CANDIDATE GENES FOR OBESITY – HOW MIGHT THEY INTERACT WITH
ENVIRONMENT AND DIET ?
I. Sadaf Farooqi
University Departments of Medicine and Clinical Biochemistry, Box 232,
Addenbrooke’s Hospital, Cambridge. CB2 2QQ, U.K. Email: ifarooqi@hgmp.mrc.ac.uk
1. INTRODUCTION
Obesity is determined by genetic, environmental and behavioural factors acting through the physiological mediators of energy intake and energy expenditure. In the last few years, we and others have described five human disorders of energy balance that arise from genetic defects.
2. CONGENITAL LEPTIN DEFICIENCY
The first monogenic human obesity syndrome we reported was congenital leptin deficiency. 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 (∆G133), that results in a truncated protein that is not targeted normally for secretion.
These children were hyperphagic, developed severe disabling obesity, impaired T cell mediated immunity and hypogonadotropic hypogonadism. In a clinical trial of daily subcutaneous injections of recombinant human leptin, sustained, beneficial effects on appetite, fat mass, hyperinsulinaemia and hyperlipidaemia have been observed.
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34 I. Sadaf Farooqi Leptin administration also permits the full progression of appropriately timed puberty and reverses impaired T cell mediated immunity.
3. LOSS OF FUNCTION MUTATIONS IN THE MELANOCORTIN 4 RECEPTOR
We have recruited over 1150 severely obese children to the Genetics of Obesity Study (GOOS). Using a candidate gene approach, we have identified several loss of function mutations in the melanocortin 4 receptor (MC4R), which cause a dominantly inherited syndrome that accounts for up to 5% of patients with severe, early-onset obesity. MC4R deficiency is characterised by hyperphagia, severe hyperinsulinaemia and increased linear growth and there is evidence for a genotype- phenotype correlation, as complete loss of function mutations result in a more severe phenotype.
4. CONCLUSIONS
These studies have highlighted the role of leptin and the melanocortin axis in humans and the characterization of these syndromes has shed light on the molecular and physiological mechanisms underlying the regulation of appetite and body weight.
