Genetic Mapping of Obesity-Related Genes

The increasing prevalence of obesity is a major public health concern. According to a World Health Organization (WHO) expert committee, there are about 1 billion overweight adults and one-third of a billion are labeled as clinically obese. Obesity is a multifactorial disease in which the environmental and genetic factors interact resulting in disorder of energy balance.

Excess food intake and lack of physical activity are the major lifestyle factors causing obesity, but until today, the role of genetic factors is still a challenge to scientists concerned. It has been known since the last century that both familial and nonfamilial factors play a major role in the development of obesity and the genetic component is fundamental to this [Page 320]medical problem. From the mid-1980s, the evidence for genetic basis to human obesity came from a number of identical twins and family studies, which reported that 50 to 90 percent of obesity prevalence is genetic and 10 to 50 percent is heritable. The question of a major gene or potential chromosomal candidate gene in the development of human obesity is a particular challenge.

Published data have clearly demonstrated the complexity of genetics in obesity, which poses a great challenge to understanding the role of genetics associated with this medical condition. Although there is substantial evidence to show that genetics plays an important role in the body weight, knowledge about the genetic role is still in its first steps. Large numbers of different family studies has established an increase of obesity risk among obese families. This suggests the role of genetics in obesity, and at the same time explains the nature of polygenic obesity.

Obesity is a multifactorial disease that is likely affected by a multitude of genes. In rare instances, there are single dysfunctional genes that can result in a phenotype of severe obesity (eg., the ob/ob mouse that is deficient in the hormone leptin). But, most cases of obesity are likely polygenic, where numerous genes contribute to the resulting phenotype. To date, 250 genes have been found that relate to some form of human obesity, so the picture is quite complicated.

To date, about 200 medical conditions have been associated with single-gene mutation involving 11 genes. This clinical condition obeys Mendelian genetics and is characterized by severe phenotepics feature presenting early in life and associated with mental, developmental, and endocrine disorders. A large-scale linkage analysis in mice led to detection of disease loci and the identification of the candidate gene in the majority of mutations underlying monogenic murine obesity. The characterization of naturally occurring obese models such as the ob/ob, db/db, fat, and tubby mice led to the discovery of recessive mutations in the genes encoding leptin (lep or ob), leptin receptor (Lepr or bd), carboxypeptidase E (Cpe or fat), and tubby (Tub). Several additional monogenic obesity genes were discovered like single-minded homolog 1 (Drosophila) (SIM1) identified in a girl with early-onset obesity that expressed in the paraventricular nucleus of the hypothalamus, which appears to regulate feeding. Melanocortin 4 receptor MC4R-linked obesity is the most prevalent form of monogenic obesity identified to date, which represents two to three percent of childhood and adult obesity. Recent discovery of rare functional mutations in regions of proopiomelanocortin (POMC) encoding for alpha melanocyte stimulating hormone a-MSH provides support for the use of genetic screens to identify factors upstream and downstream of MC4R in early-onset and severe human obesity.

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