Leptin is a hormone whose circulating levels correlate closely to the amount of fat mass. A fall in leptin levels with fasting or caloric restriction triggers a set of responses to restore energy balance predominantly by increasing food intake. In this way, leptin functions as a signal to defend against starvation. 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 (publications).
Congenital leptin deficiency is characterised by severe hyperphagia, frequent infections, hypogonadism and undetectable leptin levels. In a small number of cases, leptin can be detectable but bio-inactive. If a diagnosis of congenital leptin deficiency is confirmed by sequencing the gene, 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 (recruit a patient).
Homozygous loss of function 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 homozygous or compound heterozygous 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.
Mutations that disrupt the single-minded 1 (SIM1) transcription factor increase food intake and are associated with autonomic dysfunction and sometimes contribute to abnormal behaviours as do mutations in SH2B1.
So far, the genes we have identified have been involved in the control of body weight through an effect on appetite, but for a long time it has been speculated that some people may burn calories more slowly than others. We have recently found that in addition to hyperphagia, patients with mutations in the kinase suppressor of Ras 2 (KSR2) gene have a low heart rate and a reduced metabolic rate. KSR2 is a scaffolding protein which is important in ensuring that cells process hormonal signals to regulate cell division and growth.
Our current programme involves a number of approaches to gene discovery, the investigation of molecular mechanisms, physiology and eating behaviour.