia, and alterations in immune function. Affected individuals may also exhibit hypogonadotropic hypogonadism, leading to delayed or absent puberty, as well as reduced secretion of growth hormone and thyrotropin. Some patients may have recurrent infections due to impaired T-cell mediated immunity. Unlike leptin deficiency, serum leptin levels in these patients are typically elevated or normal, reflecting the large fat mass, but the body is unable to respond to the hormone. Historically, treatment options were limited to dietary management and behavioral interventions, which are often insufficient due to the severity of hyperphagia. In recent years, setmelanotide, a melanocortin 4 receptor (MC4R) agonist, has been approved for the treatment of obesity due to LEPR deficiency in patients aged 6 years and older. This targeted therapy works downstream of the leptin receptor in the leptin-melanocortin signaling pathway and has been shown to significantly reduce hunger and body weight in clinical trials. Bariatric surgery has also been considered in some cases, though long-term outcomes in this specific genetic context require further study.

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