ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2004) 7 S6

Learning from experiments of nature

S Farooqi

University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.

The identification and characterization of patients with morbid obesity due to mutations in single genes has shed light on the molecular mechanisms underlying the hypothalamic regulation of appetite, body weight and endocrine axes.

Two severely obese cousins in a consanguineous family were found to have undetectable levels of serum leptin and were homozygous for a frameshift mutation in the ob gene. These children were severely hyperphagic, constantly demanding food and developed severe disabling obesity, impaired T cell mediated immunity and hypogonadotropic hypogonadism. Treatment with recombinant human leptin for up to six years led to sustained, beneficial effects on appetite, fat mass, hyperinsulinaemia and hyperlipidaemia. The major impact of leptin was on food intake with a marked reduction in caloric consumption during a test meal. Leptin administration permits the full progression of appropriately timed puberty but does not appear to cause precocious activation of puberty in younger children. Mutations in the leptin receptor result in a similar phenotype.

We have recruited over 1000 patients with severe, early onset obesity as part of the Genetics of Obesity Study (GOOS). Complete loss of pro-opiomelanocortin derived peptides results in isolated ACTH deficiency, red hair, pale skin and obesity. We have recently identified a second patient who is a compound heterozygote for mutations in pro-hormone convertase-1 which results in a complex endocrinopathy and enteropathy due to a failure of prohormone processing. Loss of function mutations in the melanocortin 4 receptor (MC4R) cause a dominantly inherited obesity syndrome that accounts for up to 6% of patients with severe, early-onset obesity. MC4R deficiency is characterised by hyperphagia, severe hyperinsulinaemia and increased linear growth. These studies provide evidence for the pivotal role of the leptin-melanocortin system in energy balance and neuroendocrine function in humans.

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