Leptin is a hormone whose circulating levels correlate closely to the amount of fat mass. Many of the physiological effects of leptin are mediated through the brain, particularly the hypothalamus, where the leptin receptor is highly expressed.
Hypothalamic pathways interact with other brain centres to co-ordinate appetite, energy expenditure and neuroendocrine function. We have shown that mutations that disrupt leptin and its hypothalamic targets cause severe early onset obesity in 8% of the GOOS cohort (find our publications).
Congenital leptin deficiency is characterised by severe hyperphagia, frequent infections, hypogonadism and low leptin levels. Patients can be treated with injections of recombinant human leptin which has long term beneficial effects on appetite and weight and permits the onset of puberty at an appropriate age. We co-ordinate treatment for patients with congenital leptin deficiency from several countries and are happy to hear about any patients with similar clinical features.
Homozygous mutations in the leptin receptor gene (LEPR) result in a similar clinical phenotype. Leptin levels are usually appropriate for the degree of obesity; rarely very high leptin levels are seen when mutations lead to abnormal leptin binding.
Homozygous mutations in the pro-opiomelanocortin (POMC) gene lead to obesity, isolated ACTH deficiency and hypopigmentation.
Neonatal enteropathy, impaired prohormone processing (ACTH, TRH, GnRH) and postprandial hypoglycaemia can be caused by mutations in prohormone convertase 1 (PCSK1).
The commonest genetic form of obesity involves heterozygous mutations in the melanocortin 4 receptor, MC4R, which are found in 5-6% of patients with severe, early-onset obesity. Clinical features include hyperphagia, increased linear growth and lean mass giving an appearance of being “big-boned”. These mutations are dominantly inherited with variable penetrance within families.
Genetic disruption of the brain-derived neurotrophic factor (BDNF) and its receptor (TrkB) result in developmental delay, impaired speech and language development, hyperactivity and repetitive behaviours.
Our current programme involves a number of approaches to gene discovery, the investigation of molecular mechanisms, physiology and eating behaviour.