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Leptin receptor deficiency
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Leptin receptor deficiency

Leptin receptor deficiency is a rare genetic condition characterized by constant hunger and severe, early-onset obesity, often accompanied by delayed sexual development.

Overview

Leptin receptor deficiency causes severe obesity beginning in the first few months of life. While affected individuals are of normal weight at birth, they experience constant hunger, leading to chronic excessive eating, known as hyperphagia. By early childhood, individuals often develop abnormal eating behaviors, such as fighting over food, hoarding, and eating in secret.

Affected individuals also have hypogonadotropic hypogonadism, a condition caused by reduced production of hormones that direct sexual development. This results in delayed or absent puberty and potential infertility.

Frequency

Leptin receptor deficiency is a rare cause of obesity, and its prevalence is unknown.

Causes

The condition is caused by mutations in the LEPR gene, which provides instructions for making the leptin receptor. This protein is found on the surface of cells in many organs, including the hypothalamus, the part of the brain that controls hunger, thirst, sleep, mood, and body temperature.

Normally, fat cells release a hormone called leptin in proportion to their size. When leptin binds to the leptin receptor, it triggers chemical signals in the hypothalamus that regulate hunger and produce a feeling of fullness (satiety). Mutations in the LEPR gene prevent the receptor from responding to leptin, leading to the excessive hunger and weight gain associated with the disorder. Researchers believe the signaling pathway is also involved in regulating sexual development, though the exact mechanism remains unknown.

Gene Associated with Leptin Receptor Deficiency

  • LEPR

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. Parents of an affected individual each carry one copy of the mutated gene but typically do not show signs or symptoms of the condition.

Other Names for This Condition

  • Congenital deficiency of the leptin receptor
  • Leptin receptor-related monogenic obesity
  • Obesity due to leptin receptor gene deficiency
  • Obesity, morbid, due to leptin receptor deficiency
  • Obesity, morbid, nonsyndromic 2

Frequently Asked Questions

The only FDA‑approved medication for monogenic obesity due to LEPR deficiency is setmelanotide, an MC4R agonist, administered subcutaneously (dose titrated to effect). It can reduce hunger and promote weight loss. Adjunctive measures include structured behavioral feeding programs, high‑protein low‑energy‑density diets, and, in selected cases, bariatric surgery after careful endocrinologic assessment.
Implement a consistent meal schedule with limited portion sizes, use visual cues (plate size, timers), and keep high‑calorie foods out of easy reach. Involve a multidisciplinary team—dietitian, psychologist, and occupational therapist—to teach coping skills, set environmental controls, and address emotional eating. Monitoring weight weekly and keeping a food log can help identify triggers and adjust interventions promptly.
fter clinical suspicion (severe obesity before age 2, hyperphagia, delayed puberty), serum leptin levels are measured; they are usually markedly elevated. Definitive confirmation requires molecular genetic testing that identifies biallelic pathogenic variants in the LEPR gene.
The defect disrupts leptin signaling that normally stimulates the hypothalamic‑pituitary‑gonadal axis, leading to hypogonadotropic hypogonadism and delayed or absent puberty. Sex hormone replacement (e.g., testosterone for males, estrogen/progesterone for females) can induce secondary sexual characteristics and support bone health, but it does not correct the underlying appetite drive.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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