LEP: The Leptin Gene and Its Correlation to Obesity Lindsay Camm March 8, 2007

The LEP Gene The leptin gene, LEP, is found in humans on the 7th chromosome. Homologous to the OB gene in mice Controversial gene with some evidence that its mutation causes obesity

LEP Gene Structure Three exons separated by two introns 20 kilobases long First intron and exon occur at the 5’ untranslated region Second exon codes for 48 amino acids Third exon occurs in the coding region and 3’ untranslated region and codes for 118 or 119 amino acids

LEP Gene Structure Cont... Two different cDNA encode the leptin protein The leptin protein can either be 166 or 167 amino acids long If an internal alternative splice adds glutamine +49, the protein will have 167 AA’s

Chromosomal Assignment of the LEP Gene Staining of metaphase chromosomes with propidium iodide has shown that homologous chromosomes 7 have the same twin-spot signals that are found on an isolated LEP gene

LEP Function Produces the 167 amino acid protein leptin When adipose cells grow due to increased food uptake, leptin is released and sent to the hypothalamus Leptin regulates appetite and stimulates the release of hormones involved in reproduction It sends a satiety signal, inhibiting food intake and stimulating energy expenditure

Leptin’s Mechanism

Why is evidence of a LEP mutation important? Obesity is a major epidemic, effecting 32.9% of Americans It is a predisposing factor to the leading causes of death including heart disease, high blood pressure, stroke, diabetes, and some cancers If we can understand ALL of the causes of obesity, including the genetic factor, we can work to prevent this disease

LEP Gene Mutations Autosomal recessive frameshift mutation Leptin gene mutations cause a significant decrease in leptin production Most current research has found that leptin secretion deficiencies rarely cause obesity HOWEVER, some studies on homozygous gene mutations show incidence of morbid obesity

The Research Says... Most obese individuals studied showed no mutation in the LEP gene or leptin levels A significant number of subjects studied who were heterozygous for the mutation were moderately obese Extremely inbred families studied who were homozygous for the mutation had decreased leptin levels, were morbidly obese, and had sexual immaturity

In order to see an increase in body mass due to decreased leptin levels, a person must be homozygous for the mutation

Research in Mice There is more research and conclusive evidence that mutation in the OB gene in mice leads to obesity The OB gene was first discovered in mice in 1950, before the discovery of the human homologue The structure of the OB gene in mice is almost identical to the LEP gene in humans

Therapy Treatment for individuals with the homozygous mutation involves leptin injections Since the gene cannot adequately produce leptin, the protein must be injected into the bloodstream Studies conducted in mice showed that after two weeks of leptin treatments, the body weight of the mice decreased by 30%

Results of Leptin Treatment in Mice with and without the OB gene mutation

Conclusion The LEP gene in humans and corresponding OB gene in mice produces leptin, a protein regulating appetite and reproduction Evidence that a mutation of this gene causes obesity is controversial Research on this possible genetic predisposal to obesity is currently very popular in order to find more treatments for morbid obesity While there is no substitute for healthy diet and exercise, other auxiliary treatments like leptin injections may be beneficial in fighting obesity